# gene_set_details

description_brief: Leishmania infection
systematic_name: M3126
exact_source: hsa05140
external_details_URL: http://www.genome.jp/pathway/hsa05140
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  Leishmania is an intracellular protozoan parasite of macrophages that causes visceral, mucosal, and cutaneous diseases. The parasite is transmitted to humans by sandflies, where they survive and proliferate intracellularly by deactivating the macrophage. Successful infection of Leishmania is achieved by alteration of signaling events in the host cell, leading to enhanced production of the autoinhibitory molecules like TGF-beta and decreased induction of cytokines such as IL12 for protective immunity. Nitric oxide production is also inhibited. In addition, defective expression of major histocompatibility complex (MHC) genes silences subsequent T cell activation mediated by macrophages, resulting in abnormal immune responses.


description_brief: Colorectal cancer
systematic_name: M14631
exact_source: hsa05210
external_details_URL: http://www.genome.jp/pathway/hsa05210
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  Classically, colorectal cancer (CRC) has been believed to develop from normal mucosa through the premalignant adenoma by the step-wise accumulation of mutations. All CRC display either microsatellite instability (MSI) or chromosome instability (CIN). MSI occurs in 15% of colon cancers and results from inactivation of the DNA mismatch repair (MMR) system by either MMR gene mutations or hypermethylation of the MLH1 promoter. MSI promotes tumorigenesis through generating mutations in target genes that possess coding microsatellite repeats, such as beta-catenin, TGFBR2 and BAX. CIN is found in the majority of colon cancers and leads to a different pattern of gene alterations that contribute to tumor formation. Genes involved in CIN are those coding for APC, K-ras, SMAD4 and p53.


description_brief: Renal cell carcinoma
systematic_name: M13266
exact_source: hsa05211
external_details_URL: http://www.genome.jp/pathway/hsa05211
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  Renal cell carcinoma (RCC) is a heterogenous term comprising a group of neoplasms of renal origin. There are 4 major histologic subtypes of RCC: conventional (clear cell RCC, 75%), papillary (15%), chromophobic (5%), and collecting duct (2%). Multiple genes are involved in the molecular pathogenesis of RCC. VHL is a tumor suppressor gene responsible for hereditary (von Hippel-Lindau) and sporadic variants of conventional (clear cell) RCC. In the absence of VHL, hypoxia-inducible factor alpha (HIF-alpha) accumulates, leading to production of several growth factors, including vascular endothelial growth factor and platelet-derived growth factor. An oncogene, MET has been found to be mutant in cases of hereditary papillary renal cancer (HPRC), although the incidence of c-MET mutations is low in sporadic papillary RCC. Once activated, MET mediates a number of biological effects including motility, invasion of extracellular matrix, cellular transformation, prevention of apoptosis and metastasis formation. Mutations in the fumarate hydratase (FH) gene cause hereditary leiomyomatosis and renal cancer syndrome (HLRCC) papillary renal tumors, although the incidence of FH mutations in sporadic tumors is unknown. Loss of functional FH leads to accumulation of fumarate in the cell, triggering inhibition of HPH and preventing targeted pVHL-mediated degradation of HIF-alpha. BHD mutations cause the Birt-Hogg-Dube syndrome and its associated chromophobe, hybrid oncocytic, and conventional (clear cell) RCC. The incidence of BHD mutations in sporadic renal tumors is not known.


description_brief: Pancreatic cancer
systematic_name: M9726
exact_source: hsa05212
external_details_URL: http://www.genome.jp/pathway/hsa05212
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  Normal duct epithelium progresses to infiltrating cancer through a series of histologically defined precursors (PanINs). The overexpression of HER-2/neu and activating point mutations in the K-ras gene occur early, inactivation of the p16 gene at an intermediate stage, and the inactivation of p53, SMAD4, and BRCA2 occur relatively late. Activated K-ras engages multiple effector pathways. Although EGF receptors are conventionally regarded as upstream activators of RAS proteins, they can also act as RAS signal transducers via RAS-induced autocrine activation of the EGFR family ligands. Pancreatic ductal adenocarcinoma (PDA) show elevated expression of EGF receptors (e.g. HER2/neu) and their ligands (e.g.TGF-alpha) consistent with the presence of this autocrine loop. Moreover, PDA shows extensive genomic instability and aneuploidy. Telomere attrition and mutations in p53 and BRCA2 are likely to contribute to these phenotypes. Inactivation of the SMAD4 tumour suppressor gene leads to loss of the inhibitory influence of the transforming growth factor-beta signalling pathway.


description_brief: Endometrial cancer
systematic_name: M19877
exact_source: hsa05213
external_details_URL: http://www.genome.jp/pathway/hsa05213
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  Two types of endometrial carcinoma are distinguished with respect to biology and clinical course. Type-I carcinoma is related to hyperestrogenism by association with endometrial hyperplasia, frequent expression of estrogen and progesterone receptors and younger age, whereas type-II carcinoma is unrelated to estrogen, associated with atrophic endometrium, frequent lack of estrogen and progesterone receptors and older age. This classification has also been justified at the molecular level with Type 1 tumours being more commonly associated with abnormalities of DNA-mismatch repair genes, K-ras, PTEN and beta-catenin, and Type 2 tumours with abnormalities of p53 and HER2/neu.


description_brief: Glioma
systematic_name: M1835
exact_source: hsa05214
external_details_URL: http://www.genome.jp/pathway/hsa05214
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  Glioblastoma multiforme (GBM) formation is either de novo (primary GBMs) or due to the progression of a lower grade glioma to a higher grade one through the acquisition of additional mutations (secondary GBMs). In primary GBM, disruption of the p53 pathway often occurs through loss of ARF, or less frequently through amplification of MDM2. Disruption of the RB pathway occurs through loss of INK4A. Amplification and/or mutation of the epidermal growth factor receptor (EGFR) is the most frequently detected genetic defect that is associated with primary GBM. In secondary GBM, loss of p53 and activation of the growth-factorreceptor-tyrosine-kinase signalling pathway (such as through overexpression of PDGF/PDGFR ) initiates tumour formation,whereas disruption of the retinoblastoma (RB) pathway contributes to the progression of tumour development. Loss of PTEN has been implicated in both pathways, although it is much more common in the pathogenesis of primary GBM.


description_brief: Prostate cancer
systematic_name: M13191
exact_source: hsa05215
external_details_URL: http://www.genome.jp/pathway/hsa05215
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  The identification of key molecular alterations in prostate-cancer cells implicates carcinogen defenses (GSTP1), growth-factor-signaling pathways (NKX3.1, PTEN, and p27), and androgens (AR) as critical determinants of the phenotype of prostate-cancer cells. Glutathione S-transferases (GSTP1) are detoxifying enzymes that catalyze conjunction of glutathione with harmful, electrophilic molecules, thereby protecting cells from carcinogenic factors. Cells of prostatic intraepithelial neoplasia, devoid of GSTP1, undergo genomic damage mediated by such carcinogens. NKX3.1, PTEN, and p27 regulate the growth and survival of prostate cells in the normal prostate. Inadequate levels of PTEN and NKX3.1 lead to a reduction in p27 levels and to increased proliferation and decreased apoptosis. After therapeutic reduction in the levels of testosterone and dihydrotestosterone, the emergence of androgen-independent prostate cancer has been associated with mutations in the androgen receptor (AR) that permit receptor activation by other ligands, increased expression of androgen receptors accompanying AR amplification, and ligand-independent androgen-receptor activation.


description_brief: Thyroid cancer
systematic_name: M523
exact_source: hsa05216
external_details_URL: http://www.genome.jp/pathway/hsa05216
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  Papillary thyroid carcinoma (PTC), the most frequent neoplasia originating from the thyroid epithelium, accounts for about 80% of all thyroid cancers. Chimeric oncogenes, created by chromosomal rearrangements involving prevalently RET and, to a less extent, NTRK1 loci, are implicated in the development of papillary carcinoma.These are inappropriately expressed and stimulate constitutive signaling, bypassing the need for receptor activation by growth factors. Alternatively, mutant RAS directly stimulates BRAF, whereas mutant BRAF directly stimulates MEK. Of all thyroid cancers, 15-20% are follicular thyroid carcinoma (FTC). The most distinctive molecular features of follicular carcinoma are the prominence of aneuploidy and the high prevalence of RAS mutations and PAX8-PPAR-gamma rearrangements. The PPAR-gamma rearrangement functions through a dominant-negative effect on the transcriptional activity of wild-type PPAR-gamma. The fusion oncoprotein contributes to malignant transformation by targeting several cellular pathways, some of which are normally engaged by PPAR-gamma. Most poorly differentiated and undifferentiated thyroid carcinomas are considered to derive from pre-existing well-differentiated thyroid carcinoma through additional genetic events, including beta-catenin nuclear accumulation and p53 inactivation, but de novo occurrence might also occur.


description_brief: Basal cell carcinoma
systematic_name: M17807
exact_source: hsa05217
external_details_URL: http://www.genome.jp/pathway/hsa05217
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  The development of basal cell carcinoma is associated with constitutive activation of sonic hedgehog signaling. Normally, ligand-dependent signaling by Hedgehog (Hh) homologs proceeds through binding to the Patched receptor. This binding relieves the Patched-mediated inhibition of signaling through the Smoothened (SMOH) gene product. This signaling ultimately results in the dissociation of the Gli1 transcription factor from an inhibitory complex in the cytoplasm, its subsequent translocation to the nucleus, and activation of target gene expression. The mutations in SMOH, PTCH1, and SHH in BCCs result in continuous activation of target genes. At a cellular level, sonic hedgehog signaling promotes cell proliferation. Mutations in TP53 are also found with high frequency (>50%) in sporadic BCC.


description_brief: Melanoma
systematic_name: M15798
exact_source: hsa05218
external_details_URL: http://www.genome.jp/pathway/hsa05218
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  Five distinct stages have been proposed in the evolution of melanoma on the basis of histological criteria: common acquired and congenital nevi without dysplastic changes; dysplastic nevi with structural and architectural atypia; radial-growth phase (RGP) melanoma; vertical-growth phase (VGP) melanoma; and metastatic melanoma. Oncogenic NRAS mutations activate both effector pathways Raf-MEK-ERK and PI3K-Akt. The Raf-MEK-ERK pathway may also be activated via mutations in the BRAF gene. The PI3K-Akt pathway may be activated through loss or mutation of the inhibitory tumor suppressor gene PTEN. These mutations arise early during melanoma pathogenesis and are preserved throughout tumor progression. Moreover, melanoma development is strongly associated with inactivation of the p16INK4a/CDK4,6/pRb and p14ARF/HMD2/p53 tumor suppressor pathways. The vertical-growth phase and metastatic melanoma are notable for striking changes in the control of cell adhesion. Recently, amplification of the MITF gene was demonstrated in 10% of primary melanomas and 20% of metastatic melanomas, suggesting that MITF is a melanoma oncogene.


description_brief: Bladder cancer
systematic_name: M19096
exact_source: hsa05219
external_details_URL: http://www.genome.jp/pathway/hsa05219
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  Bladder cancer arise and progress along two distinctive pathways. The first of these is often preceded by simple and papillary hyperplasia and exhibits a tumour morphology that is low-grade, superficial and papillary. Papillary carcinoma has a tendency to recur locally, but rarely invades and metastasizes. These tumors frequently show a constitutive activation of the receptor tyrosine kinase-Ras pathway, exhibiting activating mutations in the HRAS and fibroblast growth factor receptor 3 (FGFR3) genes. The second tumour pathway is characterized by high-grade muscle-invasive tumours, which either originate from flat carcinoma in situ (CIS)/severe dysplasia or arise de novo. Over half of these tumours show defects in the tumour suppressors p53 and/or the retinoblastoma protein (RB) genes and pathways, and over 50% of these tumours progress to local and distant metastases. Some of the cell cycle-related molecules show evidence of epigenetic modulation through aberrant promoter hypermethylation in invasive bladder cancer. Invasion and metastases are promoted by several factors that alter the tumour microenvironment, including the aberrant expression of E-cadherins (E-cad), matrix metalloproteinases (MMPs), angiogenic factors such as vascular endothelial growth factor (VEGF).


description_brief: Chronic myeloid leukemia
systematic_name: M321
exact_source: hsa05220
external_details_URL: http://www.genome.jp/pathway/hsa05220
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  Chronic myelogenous leukaemia (CML) is a biphasic disease, initiated by expression of the BCR/ABL fusion gene product in self-renewing, haematopoietic stem cells (HSCs). HSCs can differentiate into common myeloid progenitors (CMPs), which then differentiate into granulocyte/macrophage progenitors (GMPs). HSCs can also differentiate into common lymphoid progenitors (CLPs), which are the progenitors of lymphocytes such as T cells and B cells. The initial chronic phase of CML (CML-CP) is characterized by a massive expansion of the granulocytic-cell series. Acquisition of additional genetic mutations beyond expression of BCR/ABL causes the progression of CML from chronic phase to blast phase (CML-BP), characterized by an accumulation of myeloid or lymphoid blast cells. The BCR/ABL fusion gene encodes p210BCR/ABL, an oncoprotein, which, unlike the normal p145 c-Abl, has constitutive tyrosine kinase activity and is predominantly localized in the cytoplasm. The tyrosine kinase activity is essential for cell transformation and the cytoplasmic localization of BCR/ABL allows the assembly of phosphorylated substrates in multiprotein complexes that transmit mitogenic and antiapoptotic signals. Additional cytogenetic and molecular changes are frequently found in patients with CML during the progression of the disease from chronic to blast phase. Some of the genetic changes include mutations in TP53, RB, and CDKN2A (also known as p16INK4A), or overexpression of genes such as EVI1. Additional chromosome translocations are also observed, such as t(3;21)(q26;q22), which generates AML1/EVI1. AML1/EVI-1 represses TGF-beta-mediated growth inhibitory signal.


description_brief: Acute myeloid leukemia
systematic_name: M19888
exact_source: hsa05221
external_details_URL: http://www.genome.jp/pathway/hsa05221
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  Two major types of genetic events are crucial for the molecular pathogenesis of acute myeloid leukemias (AML) : activating mutations of signal transduction intermediates and alterations in myeloid transcription factors governing hematopoietic differentiation. Both aberrant and constitutive activation of signal transduction molecules are found in about 50% of primary AML bone marrow samples, and seem to contribute to the increased proliferation and apoptosis resistance. The most common of these activating events were observed in the RTK Flt3, in N-Ras and K-Ras, in Kit, and sporadically in other RTKs. Specific haematopoietic transcription factors are crucial for differentiation to particular lineages during normal differentiation, but are frequently disrupted in AML. Some mechanisms of disruption involve the effect of fusion proteins that are generated by chromosomal translocations on haematopoietic transcription factors. In other cases, the transcription factors themselves are mutated.


description_brief: Small cell lung cancer
systematic_name: M3228
exact_source: hsa05222
external_details_URL: http://www.genome.jp/pathway/hsa05222
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  Small cell lung carcinoma (SCLC) is a highly aggressive neoplasm, which accounts for approximately 20% of all lung cancer cases. Molecular mechanisms altered in SCLC include induced expression of oncogene, MYC, and loss of tumorsuppressor genes, such as p53, PTEN, RB, and FHIT. The overexpression of MYC proteins in SCLC is largely a result of gene amplification. Such overexpression leads to more rapid proliferation and loss of terminal differentiation. Mutation or deletion of p53 or PTEN can lead to more rapid proliferation and reduced apoptosis. The retinoblastoma gene RB1 encodes a nuclear phosphoprotein that helps to regulate cell-cycle progression. The fragile histidine triad gene FHIT encodes the enzyme diadenosine triphosphate hydrolase, which is thought to have an indirect role in proapoptosis and cell-cycle control.


description_brief: Non-small cell lung cancer
systematic_name: M19818
exact_source: hsa05223
external_details_URL: http://www.genome.jp/pathway/hsa05223
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  Non-small-cell lung cancer (NSCLC) accounts for approximately 80% of lung cancer and represents a heterogeneous group of cancers, consisting mainly of squamous cell (SCC), adeno (AC) and large-cell carcinoma. Molecular mechanisms altered in NSCLC include activation of oncogenes, such as K-RAS and c-erbB-2, and inactivation of tumorsuppressor genes, such as p53, p16INK4a, RAR-beta, and RASSF1. Point mutations within the K-RAS gene inactivate GTPase activity and the p21-RAS protein continuously transmits growth signals to the nucleus. Overexpression of c-erbB-2 or EGFR leads to a proliferative advantage. Inactivating mutation of p53 can lead to more rapid proliferation and reduced apoptosis. The protein encoded by the p16INK4a inhibits formation of CDK-cyclin-D complexes by competitive binding of CDK4 and CDK6. Loss of p16INK4a expression is a common feature of NSCLC RAR-beta is a nuclear receptor that bears vitamin-A-dependent transcriptional activity. RASSF1A is able to form heterodimers with Nore-1, an RAS effector.Therefore loss of RASSF1A might shift the balance of RAS activity towards a growth-promoting effect.


description_brief: Asthma
systematic_name: M13950
exact_source: hsa05310
external_details_URL: http://www.genome.jp/pathway/hsa05310
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  Inhaled allergens encounter antigen presenting cells (APC) that line the airway. Upon recognition of the antigen and activation by APC, naive T cells differentiate into TH2 cells, a process that is promoted by interleukin 4 (IL-4). Activated TH2 cells stimulate B cells to produce IgE antibodies in response to IL-4 and IL-13. IgE binds the high affinity IgE receptor at the surface of mast cells, the proliferation and differentiation of which is promoted by IL-9.The crosslinking of mast-cell-bound IgE by allergens leads to the release of biologically active mediators (histamine, leukotrienes) by means of degranulation and, so, to the immediate symptoms of allergy. Activated mast cells and Th2 cells also induce the production of IL-5. IL-5 travels to the bone marrow and regulates the differentiation and egress of eosinophils from the bone marrow into the blood. Moreover activated mast cells and Th2 cells in the lung generate the cytokines interleukin IL-4, IL-13 and tumour necrosis factor (TNF)-alpha. These cytokines stimulate the generation of eotaxin by lung epithelial cells, fibroblasts and smooth muscle cells. Eotaxin then stimulates the selective recruitment of eosinophils from the airway microvessels into the lung tissue. The activation of eosinophils leads to release of toxic granules and oxygen free radicals that lead to tissue damage and promote the development of chronic inflammation.


description_brief: Autoimmune thyroid disease
systematic_name: M13103
exact_source: hsa05320
external_details_URL: http://www.genome.jp/pathway/hsa05320
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  The classification of autoimmune throid disease (AITD) includes Hashimoto's thyroiditis (HT) or chronic autoimmune thyroiditis and its variants, Graves' disease (GD) and autoimmune atrophic thyroiditis or primary myxedema. HT is characterized by the presence of goitre, thyroid autoantibodies against thyroid peroxidase (TPO) and thyroglobulin (Tg) in serum and varying degrees of thyroid dysfunction. During HT, self-reactive CD4+ T lymphocytes (Th) recruit B cells and CD8+ T cells (CTL) into the thyroid. Disease progression leads to the death of thyroid cells and hypothyroidism. Both autoantibodies and thyroid-specific cytotoxic T lymphocytes (CTLs) have been proposed to be responsible for autoimmune thyrocyte depletion. In GD, the TSH-R is the most important autoantigen. Antibodies directed against it mimic the effects of the hormone on thyroid cells, TSH, stimulating autonomous production of thyroxine and triiodothyronine and causing hyperthyroidism. The presence of TSH-R-blocking antibodies that bind the TSH receptor in a similar fashion to the antibodies in patients with Graves' disease but that block rather than activate the receptor explains some cases of atrophic hypothyroidism.


description_brief: Allograft rejection
systematic_name: M18615
exact_source: hsa05330
external_details_URL: http://www.genome.jp/pathway/hsa05330
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  After transplantation of organ allografts, there are two pathways of antigen presentation. In the direct pathway, recipient T cells react to intact allogeneic MHC molecules expressed on the surface of donor cells. This pathway would activate host CD4 or CD8 T cells. In contrast, donor MHC molecules (and all other proteins) shed from the graft can be taken up by host APCs and presented to recipient T cells in the context of self-MHC molecules - the indirect pathway. Such presentation activates predominantly CD4 T cells. A direct cytotoxic T-cell attack on graft cells can be made only by T cells that recognize the graft MHC molecules directly. Nontheless, T cells with indirect allospecificity can contribute to graft rejection by activating macrophages, which cause tissue injury and fibrosis, and are also likely to be important in the development of an alloantibody response to graft.


description_brief: Graft-versus-host disease
systematic_name: M13519
exact_source: hsa05332
external_details_URL: http://www.genome.jp/pathway/hsa05332
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  Graft-versus-host disease (GVHD) pathophysiology can be summerized in a three-step process. During step 1, the conditioning regimen (irradiation and/or chemotherapy) leads to damage, activation of host tissues and induction of inflammatory cytokines secretion. Increased expression of major histocompatibility complex (MHC) antigens and adhesion molecules leads to enhancement of the recognition of host MHC and/or minor histocompatibility antigens by mature donor T cells. Donor T-cell activation in step II is characterized by the predominance of Th1 cells and the secretion of IL-2 and IFN-gamma. These cytokines induce further T-cell expansion, induce cytotoxic T lymphocytes (CTL) and natural killer (NK) cells responses and prime additional mononuclear phagocytes to produce TNF-alpha and IL-1. Also, nitric oxide (NO) is produced by activated macrophages, and it may contribute to the tissue damage seen during step 3. Lipopolysaccharide (LPS), which leaks through the intestinal mucosa that was damaged during step 1, together with IFN-gamma, from step 2, further stimulate macrophages to secrete cytokines and NO. During step 3, the effector phase, activated CTL and NK cells mediate cytotoxicity against target host cells through Fas-Fas ligand interactions and perforin-granzyme B.


description_brief: Viral myocarditis
systematic_name: M12294
exact_source: hsa05416
external_details_URL: http://www.genome.jp/pathway/hsa05416
source_species_code: HS
contributor: KEGG
contrib_organization: Kyoto Encyclopedia of Genes and Genomes
description_full:
  Myocarditis is a cardiac disease associated with inflammation and injury of the myocardium. It results from various etiologies, both noninfectious and infectious, but coxsackievirus B3 (CVB3) is still considered the dominant etiological agent. Myocarditis may be caused by direct cytopathic effects of virus, a pathologic immune response to persistent virus, or autoimmunity triggered by the viral infection. The virus enters the myocyte through internalization of the coxsackie-adenoviral receptor (CAR) and its coreceptor, decay-accelerating factor (DAF). Viral proteases cleave various proteins in the host cell. One example is viral protease 2A, which cleaves eukaryote initiation factor 4G (eIF4G) and the dystrophin protein, resulting in a complete shutdown of cap-dependent RNA translation and cytoskeletal destruction in infected cardiomyocytes, respectively. CVB3 also cleaves the member of the Bcl-2 family Bid, leading to apoptosis. CVB3 infection also induces the cleavage of cyclin D protein through a proteasome-dependent pathway, leading to the host cell-growth arrest. Viral infection and necrosis of myocytes may lead to the release of intracellular antigens, resulting in activation of self-reactive T cells. CVB infection is a significant cause of dilated cardiomyopathy (DCM) as well as myocarditis. Epidemiologically, myocarditis underlies a significant portion of patients with DCM.


systematic_name: M17200
source_species_code: HS
contributor: SigmaAldrich
contrib_organization: SigmaAldrich
description_brief:
  Antigen binding to B cell receptors activates protein tyrosine kinases, such as the Src family, which ultimate activate MAP kinases.


systematic_name: M12771
source_species_code: HS
contributor: SigmaAldrich
contrib_organization: SigmaAldrich
description_brief:
  PTEN is a tumor suppressor that dephosphorylates the lipid messenger phosphatidylinositol triphosphate.


systematic_name: M3686
source_species_code: HS
contributor: SigmaAldrich
contrib_organization: SigmaAldrich
description_brief:
  Expression of cyclins regulates progression through the cell cycle by activating cyclin-dependent kinases.


systematic_name: M18895
source_species_code: HS
contributor: SigmaAldrich
contrib_organization: SigmaAldrich
description_brief:
  The TrkA receptor binds nerve growth factor to activate MAP kinase pathways and promote cell growth.


systematic_name: M14869
source_species_code: HS
contributor: Xiaohui Xie
contrib_organization: Broad Institute
description_brief:
  Genes having at least one occurence of the motif ATAACCT in their 3' untranslated region. The motif represents putative target (that is, seed match) of human mature miRNA hsa-miR-154 (v7.1 miRBase).


systematic_name: M9471
source_species_code: HS
contributor: Xiaohui Xie
contrib_organization: Broad Institute
description_brief:
  Genes having at least one occurence of the motif ACGCACA in their 3' untranslated region. The motif represents putative target (that is, seed match) of human mature miRNA hsa-miR-210 (v7.1 miRBase).


systematic_name: M15158
source_species_code: HS
contributor: Xiaohui Xie
contrib_organization: Broad Institute
description_brief:
  Genes having at least one occurence of the motif GGCGGCA in their 3' untranslated region. The motif represents putative target (that is, seed match) of human mature miRNA hsa-miR-371 (v7.1 miRBase).


systematic_name: M9995
source_species_code: HS
contributor: Xiaohui Xie
contrib_organization: Broad Institute
description_brief:
  Genes having at least one occurrence of the motif TWSGCGCGAAAAYKR in the regions spanning 4 kb centered on their transcription starting sites [-2kb, +2kb].  This matches the transcription factor binding site V$E2F_01 (v7.4 TRANSFAC).


systematic_name: M17867
source_species_code: HS
contributor: Xiaohui Xie
contrib_organization: Broad Institute
description_brief:
  Genes having at least one occurrence of the motif TTTSGCGC in the regions spanning 4 kb centered on their transcription starting sites [-2kb, +2kb].  This matches the transcription factor binding site V$E2F_02 (v7.4 TRANSFAC).


systematic_name: M7737
source_species_code: HS
contributor: Xiaohui Xie
contrib_organization: Broad Institute
description_brief:
  Genes having at least one occurrence of the motif CACCRATANNTATBG in the regions spanning 4 kb centered on their transcription starting sites [-2kb, +2kb].  This matches the CUTL1 [GeneSymbol=CUTL1] transcription factor binding site V$CDPCR3_01 (v7.4 TRANSFAC).


systematic_name: M8270
source_species_code: HS
contributor: Xiaohui Xie
contrib_organization: Broad Institute
description_brief:
  Genes having at least one occurrence of the motif RTGACGCATAYCCCC in the regions spanning 4 kb centered on their transcription starting sites [-2kb, +2kb].  This matches the transcription factor binding site V$TAXCREB_02 (v7.4 TRANSFAC).


systematic_name: M19407
source_species_code: HS
contributor: Xiaohui Xie
contrib_organization: Broad Institute
description_brief:
  Genes having at least one occurrence of the motif TCGTCACRCTTHM in the regions spanning 4 kb centered on their transcription starting sites [-2kb, +2kb].  This matches the PAX3 [GeneSymbol=PAX3] transcription factor binding site V$PAX3_01 (v7.4 TRANSFAC).


systematic_name: M12497
source_species_code: HS
contributor: Xiaohui Xie
contrib_organization: Broad Institute
description_brief:
  Genes having at least one occurrence of the motif TTTCGCGC in the regions spanning 4 kb centered on their transcription starting sites [-2kb, +2kb].  This matches the transcription factor binding site V$E2F_Q3 (v7.4 TRANSFAC).


systematic_name: M10115
source_species_code: HS
contributor: Xiaohui Xie
contrib_organization: Broad Institute
description_brief:
  Genes having at least one occurrence of the motif TTTSGCGS in the regions spanning 4 kb centered on their transcription starting sites [-2kb, +2kb].  This matches the transcription factor binding site V$E2F_Q4 (v7.4 TRANSFAC).


systematic_name: M19064
source_species_code: HS
contributor: Xiaohui Xie
contrib_organization: Broad Institute
description_brief:
  Genes having at least one occurrence of the motif TTTSGCGS in the regions spanning 4 kb centered on their transcription starting sites [-2kb, +2kb].  This matches the transcription factor binding site V$E2F_Q6 (v7.4 TRANSFAC).


systematic_name: M1485
source_species_code: HS
contributor: Xiaohui Xie
contrib_organization: Broad Institute
description_brief:
  Genes having at least one occurrence of the motif NKTSSCGC in the regions spanning 4 kb centered on their transcription starting sites [-2kb, +2kb].  This matches the E2F1 [GeneSymbol=E2F1] transcription factor binding site V$E2F1_Q3 (v7.4 TRANSFAC).


systematic_name: M5000
source_species_code: HS
contributor: Xiaohui Xie
contrib_organization: Broad Institute
description_brief:
  Genes having at least one occurrence of the motif NTTSGCGG in the regions spanning 4 kb centered on their transcription starting sites [-2kb, +2kb].  This matches the E2F1 [GeneSymbol=E2F1] transcription factor binding site V$E2F1_Q4 (v7.4 TRANSFAC).


systematic_name: M9279
source_species_code: HS
contributor: Xiaohui Xie
contrib_organization: Broad Institute
description_brief:
  Genes having at least one occurrence of the motif TTTSGCGS in the regions spanning 4 kb centered on their transcription starting sites [-2kb, +2kb].  This matches the E2F1 [GeneSymbol=E2F1] transcription factor binding site V$E2F1_Q6 (v7.4 TRANSFAC).


systematic_name: M7827
source_species_code: HS
contributor: Xiaohui Xie
contrib_organization: Broad Institute
description_brief:
  Genes having at least one occurrence of the motif CAAGTGCGTG in the regions spanning 4 kb centered on their transcription starting sites [-2kb, +2kb].  This matches the HMX1 [GeneSymbol=HMX1] transcription factor binding site V$HMX1_01 (v7.4 TRANSFAC).


systematic_name: M5297
source_species_code: HS
contributor: Xiaohui Xie
contrib_organization: Broad Institute
description_brief:
  Genes having at least one occurrence of the motif GCACCCAWGGGTGM in the regions spanning 4 kb centered on their transcription starting sites [-2kb, +2kb].  This matches the ZNF423 [GeneSymbol=ZNF423] transcription factor binding site V$ROAZ_01 (v7.4 TRANSFAC).


systematic_name: M4220
source_species_code: HS
contributor: Xiaohui Xie
contrib_organization: Broad Institute
description_brief:
  Genes having at least one occurrence of the motif TTTSGCGCGMNR in the regions spanning 4 kb centered on their transcription starting sites [-2kb, +2kb].  This matches the transcription factor binding site V$E2F_03 (v7.4 TRANSFAC).


systematic_name: M12402
source_species_code: HS
contributor: Xiaohui Xie
contrib_organization: Broad Institute
description_brief:
  Genes having at least one occurrence of the motif TTTCSCGC in the regions spanning 4 kb centered on their transcription starting sites [-2kb, +2kb].  This matches the E2F1 [GeneSymbol=E2F1], TFDP1 [GeneSymbol=TFDP1] transcription factor binding site V$E2F1DP1_01 (v7.4 TRANSFAC).


systematic_name: M12555
source_species_code: HS
contributor: Xiaohui Xie
contrib_organization: Broad Institute
description_brief:
  Genes having at least one occurrence of the motif TTTSSCGC in the regions spanning 4 kb centered on their transcription starting sites [-2kb, +2kb].  This matches the E2F1 [GeneSymbol=E2F1], TFDP2 [GeneSymbol=TFDP2] transcription factor binding site V$E2F1DP2_01 (v7.4 TRANSFAC).


systematic_name: M10526
source_species_code: HS
contributor: Xiaohui Xie
contrib_organization: Broad Institute
description_brief:
  Genes having at least one occurrence of the motif TTTSGCGC in the regions spanning 4 kb centered on their transcription starting sites [-2kb, +2kb].  This matches the E2F4 [GeneSymbol=E2F4], TFDP1 [GeneSymbol=TFDP1] transcription factor binding site V$E2F4DP1_01 (v7.4 TRANSFAC).


systematic_name: M19298
source_species_code: HS
contributor: Xiaohui Xie
contrib_organization: Broad Institute
description_brief:
  Genes having at least one occurrence of the motif TTTCSCGC in the regions spanning 4 kb centered on their transcription starting sites [-2kb, +2kb].  This matches the E2F4 [GeneSymbol=E2F4], TFDP2 [GeneSymbol=TFDP2] transcription factor binding site V$E2F4DP2_01 (v7.4 TRANSFAC).


systematic_name: M5768
source_species_code: HS
contributor: Xiaohui Xie
contrib_organization: Broad Institute
description_brief:
  Genes having at least one occurrence of the motif TTTSGCGC in the regions spanning 4 kb centered on their transcription starting sites [-2kb, +2kb].  This matches the E2F1 [GeneSymbol=E2F1], TFDP1 [GeneSymbol=TFDP1], RB1 [GeneSymbol=RB1] transcription factor binding site V$E2F1DP1RB_01 (v7.4 TRANSFAC).


systematic_name: M17117
source_species_code: HS
contributor: Xiaohui Xie
contrib_organization: Broad Institute
description_brief:
  Genes having at least one occurrence of the motif TTTSGCGSG in the regions spanning 4 kb centered on their transcription starting sites [-2kb, +2kb].  This matches the E2F [GeneSymbol=E2F], TFDP1 [GeneSymbol=TFDP1] transcription factor binding site V$E2F_Q3_01 (v7.4 TRANSFAC).


systematic_name: M102
source_species_code: HS
contributor: Xiaohui Xie
contrib_organization: Broad Institute
description_brief:
  Genes having at least one occurrence of the motif NCSCGCSAAAN in the regions spanning 4 kb centered on their transcription starting sites [-2kb, +2kb].  This matches the E2F [GeneSymbol=E2F], TFDP1 [GeneSymbol=TFDP1] transcription factor binding site V$E2F_Q4_01 (v7.4 TRANSFAC).


systematic_name: M15729
source_species_code: HS
contributor: Xiaohui Xie
contrib_organization: Broad Institute
description_brief:
  Genes having at least one occurrence of the motif NKCGCGCSAAAN in the regions spanning 4 kb centered on their transcription starting sites [-2kb, +2kb].  This matches the E2F [GeneSymbol=E2F], TFDP1 [GeneSymbol=TFDP1] transcription factor binding site V$E2F_Q6_01 (v7.4 TRANSFAC).


systematic_name: M17736
source_species_code: HS
contributor: Xiaohui Xie
contrib_organization: Broad Institute
description_brief:
  Genes having at least one occurrence of the motif TTGGCGCGRAANNGNM in the regions spanning 4 kb centered on their transcription starting sites [-2kb, +2kb].  This matches the E2F1 [GeneSymbol=E2F1] transcription factor binding site V$E2F1_Q3_01 (v7.4 TRANSFAC).


systematic_name: M8998
source_species_code: HS
contributor: Xiaohui Xie
contrib_organization: Broad Institute
description_brief:
  Genes having at least one occurrence of the motif TTTSGCGSG in the regions spanning 4 kb centered on their transcription starting sites [-2kb, +2kb].  This matches the E2F [GeneSymbol=E2F], TFDP1 [GeneSymbol=TFDP1] transcription factor binding site V$E2F1_Q4_01 (v7.4 TRANSFAC).


systematic_name: M3037
source_species_code: HS
contributor: Xiaohui Xie
contrib_organization: Broad Institute
description_brief:
  Genes having at least one occurrence of the motif NTTTCGCGCS in the regions spanning 4 kb centered on their transcription starting sites [-2kb, +2kb].  This matches the E2F1 [GeneSymbol=E2F1] transcription factor binding site V$E2F1_Q6_01 (v7.4 TRANSFAC).


systematic_name: M3383
source_species_code: HS
contributor: Xiaohui Xie
contrib_organization: Broad Institute
description_brief:
  Genes having at least one occurrence of the highly conserved motif M112 KTGGYRSGAA in the regions spanning 4 kb centered on their transcription starting sites [-2kb,+2kb].  The motif does not match any known transcription factor binding site.

description_full:
[cell repeats an earlier one in this file: 987 characters]


systematic_name: M4778
source_species_code: HS
contributor: Xiaohui Xie
contrib_organization: Broad Institute
description_brief:
  Genes having at least one occurrence of the highly conserved motif M146 RRCCGTTA in the regions spanning 4 kb centered on their transcription starting sites [-2kb,+2kb].  The motif does not match any known transcription factor binding site.

description_full:
[cell repeats an earlier one in this file: 987 characters]


systematic_name: M1905
source_species_code: HS
contributor: Xiaohui Xie
contrib_organization: Broad Institute
description_brief:
  Genes having at least one occurrence of the highly conserved motif M69 SGCGSSAAA in the regions spanning 4 kb centered on their transcription starting sites [-2kb, +2kb].  This matches the E2F1 [GeneSymbol=E2F1], TFDP1 [GeneSymbol=TFDP1], RB1 [GeneSymbol=RB1] transcription factor binding site V$E2F1DP2_01 (v7.4 TRANSFAC).

description_full:
[cell repeats an earlier one in this file: 987 characters]


description_brief: Neighborhood of CARD15
systematic_name: M7032
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_full:
  Neighborhood of CARD15 caspase recruitment domain family, member 15  in the GNF2 expression compendium


description_brief: Neighborhood of CASP1
systematic_name: M4396
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_full:
  Neighborhood of CASP1 caspase 1, apoptosis-related cysteine peptidase (interleukin 1, beta, convertase)  in the GNF2 expression compendium


description_brief: Neighborhood of FGR
systematic_name: M5798
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_full:
  Neighborhood of FGR Gardner-Rasheed feline sarcoma viral (v-fgr) oncogene homolog  in the GNF2 expression compendium


description_brief: Neighborhood of FOS
systematic_name: M19427
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_full:
  Neighborhood of FOS v-fos FBJ murine osteosarcoma viral oncogene homolog  in the GNF2 expression compendium


description_brief: Neighborhood of ITGB2
systematic_name: M1953
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_full:
  Neighborhood of ITGB2 integrin, beta 2 (complement component 3 receptor 3 and 4 subunit)  in the GNF2 expression compendium


description_brief: Neighborhood of MCL1
systematic_name: M1250
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_full:
  Neighborhood of MCL1 myeloid cell leukemia sequence 1 (BCL2-related)  in the GNF2 expression compendium


description_brief: Neighborhood of PECAM1
systematic_name: M17265
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_full:
  Neighborhood of PECAM1 platelet/endothelial cell adhesion molecule (CD31 antigen)  in the GNF2 expression compendium


description_brief: Neighborhood of SPI1
systematic_name: M9
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_full:
  Neighborhood of SPI1 spleen focus forming virus (SFFV) proviral integration oncogene spi1  in the GNF2 expression compendium


description_brief: Neighborhood of TNFRSF1B
systematic_name: M356
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_full:
  Neighborhood of TNFRSF1B tumor necrosis factor receptor superfamily, member 1B  in the GNF2 expression compendium


description_brief: Neighborhood of TNFSF10
systematic_name: M5552
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_full:
  Neighborhood of TNFSF10 tumor necrosis factor (ligand) superfamily, member 10  in the GNF2 expression compendium


description_brief: Neighborhood of BECN1
systematic_name: M5038
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_full:
  Neighborhood of BECN1 beclin 1 (coiled-coil, myosin-like BCL2 interacting protein)  in the MORF expression compendium


description_brief: Neighborhood of BUB1
systematic_name: M10554
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_full:
  Neighborhood of BUB1 BUB1 budding uninhibited by benzimidazoles 1 homolog (yeast)  in the MORF expression compendium


description_brief: Neighborhood of BUB3
systematic_name: M13419
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_full:
  Neighborhood of BUB3 BUB3 budding uninhibited by benzimidazoles 3 homolog (yeast)  in the MORF expression compendium


description_brief: Neighborhood of GPX4
systematic_name: M14152
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_full:
  Neighborhood of GPX4 glutathione peroxidase 4 (phospholipid hydroperoxidase)  in the MORF expression compendium


description_brief: Neighborhood of MSH2
systematic_name: M17234
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_full:
  Neighborhood of MSH2 mutS homolog 2, colon cancer, nonpolyposis type 1 (E. coli)  in the MORF expression compendium


description_brief: Neighborhood of PSMC1
systematic_name: M19325
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_full:
  Neighborhood of PSMC1 proteasome (prosome, macropain) 26S subunit, ATPase, 1  in the MORF expression compendium


description_brief: Neighborhood of PSMC2
systematic_name: M11641
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_full:
  Neighborhood of PSMC2 proteasome (prosome, macropain) 26S subunit, ATPase, 2  in the MORF expression compendium


description_brief: Neighborhood of PRKDC
systematic_name: M13609
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_full:
  Neighborhood of PRKDC protein kinase, DNA-activated, catalytic polypeptide  in the MORF expression compendium


description_brief: Neighborhood of SOD1
systematic_name: M7895
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_full:
  Neighborhood of SOD1 superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))  in the MORF expression compendium


description_brief: Neighborhood of TERF1
systematic_name: M1209
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_full:
  Neighborhood of TERF1 telomeric repeat binding factor (NIMA-interacting) 1  in the MORF expression compendium


description_brief: Neighborhood of TERF2IP
systematic_name: M7126
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_full:
  Neighborhood of TERF2IP telomeric repeat binding factor 2, interacting protein  in the MORF expression compendium


description_brief: Neighborhood of XPC
systematic_name: M1715
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_full:
  Neighborhood of XPC xeroderma pigmentosum, complementation group C  in the MORF expression compendium


description_brief: Neighborhood of XRCC5
systematic_name: M18997
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_full:
  Neighborhood of XRCC5 X-ray repair complementing defective repair in Chinese hamster cells 5 (double-strand-break rejoining; Ku autoantigen, 80kDa)  in the MORF expression compendium


description_brief: Neighborhood of ANP32B
systematic_name: M19884
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_full:
  Neighborhood of ANP32B acidic (leucine-rich) nuclear phosphoprotein 32 family, member B  in the MORF expression compendium


description_brief: Neighborhood of AP2M1
systematic_name: M2967
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_full:
  Neighborhood of AP2M1 adaptor-related protein complex 2, mu 1 subunit  in the MORF expression compendium


description_brief: Neighborhood of AP3D1
systematic_name: M16449
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_full:
  Neighborhood of AP3D1 adaptor-related protein complex 3, delta 1 subunit  in the MORF expression compendium


description_brief: Neighborhood of BUB1B
systematic_name: M5625
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_full:
  Neighborhood of BUB1B BUB1 budding uninhibited by benzimidazoles 1 homolog beta (yeast)  in the MORF expression compendium


description_brief: Neighborhood of CDC16
systematic_name: M19935
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_full:
  Neighborhood of CDC16 CDC16 cell division cycle 16 homolog (S. cerevisiae)  in the MORF expression compendium


description_brief: Neighborhood of DDB1
systematic_name: M5047
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_full:
  Neighborhood of DDB1 damage-specific DNA binding protein 1, 127kDa  in the MORF expression compendium


description_brief: Neighborhood of DEAF1
systematic_name: M4797
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_full:
  Neighborhood of DEAF1 deformed epidermal autoregulatory factor 1 (Drosophila)  in the MORF expression compendium


description_brief: Neighborhood of EIF3S2
systematic_name: M18698
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_full:
  Neighborhood of EIF3S2 eukaryotic translation initiation factor 3, subunit 2 beta, 36kDa  in the MORF expression compendium


description_brief: Neighborhood of EIF3S6
systematic_name: M4246
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_full:
  Neighborhood of EIF3S6 eukaryotic translation initiation factor 3, subunit 6 48kDa  in the MORF expression compendium


description_brief: Neighborhood of EIF4A2
systematic_name: M334
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_full:
  Neighborhood of EIF4A2 eukaryotic translation initiation factor 4A, isoform 2  in the MORF expression compendium


description_brief: Neighborhood of GNB1
systematic_name: M18398
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_full:
  Neighborhood of GNB1 guanine nucleotide binding protein (G protein), beta polypeptide 1  in the MORF expression compendium


description_brief: Neighborhood of NME2
systematic_name: M19908
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_full:
  Neighborhood of NME2 non-metastatic cells 2, protein (NM23B) expressed in  in the MORF expression compendium


description_brief: Neighborhood of NPM1
systematic_name: M9993
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_full:
  Neighborhood of NPM1 nucleophosmin (nucleolar phosphoprotein B23, numatrin)  in the MORF expression compendium


description_brief: Neighborhood of PAPSS1
systematic_name: M15846
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_full:
  Neighborhood of PAPSS1 3'-phosphoadenosine 5'-phosphosulfate synthase 1  in the MORF expression compendium


description_brief: Neighborhood of PPP1CA
systematic_name: M7181
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_full:
  Neighborhood of PPP1CA protein phosphatase 1, catalytic subunit, alpha isoform  in the MORF expression compendium


description_brief: Neighborhood of PPP1CC
systematic_name: M18610
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_full:
  Neighborhood of PPP1CC protein phosphatase 1, catalytic subunit, gamma isoform  in the MORF expression compendium


description_brief: Neighborhood of PPP2CA
systematic_name: M16886
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_full:
  Neighborhood of PPP2CA protein phosphatase 2 (formerly 2A), catalytic subunit, alpha isoform  in the MORF expression compendium


description_brief: Neighborhood of PPP2R4
systematic_name: M13790
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_full:
  Neighborhood of PPP2R4 protein phosphatase 2A, regulatory subunit B' (PR 53)  in the MORF expression compendium


description_brief: Neighborhood of PPP2R5E
systematic_name: M9981
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_full:
  Neighborhood of PPP2R5E protein phosphatase 2, regulatory subunit B (B56), epsilon isoform  in the MORF expression compendium


description_brief: Neighborhood of PRKAG1
systematic_name: M1964
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_full:
  Neighborhood of PRKAG1 protein kinase, AMP-activated, gamma 1 non-catalytic subunit  in the MORF expression compendium


description_brief: Neighborhood of PRKAR1A
systematic_name: M18071
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_full:
  Neighborhood of PRKAR1A protein kinase, cAMP-dependent, regulatory, type I, alpha (tissue specific extinguisher 1)  in the MORF expression compendium


description_brief: Neighborhood of PTPN11
systematic_name: M7770
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_full:
  Neighborhood of PTPN11 protein tyrosine phosphatase, non-receptor type 11 (Noonan syndrome 1)  in the MORF expression compendium


description_brief: Neighborhood of RAC1
systematic_name: M5796
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_full:
  Neighborhood of RAC1 ras-related C3 botulinum toxin substrate 1 (rho family, small GTP binding protein Rac1)  in the MORF expression compendium


description_brief: Neighborhood of RAF1
systematic_name: M1232
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_full:
  Neighborhood of RAF1 v-raf-1 murine leukemia viral oncogene homolog 1  in the MORF expression compendium


description_brief: Neighborhood of SART1
systematic_name: M15851
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_full:
  Neighborhood of SART1 squamous cell carcinoma antigen recognised by T cells  in the MORF expression compendium


description_brief: Neighborhood of SKP1A
systematic_name: M12287
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_full:
  Neighborhood of SKP1A S-phase kinase-associated protein 1A (p19A)  in the MORF expression compendium


description_brief: Neighborhood of SNRP70
systematic_name: M10882
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_full:
  Neighborhood of SNRP70 small nuclear ribonucleoprotein 70kDa polypeptide (RNP antigen)  in the MORF expression compendium


description_brief: Neighborhood of UBE2A
systematic_name: M173
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_full:
  Neighborhood of UBE2A ubiquitin-conjugating enzyme E2A (RAD6 homolog)  in the MORF expression compendium


description_brief: Neighborhood of UBE2I
systematic_name: M10939
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_full:
  Neighborhood of UBE2I ubiquitin-conjugating enzyme E2I (UBC9 homolog, yeast)  in the MORF expression compendium


description_brief: Neighborhood of UBE2N
systematic_name: M1109
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_full:
  Neighborhood of UBE2N ubiquitin-conjugating enzyme E2N (UBC13 homolog, yeast)  in the MORF expression compendium


description_brief: Neighborhood of USP5
systematic_name: M19913
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_full:
  Neighborhood of USP5 ubiquitin specific peptidase 5 (isopeptidase T)  in the MORF expression compendium


description_brief: Neighborhood of PSME1
systematic_name: M12304
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_full:
  Neighborhood of PSME1 proteasome (prosome, macropain) activator subunit 1 (PA28 alpha)  in the GCM expression compendium


description_brief: Neighborhood of ANP32B
systematic_name: M14741
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_full:
  Neighborhood of ANP32B acidic (leucine-rich) nuclear phosphoprotein 32 family, member B  in the GCM expression compendium


description_brief: Neighborhood of APEX1
systematic_name: M15698
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_full:
  Neighborhood of APEX1 APEX nuclease (multifunctional DNA repair enzyme) 1  in the GCM expression compendium


description_brief: Neighborhood of NPM1
systematic_name: M1086
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_full:
  Neighborhood of NPM1 nucleophosmin (nucleolar phosphoprotein B23, numatrin)  in the GCM expression compendium


description_brief: Neighborhood of PPP1CC
systematic_name: M12309
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_full:
  Neighborhood of PPP1CC protein phosphatase 1, catalytic subunit, gamma isoform  in the GCM expression compendium


description_brief: Neighborhood of RAF1
systematic_name: M7638
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_full:
  Neighborhood of RAF1 v-raf-1 murine leukemia viral oncogene homolog 1  in the GCM expression compendium


description_brief: Neighborhood of TPR
systematic_name: M3625
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_full:
  Neighborhood of TPR translocated promoter region (to activated MET oncogene)  in the GCM expression compendium


description_brief: Neighborhood of IGFBP1
systematic_name: M18034
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_full:
  Neighborhood of IGFBP1 insulin-like growth factor binding protein 1  in the CAR expression compendium


description_brief: Neighborhood of BNIP3L
systematic_name: M9058
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_full:
  Neighborhood of BNIP3L BCL2/adenovirus E1B 19kDa interacting protein 3-like  in the GNF2 expression compendium


description_brief: Neighborhood of BUB1
systematic_name: M7629
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_full:
  Neighborhood of BUB1 BUB1 budding uninhibited by benzimidazoles 1 homolog (yeast)  in the GNF2 expression compendium


description_brief: Neighborhood of BUB3
systematic_name: M19951
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_full:
  Neighborhood of BUB3 BUB3 budding uninhibited by benzimidazoles 3 homolog (yeast)  in the GNF2 expression compendium


description_brief: Neighborhood of CDC20
systematic_name: M17151
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_full:
  Neighborhood of CDC20 CDC20 cell division cycle 20 homolog (S. cerevisiae)  in the GNF2 expression compendium


description_brief: Neighborhood of MLH1
systematic_name: M18640
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_full:
  Neighborhood of MLH1 mutL homolog 1, colon cancer, nonpolyposis type 2 (E. coli)  in the GNF2 expression compendium


description_brief: Neighborhood of MSH2
systematic_name: M10242
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_full:
  Neighborhood of MSH2 mutS homolog 2, colon cancer, nonpolyposis type 1 (E. coli)  in the GNF2 expression compendium


description_brief: Neighborhood of XRCC5
systematic_name: M1332
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_full:
  Neighborhood of XRCC5 X-ray repair complementing defective repair in Chinese hamster cells 5 (double-strand-break rejoining; Ku autoantigen, 80kDa)  in the GNF2 expression compendium


description_brief: Neighborhood of ANP32B
systematic_name: M12593
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_full:
  Neighborhood of ANP32B acidic (leucine-rich) nuclear phosphoprotein 32 family, member B  in the GNF2 expression compendium


description_brief: Neighborhood of APEX1
systematic_name: M8078
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_full:
  Neighborhood of APEX1 APEX nuclease (multifunctional DNA repair enzyme) 1  in the GNF2 expression compendium


description_brief: Neighborhood of BUB1B
systematic_name: M8304
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_full:
  Neighborhood of BUB1B BUB1 budding uninhibited by benzimidazoles 1 homolog beta (yeast)  in the GNF2 expression compendium


description_brief: Neighborhood of CDH11
systematic_name: M12987
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_full:
  Neighborhood of CDH11 cadherin 11, type 2, OB-cadherin (osteoblast)  in the GNF2 expression compendium


description_brief: Neighborhood of CEBPA
systematic_name: M3221
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_full:
  Neighborhood of CEBPA CCAAT/enhancer binding protein (C/EBP), alpha  in the GNF2 expression compendium


description_brief: Neighborhood of CYP2B6
systematic_name: M19409
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_full:
  Neighborhood of CYP2B6 cytochrome P450, family 2, subfamily B, polypeptide 6  in the GNF2 expression compendium


description_brief: Neighborhood of EIF3S6
systematic_name: M3758
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_full:
  Neighborhood of EIF3S6 eukaryotic translation initiation factor 3, subunit 6 48kDa  in the GNF2 expression compendium


description_brief: Neighborhood of GLTSCR2
systematic_name: M8167
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_full:
  Neighborhood of GLTSCR2 glioma tumor suppressor candidate region gene 2  in the GNF2 expression compendium


description_brief: Neighborhood of HMMR
systematic_name: M12521
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_full:
  Neighborhood of HMMR hyaluronan-mediated motility receptor (RHAMM)  in the GNF2 expression compendium


description_brief: Neighborhood of IGF1
systematic_name: M16314
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_full:
  Neighborhood of IGF1 insulin-like growth factor 1 (somatomedin C)  in the GNF2 expression compendium


description_brief: Neighborhood of MCM4
systematic_name: M17594
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_full:
  Neighborhood of MCM4 MCM4 minichromosome maintenance deficient 4 (S. cerevisiae)  in the GNF2 expression compendium


description_brief: Neighborhood of MCM5
systematic_name: M11522
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_full:
  Neighborhood of MCM5 MCM5 minichromosome maintenance deficient 5, cell division cycle 46 (S. cerevisiae)  in the GNF2 expression compendium


description_brief: Neighborhood of MKI67
systematic_name: M6132
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_full:
  Neighborhood of MKI67 antigen identified by monoclonal antibody Ki-67  in the GNF2 expression compendium


description_brief: Neighborhood of MMP1
systematic_name: M5587
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_full:
  Neighborhood of MMP1 matrix metallopeptidase 1 (interstitial collagenase)  in the GNF2 expression compendium


description_brief: Neighborhood of MYL2
systematic_name: M8715
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_full:
  Neighborhood of MYL2 myosin, light chain 2, regulatory, cardiac, slow  in the GNF2 expression compendium


description_brief: Neighborhood of MYL3
systematic_name: M11742
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_full:
  Neighborhood of MYL3 myosin, light chain 3, alkali; ventricular, skeletal, slow  in the GNF2 expression compendium


description_brief: Neighborhood of NPM1
systematic_name: M9226
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_full:
  Neighborhood of NPM1 nucleophosmin (nucleolar phosphoprotein B23, numatrin)  in the GNF2 expression compendium


description_brief: Neighborhood of PTX3
systematic_name: M11282
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_full:
  Neighborhood of PTX3 pentraxin-related gene, rapidly induced by IL-1 beta  in the GNF2 expression compendium


description_brief: Neighborhood of SPTA1
systematic_name: M13711
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_full:
  Neighborhood of SPTA1 spectrin, alpha, erythrocytic 1 (elliptocytosis 2)  in the GNF2 expression compendium


description_brief: Neighborhood of SPTB
systematic_name: M5633
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_full:
  Neighborhood of SPTB spectrin, beta, erythrocytic (includes spherocytosis, clinical type I)  in the GNF2 expression compendium


description_brief: Neighborhood of ST13
systematic_name: M148
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_full:
  Neighborhood of ST13 suppression of tumorigenicity 13 (colon carcinoma) (Hsp70 interacting protein)  in the GNF2 expression compendium


description_brief: Neighborhood of UBE2I
systematic_name: M4591
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_full:
  Neighborhood of UBE2I ubiquitin-conjugating enzyme E2I (UBC9 homolog, yeast)  in the GNF2 expression compendium


description_brief: Genes down-regulated in mouse fibroblasts over-expressing E2F1 [Gene ID=1869] gene.
systematic_name: M2630
exact_source: E2F1 vs BetaGal; bottom 200 genes (diff. of means)
source_species_code: MM
GEO_id: GSE498
contributor: Pablo Tamayo
contrib_organization: Broad Institute
description_full:
  Identification of E2F1-regulated genes that modulate the transition from quiescence into DNA synthesis, or have roles in apoptosis, signal transduction, membrane biology, and transcription repression.


systematic_name: M2634
exact_source: EGFR vs contol; top 200 genes (diff. of means)
source_species_code: HS
GEO_id: GSE3542
contributor: Pablo Tamayo
contrib_organization: Broad Institute
description_brief:
  Genes up-regulated in MCF-7 cells (breast cancer) positive for ESR1 [Gene ID=2099] and engineered to express ligand-activatable EGFR [Gene ID=1956].

description_full:
  Profiling of MCF-7 cell lines stably overexpressing ligand-activatable EGFR as models of overexpressed growth factor signaling, as well as control vector transfected cells (coMCF-7) and control vector transfected cells long-term adapted for estrogen-independent growth (coMCF-7/lt-E2).


systematic_name: M2636
exact_source: c-erbB-2 vs control; top 200 genes
source_species_code: HS
GEO_id: GSE3542
contributor: Pablo Tamayo
contrib_organization: Broad Institute
description_brief:
  Genes up-regulated in MCF-7 cells (breast cancer) positive for ESR1 [Gene ID=2099] and engineered to express ligand-activatable ERBB2 [Gene ID=2064].

description_full:
  Profiling of MCF-7 cell lines stably overexpressing constitutively active c-erbB-2 as well as control vector transfected cells (coMCF-7) and control vector transfected cells long-term adapted for estrogen-independent growth (coMCF-7/lt-E2).


systematic_name: M2647
exact_source: cyclin D1 (K112E) vs control; bottom 200 genes (diff-means)
source_species_code: HS
contributor: Pablo Tamayo
contrib_organization: Broad Institute
description_brief:
  Genes down-regulated in MCF-7 cells (breast cancer) over-expressing a mutant K112E form of CCND1 [Gene ID=595] gene.

description_full:
  Here we describe how patterns of gene expression in human tumors have been deconvoluted to reveal a mechanism of action for the cyclin D1 oncogene. Computational analysis of the expression patterns of thousands of genes across hundreds of tumor specimens suggested that a transcription factor, C/EBPbeta/Nf-Il6, participates in the consequences of cyclin D1 overexpression. Functional analyses confirmed the involvement of C/EBPbeta in the regulation of genes affected by cyclin D1 and established this protein as an indispensable effector of a potentially important facet of cyclin D1 biology. This work demonstrates that tumor gene expression databases can be used to study the function of a human oncogene in situ.


systematic_name: M2664
exact_source: AKT_PLACEBO vs AKT_RAD001; bottom 150 genes (diff. of means)
source_species_code: MM
GEO_id: GSE1413
contributor: Pablo Tamayo
contrib_organization: Broad Institute
description_brief:
  Genes down-regulated by everolimus [PubChem = 6442177] in mouse prostate tissue transgenically expressing human AKT1 gene [Gene ID=207]  vs untreated controls.

description_full:
  Transgenic (Probasin driven Myr-AKT) or wild-type littermates were treated with RAD001 or placebo and sacrificed at 12 and 48 hours following the beginning of treatment


systematic_name: M2666
exact_source: AKT_PLACEBO vs WT_PLACEBO; bottom 150 genes (diff. of means)
source_species_code: MM
GEO_id: GSE1413
contributor: Pablo Tamayo
contrib_organization: Broad Institute
description_brief:
  Genes down-regulated in mouse prostate by transgenic expression of human AKT1 gene [Gene ID=207]  vs controls.

description_full:
  Transgenic (Probasin driven Myr-AKT) or wild-type littermates were treated with RAD001 or placebo and sacrificed at 12 and 48 h following the beginning of treatment.


description_brief: Genes down-regulated by everolimus [PubChem = 6442177] in prostate tissue.
systematic_name: M2670
exact_source: WT_PLACEBO vs WT_RAD001; bottom 200 genes (diff. of means)
source_species_code: MM
GEO_id: GSE1413
contributor: Pablo Tamayo
contrib_organization: Broad Institute
description_full:
  Wild-type littermates were treated with RAD001 or placebo and sacrificed at 12 and 48 h following the beginning of treatment.


description_brief: Genes down-regulated in HUVEC cells (endothelium) by treatment with VEGFA [Gene ID=7422].
systematic_name: M2675
exact_source: VEGFA vs control; bottom 200 genes (diff. of means)
source_species_code: HS
GEO_id: GSE837
contributor: Pablo Tamayo
contrib_organization: Broad Institute
description_full:
  HUVECs (human umbilical cord vein endothelial cells) are treated with the angiogenic factor VEGF-A in low or high serum media.


systematic_name: M2681
exact_source: ATF2-small vs Control; bottom 200 genes (diff. of means)
source_species_code: HS
GEO_id: GSE1059
contributor: Pablo Tamayo
contrib_organization: Broad Institute
description_brief:
  Genes down-regulated in myometrial cells over-expressing a shortened splice form of ATF2 [Gene ID=1386] gene.

description_full:
  Human myometrial cells taken from biopsies of pre-menopausal non-cancerous non-pregnant uteri were cultured in complete MEM D-valine medium plus 10% FCS, and stably-transfected with the pcDNA3.1/V5-His TOPO vector (Invitrogen) harbouring ATF2-small gene or a control empty-vector.


description_brief: Genes down-regulated in myometrial cells over-expressing ATF2 [Gene ID=1386] gene.
systematic_name: M2684
exact_source: ATF2 vs Control; bottom 200 genes (diff. of means)
source_species_code: HS
GEO_id: GSE1059
contributor: Pablo Tamayo
contrib_organization: Broad Institute
description_full:
  Human myometrial cells taken from biopsies of pre-menopausal non-cancerous non-pregnant uteri were cultured in complete MEM D-valine medium plus 10% FCS, and stably-transfected with the pcDNA3.1/V5-His TOPO vector (Invitrogen) harbouring ATF2 gene or a control empty-vector.


description_brief: Genes down-regulated in NCI-60 panel of cell lines with mutated TP53 [Gene ID=7157].
systematic_name: M2697
exact_source: p53 mutant vs wt panel of NCI-60 cell lines; bottom 200 genes (diff. of means)
source_species_code: HS
contributor: Pablo Tamayo
contrib_organization: Broad Institute
description_full:
  We examined gene expression patterns from the NCI-60 collection of cancer cell lines. We sought to use these data to identify targets of the transcription factor p53, which regulates gene expression in response to various signals of cellular stress. The mutational status of the p53 gene has been reported for 50 of the NCI-60 cell lines, with 17 being classified as normal and 33 as carrying mutations in the gene.


systematic_name: M2715
exact_source: SNF5- vs Controls; bottom 200 genes (diff. of means)
source_species_code: MM
contributor: Pablo Tamayo
contrib_organization: Broad Institute
description_brief:
  Genes down-regulated in MEF cells (embryonic fibroblasts) with knockout of SNF5 [Gene ID=6598] gene.

description_full:
  Snf5 (Ini1/Baf47/Smarcb1), a core member of the Swi/Snf chromatin remodeling complex, is a potent tumor suppressor whose mechanism of action is largely unknown. Biallelic loss of Snf5 leads to the onset of aggressive cancers in both humans and mice. We have developed an innovative and widely applicable analytical technique for cross-species validation of cancer models and show that the gene expression profiles of our Snf5 murine models closely resemble those of human Snf5-deficient rhabdoid tumors. We exploit this system to produce what we believe to be the first report documenting the effects on gene expression of inactivating a Swi/Snf subunit in normal mammalian cells and to identify the transcriptional pathways regulated by Snf5. We demonstrate that the tumor suppressor activity of Snf5 depends on its regulation of cell cycle progression; Snf5 inactivation leads to aberrant up-regulation of E2F targets and increased levels of p53 that are accompanied by apoptosis, polyploidy, and growth arrest. Further, conditional mouse models demonstrate that inactivation of p16Ink4a or Rb (retinoblastoma) does not accelerate tumor formation in Snf5 conditional mice, whereas mutation of p53 leads to a dramatic acceleration of tumor formation.


systematic_name: M2723
exact_source: long term E2 growth vs Controls; top 200 genes (diff. of means)
source_species_code: HS
GEO_id: GSE3542
contributor: Pablo Tamayo
contrib_organization: Broad Institute
description_brief:
  Genes up-regulated in MCF-7 cells (breast cancer) positive for ESR1 [Gene ID=2099] MCF-7 cells (breast cancer) and long-term adapted for estrogen-independent growth.

description_full:
  Profiling of control vector transfected cells (coMCF-7) and control vector transfected cells long-term adapted for estrogen-independent growth (coMCF-7/lt-E2).


systematic_name: M2725
exact_source: MEK vs Controls; top 200 genes (diff. of means)
source_species_code: HS
GEO_id: GSE3542
contributor: Pablo Tamayo
contrib_organization: Broad Institute
description_brief:
  Genes up-regulated in MCF-7 cells (breast cancer) positive for ESR1 [Gene ID=2099] MCF-7 cells (breast cancer) stably over-expressing constitutively active MAP2K1 [Gene ID=5604] gene.

description_full:
  Profiling of MCF-7 cell lines stably overexpressing constitutively active MEK as a model of overexpressed growth factor signaling, as well as control vector transfected cells (coMCF-7).


systematic_name: M2728
exact_source: Raf-1 vs Controls; top 200 genes (diff. of means)
source_species_code: HS
GEO_id: GSE3542
contributor: Pablo Tamayo
contrib_organization: Broad Institute
description_brief:
  Genes up-regulated in MCF-7 cells (breast cancer) positive for ESR1 [Gene ID=2099] MCF-7 cells (breast cancer) stably over-expressing constitutively active RAF1 [Gene ID=5894] gene.

description_full:
  Profiling of MCF-7 cell lines stably overexpressing constitutively active Raf-1 as a model of overexpressed growth factor signaling, as well as control vector transfected cells (coMCF-7).


systematic_name: M2757
exact_source: contol (DMSO) vs 24h of rapamycin treatment; top 200 genes (diff. of means)
source_species_code: HS
GEO_id: GSE5821
contributor: Pablo Tamayo
contrib_organization: Broad Institute
description_brief:
  Genes up-regulated in CEM-C1 cells (T-CLL) in comparison of control vs rapamycin (sirolimus) [PubChem=6610346], an mTOR pathway inhibitor.

description_full:
  CEM-C1 cells were treated with 10 nM rapamycin or DMSO and harvested for microarray analysis at 24 hours


systematic_name: M2763
exact_source: Early (12, 18 and 24 h) vs control; bottom 200 genes (diff. of means)
source_species_code: MM
GEO_id: GSE3749
contributor: Pablo Tamayo
contrib_organization: Broad Institute
description_brief:
  Genes down-regulated during early stages of differentiation of embryoid bodies from J1 embryonic stem cells.

description_full:
  An 11-point time course study on differentiating embryoid bodies from a murine J1 embryonic stem cell line. The time course includes 0 hr, 6 hr, 12 hr, 18 hr, 24 hr, 36 hr, 48 hr, 4 days, 7 days, 9 days and 14 days.


systematic_name: M2765
exact_source: Late (4, 7 and 9 days) vs control; bottom 200 genes (diff. of means)
source_species_code: MM
GEO_id: GSE3749
contributor: Pablo Tamayo
contrib_organization: Broad Institute
description_brief:
  Genes down-regulated during late stages of differentiation of embryoid bodies from J1 embryonic stem cells.

description_full:
  An 11-point time course study on differentiating embryoid bodies from a murine J1 embryonic stem cell line. The time course includes 0 hr, 6 hr, 12 hr, 18 hr, 24 hr, 36 hr, 48 hr, 4 days, 7 days, 9 days and 14 days.


systematic_name: M2769
exact_source: Early (12, 18 and 24 h) vs control; bottom 200 genes (diff. of means)
source_species_code: MM
GEO_id: GSE3231
contributor: Pablo Tamayo
contrib_organization: Broad Institute
description_brief:
  Genes down-regulated during early stages of differentiation of embryoid bodies from V6.5 embryonic stem cells.

description_full:
  An 11-point time course study comparing V6.5 embryonic stem cells versus embryoid bodies. Time course 0 hours, 6 hours, 12 hours, 18 hours, 24 hours, 36 hours, 48 hours, 4 days, 7 days, 9 days, and 14 days.


systematic_name: M2771
exact_source: Late (4, 7 and 9 days) vs control; bottom 200 genes (diff. of means)
source_species_code: MM
GEO_id: GSE3231
contributor: Pablo Tamayo
contrib_organization: Broad Institute
description_brief:
  Genes down-regulated during late stages of differentiation of embryoid bodies from V6.5 embryonic stem cells.

description_full:
  An 11-point time course study comparing V6.5 embryonic stem cells versus embryoid bodies. Time course 0 hours, 6 hours, 12 hours, 18 hours, 24 hours, 36 hours, 48 hours, 4 days, 7 days, 9 days, and 14 days.


description_full: We performed genome-wide expression profiling of cells infected with control or RPS14 shRNAs.
systematic_name: M2816
exact_source: RPS14 shRNA KD vs control; top 200 genes
source_species_code: HS
GEO_id: GSE9487
contributor: Pablo Tamayo
contrib_organization: Broad Institute
description_brief:
  Genes up-regulated in CD34+ hematopoietic progenitor cells after knockdown of RPS14 [Gene ID=6208] by RNAi.


systematic_name: M2850
exact_source: HOXA9sh vs GFPshl; top 200 genes (diff-means)
source_species_code: HS
GEO_id: GSE13714
contributor: Pablo Tamayo
contrib_organization: Broad Institute
description_brief:
  Genes up-regulated in MOLM-14 cells (AML) with knockdown of HOXA9 [Gene ID=3205] gene by RNAi vs controls.

description_full:
  RNA was purified from t(9;11) MOLM-14 AML cells 44h after transduction in triplicates with 2 of the two most effective HOXA9shRNA constructs (3 x 1F3-HOXA9shRNA; 3 x 2A5-HOXA9shRNA) or GFP-controlshRNA (6x).


description_brief: Genes up-regulated in NOMO-1 cells (AML) after knockdown of STK33 [Gene ID=65975] by RNAi.
systematic_name: M2855
exact_source: control vs KD STK33 in nomo cells; top 300 genes (diff. of means)
source_species_code: HS
GEO_id: GSE15151
contributor: Pablo Tamayo
contrib_organization: Broad Institute
description_full:
  NOMO-1 acute myeloid leukemia (AML) cells were stably transduced with different pLKO.1puro lentiviral shRNA vectors targeting STK33 or a nontargeting control shRNA. VSV-G-pseudotyped lentiviral particles were produced by cotransfection of 293T cells with pLKO.1 constructs and the compatible packaging plasmids pMD.G and pCMVR8.91. Virus was harvested 48 and 72 hours after transfection, cells were incubated with lentiviral supernatants for 30 hours, and infected cells were selected with 2ug/ml puromycin. RNA was isolated after 2 days of puromycin selection and isolation of viable cells by density gradient centrifugation, and gene expression was profiled using GeneChip Human Genome U133 Plus 2.0 microarrays (Affymetrix).


description_brief: Genes up-regulated in SKM-1 cells (AML) after knockdown of STK33 [Gene ID=65975] by RNAi.
systematic_name: M2857
exact_source: control vs KD STK33 in skm cells; top 300 genes (diff. of means)
source_species_code: HS
GEO_id: GSE15151
contributor: Pablo Tamayo
contrib_organization: Broad Institute
description_full:
  SKM-1 acute myeloid leukemia (AML) cells were stably transduced with different pLKO.1puro lentiviral shRNA vectors targeting STK33 or a nontargeting control shRNA. VSV-G-pseudotyped lentiviral particles were produced by cotransfection of 293T cells with pLKO.1 constructs and the compatible packaging plasmids pMD.G and pCMVR8.91. Virus was harvested 48 and 72 hours after transfection, cells were incubated with lentiviral supernatants for 30 hours, and infected cells were selected with 2ug/ml puromycin. RNA was isolated after 2 days of puromycin selection and isolation of viable cells by density gradient centrifugation, and gene expression was profiled using GeneChip Human Genome U133 Plus 2.0 microarrays (Affymetrix).


systematic_name: M2858
exact_source: control vs KD STK33 in nomo & skm cells; top 300 genes (diff. of means)
source_species_code: HS
GEO_id: GSE15151
contributor: Pablo Tamayo
contrib_organization: Broad Institute
description_brief:
  Genes up-regulated in NOMO-1 and SKM-1 cells (AML) after knockdown of STK33 [Gene ID=65975] by RNAi.

description_full:
  NOMO-1 and SKM-1 acute myeloid leukemia (AML) cells were stably transduced with different pLKO.1puro lentiviral shRNA vectors targeting STK33 or a nontargeting control shRNA. VSV-G-pseudotyped lentiviral particles were produced by cotransfection of 293T cells with pLKO.1 constructs and the compatible packaging plasmids pMD.G and pCMVR8.91. Virus was harvested 48 and 72 hours after transfection, cells were incubated with lentiviral supernatants for 30 hours, and infected cells were selected with 2ug/ml puromycin. RNA was isolated after 2 days of puromycin selection and isolation of viable cells by density gradient centrifugation, and gene expression was profiled using GeneChip Human Genome U133 Plus 2.0 microarrays (Affymetrix).


systematic_name: M2863
exact_source: AALE-KRAS vs AALE-Vector: top 200 genes (diff. of means)
source_species_code: HS
GEO_id: GSE17643
contributor: Pablo Tamayo
contrib_organization: Broad Institute
description_brief:
  Genes up-regulated in epithelial lung cancer cell lines over-expressing an oncogenic form of KRAS [Gene ID=3845] gene.

description_full:
  Profiling of immortalized human lung epithelial cells following oncogenic KRAS expression and TBK1 suppression. The purpose of the dataset is to analyze expression of genes induced by KRAS and regulated by TBK1. The proto-oncogene KRAS is mutated in a wide array of human cancers, most of which are aggressive and respond poorly to standard therapies. Although the identification of specific oncogenes has led to the development of clinically effective, molecularly targeted therapies in some cases, KRAS has remained refractory to this approach. An alternative strategy for targeting KRAS is to identify gene products that, when suppressed or inhibited, result in cell death only in the presence of an oncogenic allele. Here we have used systematic RNA interference (RNAi) to detect synthetic lethal partners of oncogenic KRAS and found that the non-canonical IkB kinase, TBK1, was selectively essential in cells that harbor mutant KRAS. Suppression of TBK1 induced apoptosis specifically in human cancer cell lines that depend on oncogenic KRAS expression. In these cells, TBK1 activated NF-kappaB anti-apoptotic signals involving cREL and BCL-XL that were essential for survival, providing mechanistic insights into this synthetic lethal interaction. These observations identify TBK1 as a potential therapeutic target in KRAS mutant tumors and establish a general approach for the rational identification of co-dependent pathways in cancer. Knock out of TBK1 in the contect of KRAS activation (mutant) and control (WT).


systematic_name: M2864
exact_source: AALE-KRAS + shTBK1 vs controls; top 300 genes (diff. of means)
source_species_code: HS
GEO_id: GSE17643
contributor: Pablo Tamayo
contrib_organization: Broad Institute
description_brief:
  Genes down-regulated in epithelial lung cancer cell lines upon over-expression of an oncogenic form of KRAS [Gene ID=3845] gene and knockdown of TBK1 [Gene ID=29110] gene by RNAi.

description_full:
  Profiling of immortalized human lung epithelial cells following oncogenic KRAS expression and TBK1 suppression. The purpose of the dataset is to analyze expression of genes induced by KRAS and regulated by TBK1. The proto-oncogene KRAS is mutated in a wide array of human cancers, most of which are aggressive and respond poorly to standard therapies. Although the identification of specific oncogenes has led to the development of clinically effective, molecularly targeted therapies in some cases, KRAS has remained refractory to this approach. An alternative strategy for targeting KRAS is to identify gene products that, when suppressed or inhibited, result in cell death only in the presence of an oncogenic allele. Here we have used systematic RNA interference (RNAi) to detect synthetic lethal partners of oncogenic KRAS and found that the non-canonical IkB kinase, TBK1, was selectively essential in cells that harbor mutant KRAS. Suppression of TBK1 induced apoptosis specifically in human cancer cell lines that depend on oncogenic KRAS expression. In these cells, TBK1 activated NF-kappaB anti-apoptotic signals involving cREL and BCL-XL that were essential for survival, providing mechanistic insights into this synthetic lethal interaction. These observations identify TBK1 as a potential therapeutic target in KRAS mutant tumors and establish a general approach for the rational identification of co-dependent pathways in cancer. Knock out of TBK1 in the contect of KRAS activation (mutant) and control (WT).


systematic_name: M2867
exact_source: AALE-KRAS + shTBK1 vs controls; bottom 300 genes (diff. of means)
source_species_code: HS
GEO_id: GSE17643
contributor: Pablo Tamayo
contrib_organization: Broad Institute
description_brief:
  Genes up-regulated in epithelial lung cancer cell lines upon over-expression of an oncogenic form of KRAS [Gene ID=3845] gene and knockdown of TBK1 [Gene ID=29110] gene by RNAi.

description_full:
  Profiling of immortalized human lung epithelial cells following oncogenic KRAS expression and TBK1 suppression. The purpose of the dataset is to analyze expression of genes induced by KRAS and regulated by TBK1. The proto-oncogene KRAS is mutated in a wide array of human cancers, most of which are aggressive and respond poorly to standard therapies. Although the identification of specific oncogenes has led to the development of clinically effective, molecularly targeted therapies in some cases, KRAS has remained refractory to this approach. An alternative strategy for targeting KRAS is to identify gene products that, when suppressed or inhibited, result in cell death only in the presence of an oncogenic allele. Here we have used systematic RNA interference (RNAi) to detect synthetic lethal partners of oncogenic KRAS and found that the non-canonical IkB kinase, TBK1, was selectively essential in cells that harbor mutant KRAS. Suppression of TBK1 induced apoptosis specifically in human cancer cell lines that depend on oncogenic KRAS expression. In these cells, TBK1 activated NF-kappaB anti-apoptotic signals involving cREL and BCL-XL that were essential for survival, providing mechanistic insights into this synthetic lethal interaction. These observations identify TBK1 as a potential therapeutic target in KRAS mutant tumors and establish a general approach for the rational identification of co-dependent pathways in cancer. Knock out of TBK1 in the contect of KRAS activation (mutant) and control (WT).


description_brief: Genes up-regulated in DLD1 cells (colon carcinoma) over-expressing LEF1 [Gene ID=51176].
systematic_name: M2905
exact_source: DLD1+LEF-1 vs DLD1; top 150 genes
source_species_code: HS
GEO_id: GSE3229
contributor: Pablo Tamayo
contrib_organization: Broad Institute
description_full:
  We treated DLD1 cells with an adenoviral LEF-1 expression construct, which induced EMT within 48 hours. RNA was then extracted from these cells along with untreated DLD1 cells, then subjected to microarray analysis.


systematic_name: M2633
exact_source: EGFR vs contol; bottom 200 genes (diff. of means)
source_species_code: HS
GEO_id: GSE3542
contributor: Pablo Tamayo
contrib_organization: Broad Institute
description_brief:
  Genes down-regulated in MCF-7 cells (breast cancer) positive for ESR1 [Gene ID=2099] and engineered to express ligand-activatable EGFR [Gene ID=1956].

description_full:
  Profiling of MCF-7 cell lines stably overexpressing ligand-activatable EGFR as models of overexpressed growth factor signaling, as well as control vector transfected cells (coMCF-7) and control vector transfected cells long-term adapted for estrogen-independent growth (coMCF-7/lt-E2).


systematic_name: M2635
exact_source: c-erbB-2 vs control; bottom 200 genes
source_species_code: HS
GEO_id: GSE3542
contributor: Pablo Tamayo
contrib_organization: Broad Institute
description_brief:
  Genes down-regulated in MCF-7 cells (breast cancer) positive for ESR1 [Gene ID=2099] and engineered to express ligand-activatable ERBB2 [Gene ID=2064].

description_full:
  Profiling of MCF-7 cell lines stably overexpressing constitutively active c-erbB-2 as well as control vector transfected cells (coMCF-7) and control vector transfected cells long-term adapted for estrogen-independent growth (coMCF-7/lt-E2).


description_brief: Genes up-regulated in granule cell neuron precursors (GCNPs) after stimulation with Shh for 3h.
systematic_name: M2639
exact_source: early (3 h) GCNP SHH+ vs VEHICLE; top 200 genes (diff. of means)
source_species_code: MM
GEO_id: GSE50606
contributor: Pablo Tamayo
contrib_organization: Broad Institute
description_full:
  Hedgehog pathway activation is required for proliferation of cerebellar granule cell neuron precursors during development and is etiologic in certain cerebellar tumors. To identify genes expressed specifically in granule cell neuron precursors, we used oligonucleotide microarrays to analyze regulation of 13,179 genes/expressed sequence tags in heterogeneous primary cultures of neonatal mouse cerebellum that respond to the mitogen Sonic hedgehog. In conjunction, we applied experiment-specific noise models to render a gene-by-gene robust indication of up-regulation in Sonic hedgehog-treated cultures. Twelve genes so identified were tested, and 10 (83%) showed appropriate expression in the external granular layer (EGL) of the postnatal day (PN) 7 cerebellum and down-regulation by PN 15, as verified by in situ hybridization. Whole-organ profiling of the developing cerebellum was carried out from PN 1 to 30 to generate a database of temporal gene regulation profiles (TRPs). From the database an algorithm was developed to capture the TRP typical of EGL-specific genes. The "TRP-EGL" accurately predicted expression in vivo of an additional 18 genes/expressed sequence tags with a sensitivity of 80% and a specificity of 88%. We then compared the positive predictive value of our analytical procedure with other widely used methods, as verified by the TRP-EGL in silico. These findings suggest that replicate experiments and incorporation of noise models increase analytical specificity. They further show that genome-wide methods are an effective means to identify stage-specific gene expression in the developing granule cell lineage.


description_brief: Genes up-regulated in early serum response of CRL 2091 cells (foreskin fibroblasts).
systematic_name: M2656
exact_source: CSR_early (1 to 6 h) vs Control (0 h); top 200 genes (diff. of means)
source_species_code: HS
GEO_id: GSE3945
contributor: Pablo Tamayo
contrib_organization: Broad Institute
description_full:
  Foreskin fibroblasts CRL 2091 (ATCC) were serum starved for 48 hours, and harvested at the indicated time points after switching to media with 10% FBS essentially as described (Iyer et al., 1999). RNA from all of the sampled time points were pooled as reference RNA to compare with RNA from individual time points as described (Iyer et al., 1999)


systematic_name: M2665
exact_source: AKT_PLACEBO vs AKT_RAD001; top 150 genes (diff. of means)
source_species_code: MM
GEO_id: GSE1413
contributor: Pablo Tamayo
contrib_organization: Broad Institute
description_brief:
  Genes up-regulated by everolimus [PubChem = 6442177] in mouse prostate tissue transgenically expressing human AKT1 gene [Gene ID=207]  vs untreated controls.

description_full:
  Transgenic (Probasin driven Myr-AKT) or wild-type littermates were treated with RAD001 or placebo and sacrificed at 12 and 48 hours following the beginning of treatment


systematic_name: M2669
exact_source: AKT_PLACEBO vs WT_PLACEBO; top 150 genes (diff. of means)
source_species_code: MM
GEO_id: GSE1413
contributor: Pablo Tamayo
contrib_organization: Broad Institute
description_brief:
  Genes up-regulated in mouse prostate by transgenic expression of human AKT1 gene [Gene ID=207]  vs controls.

description_full:
  Transgenic (Probasin driven Myr-AKT) or wild-type littermates were treated with RAD001 or placebo and sacrificed at 12 and 48 h following the beginning of treatment.


systematic_name: M2689
exact_source: Wnt-1 vs Controls; bottom 200 genes (diff. of means)
source_species_code: MM
GEO_id: GSE1899
contributor: Pablo Tamayo
contrib_organization: Broad Institute
description_brief:
  Genes down-regulated in C57MG cells (mammary epithelium) by over-expression of WNT1 [Gene ID=7471] gene.

description_full:
  Targets of Wnt-1 in C57MG. RNA from murine mammary C57MG cells transfected with an empty control vector (PLNCx) or an expression vector encoding Wnt-1 was isolated and analyzed on Affymetrix MG-U74Av2 arrays.


systematic_name: M2694
exact_source: p53_siRNA vs controls; top 150 genes (diff. of means)
source_species_code: HS
GEO_id: GSE1676
contributor: Pablo Tamayo
contrib_organization: Broad Institute
description_brief:
  Genes up-regulated in HEK293 cells (kidney fibroblasts) upon knockdown of TP53 [Gene ID=7157] gene by RNAi.

description_full:
  Expression profiling of cells knocked-down for p53 and control un-infected cells and cells infected with siRNA against LacZ.


systematic_name: M2696
exact_source: RELA shRNA vs WT; top 150 genes (diff. of means)
source_species_code: HS
GEO_id: GSE1676
contributor: Pablo Tamayo
contrib_organization: Broad Institute
description_brief:
  Genes up-regulated in HEK293 cells (kidney fibroblasts) upon knockdown of RELA [Gene ID=5970] gene by RNAi.

description_full:
  Expression profiling of cells knocked-down for RelA and control un-infected cells and cells infected with siRNA against LacZ.


systematic_name: M2704
exact_source: E2F3 vs GFP; bottom 200 genes (diff. of means)
source_species_code: HS
GEO_id: GSE3151
contributor: Pablo Tamayo
contrib_organization: Broad Institute
description_brief:
  Genes down-regulated in primary epithelial breast cancer cell culture over-expressing E2F3 [Gene ID=1871] gene.

description_full:
  RNA was extracted from human mammary epithelial cells expressing oncogenes (or GFP control) for gene array analysis. Experiment was performed in replicate.


systematic_name: M2708
exact_source: MYC vs GFP; bottom 200 genes
source_species_code: HS
GEO_id: GSE3151
contributor: Pablo Tamayo
contrib_organization: Broad Institute
description_brief:
  Genes down-regulated in primary epithelial breast cancer cell culture over-expressing MYC [Gene ID=4609] gene.

description_full:
  RNA was extracted from human mammary epithelial cells expressing oncogenes (or GFP control) for gene array analysis. Experiment was performed in replicate.


systematic_name: M2711
exact_source: MYC vs GFP; top 200 genes
source_species_code: HS
GEO_id: GSE3151
contributor: Pablo Tamayo
contrib_organization: Broad Institute
description_brief:
  Genes up-regulated in primary epithelial breast cancer cell culture over-expressing MYC [Gene ID=4609] gene.

description_full:
  RNA was extracted from human mammary epithelial cells expressing oncogenes (or GFP control) for gene array analysis. Experiment was performed in replicate.


systematic_name: M2713
exact_source: SRC vs GFP; bottom 200 genes
source_species_code: HS
GEO_id: GSE3151
contributor: Pablo Tamayo
contrib_organization: Broad Institute
description_brief:
  Genes down-regulated in primary epithelial breast cancer cell culture over-expressing SRC [Gene ID=6714] gene.

description_full:
[cell repeats an earlier one in this file: 155 characters]


systematic_name: M2714
exact_source: SRC vs GFP; top 200 genes
source_species_code: HS
GEO_id: GSE3151
contributor: Pablo Tamayo
contrib_organization: Broad Institute
description_brief:
  Genes up-regulated in primary epithelial breast cancer cell culture over-expressing SRC [Gene ID=6714] gene.

description_full:
[cell repeats an earlier one in this file: 155 characters]


systematic_name: M2721
exact_source: long term E2 growth vs Controls; top 200 genes (diff. of means)
source_species_code: HS
GEO_id: GSE3542
contributor: Pablo Tamayo
contrib_organization: Broad Institute
description_brief:
  Genes down-regulated in MCF-7 cells (breast cancer) positive for ESR1 [Gene ID=2099] MCF-7 cells (breast cancer) and long-term adapted for estrogen-independent growth.

description_full:
  Profiling of control vector transfected cells (coMCF-7) and control vector transfected cells long-term adapted for estrogen-independent growth (coMCF-7/lt-E2).


systematic_name: M2724
exact_source: MEK vs Controls; bottom 200 genes (diff. of means)
source_species_code: HS
GEO_id: GSE3542
contributor: Pablo Tamayo
contrib_organization: Broad Institute
description_brief:
  Genes down-regulated in MCF-7 cells (breast cancer) positive for ESR1 [Gene ID=2099] MCF-7 cells (breast cancer) stably over-expressing constitutively active MAP2K1 [Gene ID=5604] gene.

description_full:
  Profiling of MCF-7 cell lines stably overexpressing constitutively active MEK as a model of overexpressed growth factor signaling, as well as control vector transfected cells (coMCF-7).


systematic_name: M2726
exact_source: Raf-1 vs Controls; bottom 200 genes (diff. of means)
source_species_code: HS
GEO_id: GSE3542
contributor: Pablo Tamayo
contrib_organization: Broad Institute
description_brief:
  Genes down-regulated in MCF-7 cells (breast cancer) positive for ESR1 [Gene ID=2099] MCF-7 cells (breast cancer) stably over-expressing constitutively active RAF1 [Gene ID=5894] gene.

description_full:
  Profiling of MCF-7 cell lines stably overexpressing constitutively active Raf-1 as a model of overexpressed growth factor signaling, as well as control vector transfected cells (coMCF-7).


description_brief: Genes down-regulated in TIG3 cells (fibroblasts) upon knockdown of BMI1 [Gene ID=648] gene.
systematic_name: M2730
exact_source: ko vs control; bottom 200 genes
source_species_code: HS
GEO_id: GSE6015
contributor: Pablo Tamayo
contrib_organization: Broad Institute
description_full:
  The identification of gene expression changes in human embryonic fibroblast cells depleted of BMI-1.


description_brief: Genes down-regulated in TIG3 cells (fibroblasts) upon knockdown of SUZ12 [Gene ID=23512] gene.
systematic_name: M2740
exact_source: ko vs control; bottom 200 genes
source_species_code: HS
GEO_id: GSE6015
contributor: Pablo Tamayo
contrib_organization: Broad Institute
description_full:
  The identification of gene expression changes in human embryonic fibroblast cells depleted of SUZ12.


description_full: MCF10A cells in 3-D culture for 15 h after treatment with BRCA1-RNAi vs Luc-RNAi adenovirus
systematic_name: M2747
exact_source: BRCA1 KD vs LUC KD; bottom 150 genes (diff. of means)
source_species_code: HS
GEO_id: GSE4750
contributor: Pablo Tamayo
contrib_organization: Broad Institute
description_brief:
  Genes down-regulated in MCF10A cells (breast cancer) upon knockdown of BRCA1 [Gene ID=672] gene by RNAi.


description_full: MCF10A cells in 3-D culture for 15 h after treatment with CtIP-RNAi vs Luc-RNAi adenovirus.
systematic_name: M2751
exact_source: CTIP 20 vs LUC 20 KD; bottom 150 genes (diff. of means)
source_species_code: HS
GEO_id: GSE4751
contributor: Pablo Tamayo
contrib_organization: Broad Institute
description_brief:
  Genes down-regulated in MCF10A cells (breast cancer) upon knockdown of RBBP8 [GeneSymbol=RBBP8] gene by RNAi.


systematic_name: M2758
exact_source: PTEN ko vs control; bottom 300 genes (diff. of means)
source_species_code: HS
GEO_id: GSE6263
contributor: Pablo Tamayo
contrib_organization: Broad Institute
description_brief:
  Genes down-regulated in HCT116 cells (colon carcinoma) upon knockdown of PTEN [Gene ID=5728] by RNAi.

description_full:
  Two HCT116 PTEN+/+ cell lines (parental cells and a clone with random integration of the targeting vector) and three independently-derived HCT116 PTEN-/- cell lines were studied


systematic_name: M2760
exact_source: DCA vs Controls; bottom 200 genes (diff. of means)
source_species_code: HS
GEO_id: GSE6014
contributor: Pablo Tamayo
contrib_organization: Broad Institute
description_brief:
  Genes down-regulated in A549 lung carcinoma and M059K glioblastoma cells treated with dichloroacetate [PubChem=6597].

description_full:
  Analysis of A549 lung carcinoma and M059K glioblastoma cells treated with dichloroacetate (DCA), an inhibitor of the mitochondrial pyruvate dehydrogenase kinase. DCA shifts metabolism from glycolysis to glucose oxidation and decreases mitochondrial membrane potential in cancer cells.


description_full: Analysis of DAOY medulloblastoma cells following RNAi knockdown of Alk.
systematic_name: M2773
exact_source: Alk shRNA vs Wild Type; bottom 150 genes (diff. of means)
source_species_code: HS
GEO_id: GSE7578
contributor: Pablo Tamayo
contrib_organization: Broad Institute
description_brief:
  Genes down-regulated in DAOY cells (medulloblastoma) upon knockdown of ALK [Gene ID=238] gene by RNAi.


description_full: Analysis of DAOY medulloblastoma cells following RNAi knockdown of Alk.
systematic_name: M2774
exact_source: Alk shRNA vs Wild Type; top 150 genes (diff. of means)
source_species_code: HS
GEO_id: GSE7578
contributor: Pablo Tamayo
contrib_organization: Broad Institute
description_brief:
  Genes up-regulated in DAOY cells (medulloblastoma) upon knockdown of ALK [Gene ID=238] gene by RNAi.


description_full: Analysis of DAOY medulloblastoma cells following RNAi knockdown of Bmi-1 and Mel-18.
systematic_name: M2775
exact_source: Bmi1 Mel18 shRNA vs Wild Type; bottom 150 genes (diff. of means)
source_species_code: HS
GEO_id: GSE7578
contributor: Pablo Tamayo
contrib_organization: Broad Institute
description_brief:
  Genes down-regulated in DAOY cells (medulloblastoma) upon knockdown of BMI1 and PCGF2 [Gene ID=648, 7703] genes by RNAi.


description_full: Analysis of DAOY medulloblastoma cells following RNAi knockdown of Bmi-1 and Mel-18.
systematic_name: M2779
exact_source: Bmi1 Mel18 shRNA vs Wild Type; top 150 genes (diff. of means)
source_species_code: HS
GEO_id: GSE7578
contributor: Pablo Tamayo
contrib_organization: Broad Institute
description_brief:
  Genes up-regulated in DAOY cells (medulloblastoma) upon knockdown of BMI1 and PCGF2 [Gene ID=648, 7703] genes by RNAi.


description_full: Analysis of DAOY medulloblastoma cells following RNAi knockdown of Bmi-1.
systematic_name: M2781
exact_source: Bmi-1 shRNA vs Wild Type; bottom 150 genes (diff. of means)
source_species_code: HS
GEO_id: GSE7578
contributor: Pablo Tamayo
contrib_organization: Broad Institute
description_brief:
  Genes down-regulated in DAOY cells (medulloblastoma) upon knockdown of BMI1 [Gene ID=648] gene by RNAi.


description_full: Analysis of DAOY medulloblastoma cells following RNAi knockdown of Bmi-1.
systematic_name: M2782
exact_source: Bmi-1 shRNA vs Wild Type; top 150 genes (diff. of means)
source_species_code: HS
GEO_id: GSE7578
contributor: Pablo Tamayo
contrib_organization: Broad Institute
description_brief:
  Genes up-regulated in DAOY cells (medulloblastoma) upon knockdown of BMI1 [Gene ID=648] gene by RNAi.


description_full: Analysis of DAOY medulloblastoma cells following RNAi knockdown of Mel-18.
systematic_name: M2783
exact_source: Mel-18 vs Controls; bottom 150 genes
source_species_code: HS
GEO_id: GSE7578
contributor: Pablo Tamayo
contrib_organization: Broad Institute
description_brief:
  Genes down-regulated in DAOY cells (medulloblastoma) upon knockdown of PCGF2 [Gene ID=7703] gene by RNAi.


description_full: Analysis of DAOY medulloblastoma cells following RNAi knockdown of Mel-18.
systematic_name: M2784
exact_source: Mel-18 vs Controls; top 150 genes
source_species_code: HS
GEO_id: GSE7578
contributor: Pablo Tamayo
contrib_organization: Broad Institute
description_brief:
  Genes up-regulated in DAOY cells (medulloblastoma) upon knockdown of PCGF2 [Gene ID=7703] gene by RNAi.


description_brief: Genes up-regulated upon knockdown of PTEN [Gene ID=5728] by RNAi.
systematic_name: M2787
exact_source: PTEN ko vs control; top 200 genes (diff. of means)
source_species_code: HS
GEO_id: GSE7562
contributor: Pablo Tamayo
contrib_organization: Broad Institute
description_full:
  A431, HCC827 and SKBR-3 cells were retrovirally and stably transduced with a small hairpin RNA targeting human PTEN. PTEN knockdown was confirmed at the protein level by western blot to be approximately 90%. PTEN-deficient sublines were named by adding the suffix PR(for PTEN RNAi) at the end of each of the parental cell line names. For example, PTEN deficient A431 cells are called A431-PR. RNA was extracted from each of the parental and PTEN-deificient lines. Each sample was done in duplicate (ie two chips per sample) for a total of twelve samples.


systematic_name: M2789
exact_source: Controls vs DAPT; bottom 200 genes (diff. of means)
source_species_code: HS
GEO_id: GSE6495
contributor: Pablo Tamayo
contrib_organization: Broad Institute
description_brief:
  Genes up-regulated in MOLT4 cells (T-ALL) by DAPT [PubChem=16219261], an inhibitor of NOTCH signaling pathway.

description_full:
  NOTCH signaling in T-ALL cell lines. Three independent cultures of the MOLT4 cell line before and 48 hours after addition of the gamma-secretase inhibitor DAPT (5 uM).


description_brief: Genes up-regulated in primary keratinocytes from RB1 [Gene ID=5925] skin specific knockout mice.
systematic_name: M2800
exact_source: RB -/- vs WT; top 150 genes (diff. of means)
source_species_code: MM
GEO_id: GSE9562
contributor: Pablo Tamayo
contrib_organization: Broad Institute
description_full:
  The epidermal-specific ablation of Rb gene leads to increased proliferation, aberrant differentiation, and the disengagement of these processes in vivo and in vitro. These differences in phenotype are more severe with the loss of p107, demonstrating the functional compensation between pRb and p107. As p107 and p130 also exert overlapping functions in epidermis, we have generated Rb(F19/F19)K14cre;Rbl2-/- (pRb-;p130-) mice to analyze possible functional redundancies between pRb and p130. The epidermal phenotype was very similar between pRb- and pRb-;p130- mice, suggesting that pRb and p130 activities are not redundant in epidermis. Importantly, we can correlate the proliferation differences with specific changes in gene expression between pRb-, pRb-;p107- and pRb-;p130- primary keratinocytes using microarray analysis, and explain the phenotypes in the context of altered E2F expression and functionality. Our findings support a model in which the distinct retinoblastoma family members, in conjunction with E2F members, play a central role in regulating epidermal homeostasis through specific or overlapping activities.


systematic_name: M2802
exact_source: RB -/- & p107-/-; top 150 genes (diff. of means)
source_species_code: MM
GEO_id: GSE9562
contributor: Pablo Tamayo
contrib_organization: Broad Institute
description_brief:
  Genes up-regulated in primary keratinocytes from RB1 and RBL1 [Gene ID=5925, 5933] skin specific knockout mice.

description_full:
  The epidermal-specific ablation of Rb gene leads to increased proliferation, aberrant differentiation, and the disengagement of these processes in vivo and in vitro. These differences in phenotype are more severe with the loss of p107, demonstrating the functional compensation between pRb and p107. As p107 and p130 also exert overlapping functions in epidermis, we have generated Rb(F19/F19)K14cre;Rbl2-/- (pRb-;p130-) mice to analyze possible functional redundancies between pRb and p130. The epidermal phenotype was very similar between pRb- and pRb-;p130- mice, suggesting that pRb and p130 activities are not redundant in epidermis. Importantly, we can correlate the proliferation differences with specific changes in gene expression between pRb-, pRb-;p107- and pRb-;p130- primary keratinocytes using microarray analysis, and explain the phenotypes in the context of altered E2F expression and functionality. Our findings support a model in which the distinct retinoblastoma family members, in conjunction with E2F members, play a central role in regulating epidermal homeostasis through specific or overlapping activities.


systematic_name: M2805
exact_source: RB -/- & p130-/-; top 150 genes (diff. of means)
source_species_code: MM
GEO_id: GSE9562
contributor: Pablo Tamayo
contrib_organization: Broad Institute
description_brief:
  Genes up-regulated in primary keratinocytes from RB1 and RBL2 [Gene ID=5925, 5934] skin specific knockout mice.

description_full:
  The epidermal-specific ablation of Rb gene leads to increased proliferation, aberrant differentiation, and the disengagement of these processes in vivo and in vitro. These differences in phenotype are more severe with the loss of p107, demonstrating the functional compensation between pRb and p107. As p107 and p130 also exert overlapping functions in epidermis, we have generated Rb(F19/F19)K14cre;Rbl2-/- (pRb-;p130-) mice to analyze possible functional redundancies between pRb and p130. The epidermal phenotype was very similar between pRb- and pRb-;p130- mice, suggesting that pRb and p130 activities are not redundant in epidermis. Importantly, we can correlate the proliferation differences with specific changes in gene expression between pRb-, pRb-;p107- and pRb-;p130- primary keratinocytes using microarray analysis, and explain the phenotypes in the context of altered E2F expression and functionality. Our findings support a model in which the distinct retinoblastoma family members, in conjunction with E2F members, play a central role in regulating epidermal homeostasis through specific or overlapping activities.


description_full: We performed genome-wide expression profiling of cells infected with control or RPS14 shRNAs.
systematic_name: M2812
exact_source: RPS14 shRNA KD vs control; bottom 200 genes
source_species_code: HS
GEO_id: GSE9487
contributor: Pablo Tamayo
contrib_organization: Broad Institute
description_brief:
  Genes down-regulated in CD34+ hematopoietic progenitor cells after knockdown of RPS14 [Gene ID=6208] by RNAi.


systematic_name: M2819
source_species_code: HS
GEO_id: GSE8685
contributor: Pablo Tamayo
contrib_organization: Broad Institute
description_brief:
  Genes up-regulated in Sez-4 cells (T lymphocyte) that were first starved of IL2 [Gene ID=3558] and then stimulated with IL15 [Gene ID=3600].

description_full:
  Sez-4 cell line was starved of IL2 for 16h, washed twice and placed into 6-well plates in 10ml RPMI (10% FBS) for 2 h followed by addition of IL-15 (20ng/mL) or medium alone for 4 h.

exact_source:
  Sez-4 cells starved of IL-2 and activated with IL-15 vs Sez-4 cells starved of IL-2; top 200 genes (diff. of means)


systematic_name: M2822
source_species_code: HS
GEO_id: GSE8685
contributor: Pablo Tamayo
contrib_organization: Broad Institute
description_brief:
  Genes up-regulated in Sez-4 cells (T lymphocyte) that were first starved of IL2 [Gene ID=3558] and then stimulated with IL2 [Gene ID=3558].

description_full:
  Sez-4 cell line was starved of IL2 for 16h, washed twice and placed into 6-well plates in 10ml RPMI (10% FBS) for 2 h followed by addition of IL-2 (200U) or medium alone for 4 h.

exact_source:
  Sez-4 cells starved of IL-2 and activated with IL-2 vs Sez-4 cells starved of IL-2; top 200 genes (diff. of means)


systematic_name: M2827
source_species_code: HS
GEO_id: GSE8685
contributor: Pablo Tamayo
contrib_organization: Broad Institute
description_brief:
  Genes up-regulated in Sez-4 cells (T lymphocyte) that were first starved of IL2 [Gene ID=3558] and then stimulated with IL21 [Gene ID=59067].

description_full:
  Sez-4 cell line was starved of IL2 for 16h, washed twice and placed into 6-well plates in 10ml RPMI (10% FBS) for 2 h followed by addition of IL-21 (100 ng/ml) or medium alone for 4 h.

exact_source:
  Sez-4 cells starved of IL-2 and activated with IL-21 vs Sez-4 cells starved of IL-2; top 200 genes (diff. of means)


description_brief: Genes up-regulated in a panel of epithelial cell lines by TGFB1 [Gene ID=7040].
systematic_name: M2839
exact_source: stimulation with TGFB vs control; top 200 genes
source_species_code: HS
GEO_id: E-TABM-420
contributor: Pablo Tamayo
contrib_organization: Broad Institute
description_full:
  A gene expression signature typifying the TGFbeta response in human epithelial cells was obtained from transcriptomic analysis of four human cell lines (Figure 1A, Supplementary Figure 1). These cell lines include HaCaT keratinocytes, HPL1 immortalized lung epithelial cells, MCF10A breast epithelial cells, and MDA-MB-231 breast carcinoma cells. The cells were treated with TGFB1 for 3 h in order to capture direct TGFbeta gene responses .


systematic_name: M2848
exact_source: HOXA9sh vs GFPshl; top 200 genes (diff-means)
source_species_code: HS
GEO_id: GSE13714
contributor: Pablo Tamayo
contrib_organization: Broad Institute
description_brief:
  Genes down-regulated in MOLM-14 cells (AML) with knockdown of HOXA9 [Gene ID=3205] gene by RNAi vs controls.

description_full:
  RNA was purified from t(9;11) MOLM-14 AML cells 44h after transduction in triplicates with 2 of the two most effective HOXA9shRNA constructs (3 x 1F3-HOXA9shRNA; 3 x 2A5-HOXA9shRNA) or GFP-controlshRNA (6x).


systematic_name: M2874
exact_source: AALE-KRAS vs AALE-Vector: top 150 genes (diff. of means)
source_species_code: HS
GEO_id: GSE17671
contributor: Pablo Tamayo
contrib_organization: Broad Institute
description_brief:
  Genes down-regulated in four lineages of epithelial cell lines over-expressing an oncogenic form of KRAS [Gene ID=3845] gene.

description_full:
  The proto-oncogene KRAS is mutated in a wide array of human cancers, most of which are aggressive and respond poorly to standard therapies. Although the identification of specific oncogenes has led to the development of clinically effective, molecularly targeted therapies in some cases, KRAS has remained refractory to this approach. A complementary strategy for targeting KRAS is to identify gene products that, when inhibited, result in cell death only in the presence of an oncogenic allele. Here we have used systematic RNA interference to detect synthetic lethal partners of oncogenic KRAS and found that the non-canonical IkappaB kinase TBK1 was selectively essential in cells that contain mutant KRAS. Suppression of TBK1 induced apoptosis specifically in human cancer cell lines that depend on oncogenic KRAS expression. In these cells, TBK1 activated NF-kappaB anti-apoptotic signals involving c-Rel and BCL-XL (also known as BCL2L1) that were essential for survival, providing mechanistic insights into this synthetic lethal interaction. These observations indicate that TBK1 and NF-kappaB signalling are essential in KRAS mutant tumours, and establish a general approach for the rational identification of co-dependent pathways in cancer.


systematic_name: M2875
exact_source: AALE-KRAS vs AALE-Vector: top 150 genes (diff. of means)
source_species_code: HS
GEO_id: GSE17671
contributor: Pablo Tamayo
contrib_organization: Broad Institute
description_brief:
  Genes up-regulated in four lineages of epithelial cell lines over-expressing an oncogenic form of KRAS [Gene ID=3845] gene.

description_full:
  The proto-oncogene KRAS is mutated in a wide array of human cancers, most of which are aggressive and respond poorly to standard therapies. Although the identification of specific oncogenes has led to the development of clinically effective, molecularly targeted therapies in some cases, KRAS has remained refractory to this approach. A complementary strategy for targeting KRAS is to identify gene products that, when inhibited, result in cell death only in the presence of an oncogenic allele. Here we have used systematic RNA interference to detect synthetic lethal partners of oncogenic KRAS and found that the non-canonical IkappaB kinase TBK1 was selectively essential in cells that contain mutant KRAS. Suppression of TBK1 induced apoptosis specifically in human cancer cell lines that depend on oncogenic KRAS expression. In these cells, TBK1 activated NF-kappaB anti-apoptotic signals involving c-Rel and BCL-XL (also known as BCL2L1) that were essential for survival, providing mechanistic insights into this synthetic lethal interaction. These observations indicate that TBK1 and NF-kappaB signalling are essential in KRAS mutant tumours, and establish a general approach for the rational identification of co-dependent pathways in cancer.


systematic_name: M2885
exact_source: AALE-KRAS vs AALE-Vector: top 300 genes (diff. of means)
source_species_code: HS
contributor: Pablo Tamayo
contrib_organization: Broad Institute
description_brief:
  Genes down-regulated in epithelial lung and breast cancer cell lines over-expressing an oncogenic form of KRAS [Gene ID=3845] gene.


systematic_name: M2886
exact_source: AALE-KRAS vs AALE-Vector: top 300 genes (diff. of means)
source_species_code: HS
contributor: Pablo Tamayo
contrib_organization: Broad Institute
description_brief:
  Genes up-regulated in epithelial lung and breast cancer cell lines over-expressing an oncogenic form of KRAS [Gene ID=3845] gene.


systematic_name: M2887
exact_source: AALE-KRAS vs AALE-Vector: top 150 genes (diff. of means)
source_species_code: HS
contributor: Pablo Tamayo
contrib_organization: Broad Institute
description_brief:
  Genes down-regulated in epithelial breast cancer cell lines over-expressing an oncogenic form of  KRAS [Gene ID=3845] gene.


systematic_name: M2888
exact_source: AALE-KRAS vs AALE-Vector: top 150 genes (diff. of means)
source_species_code: HS
contributor: Pablo Tamayo
contrib_organization: Broad Institute
description_brief:
  Genes up-regulated in epithelial breast cancer cell lines over-expressing an oncogenic form of KRAS [Gene ID=3845] gene.


systematic_name: M2889
source_species_code: HS
contributor: Pablo Tamayo
contrib_organization: Broad Institute
description_brief:
  Genes down-regulated in epithelial kidney cancer cell lines over-expressing an oncogenic form of KRAS [Gene ID=3845] gene.

exact_source:
  AALE-KRAS vs AALE-Vector: top 150 genes (diff. of means).  Similar to GSE17643: Broad KRAS internal signatures generated by J. Boehm.


systematic_name: M2892
source_species_code: HS
contributor: Pablo Tamayo
contrib_organization: Broad Institute
description_brief:
  Genes up-regulated in epithelial kidney cancer cell lines over-expressing an oncogenic form of KRAS [Gene ID=3845] gene.

exact_source:
  AALE-KRAS vs AALE-Vector: top 150 genes (diff. of means). Similar to GSE17643: Broad KRAS internal signatures generated by J. Boehm.


systematic_name: M2893
source_species_code: HS
contributor: Pablo Tamayo
contrib_organization: Broad Institute
description_brief:
  Genes down-regulated in epithelial lung cancer cell lines over-expressing an oncogenic form of KRAS [Gene ID=3845] gene.

exact_source:
  AALE-KRAS vs AALE-Vector: bot 150 genes (diff. of means). Similar to GSE17643: Broad KRAS internal signatures generated by J. Boehm.


systematic_name: M2898
source_species_code: HS
contributor: Pablo Tamayo
contrib_organization: Broad Institute
description_brief:
  Genes down-regulated in epithelial breast cancer cell lines over-expressing an oncogenic form of  KRAS [Gene ID=3845 gene].

exact_source:
  AALE-KRAS vs AALE-Vector: top 300 genes (diff. of means). Similar to GSE17643: Broad KRAS internal signatures generated by J. Boehm.


systematic_name: M2901
source_species_code: HS
contributor: Pablo Tamayo
contrib_organization: Broad Institute
description_brief:
  Genes down-regulated in epithelial prostate cancer cell lines over-expressing an oncogenic form of KRAS [Gene ID=3845] gene.

exact_source:
  AALE-KRAS vs AALE-Vector: bot 150 genes (diff. of means). Similar to GSE17643: Broad KRAS internal signatures generated by J. Boehm.


systematic_name: M2902
source_species_code: HS
contributor: Pablo Tamayo
contrib_organization: Broad Institute
description_brief:
  Genes up-regulated in epithelial prostate cancer cell lines over-expressing an oncogenic form of KRAS [Gene ID=3845] gene.

exact_source:
  AALE-KRAS vs AALE-Vector: top 150 genes (diff. of means). Similar to GSE17643: Broad KRAS internal signatures generated by J. Boehm.


systematic_name: M10381
exact_source: Table 1S: kras-wt Down regulated genes
source_species_code: MM
contributor: Lauren Kazmierski
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in transformed NIH3T3 cells (fibroblasts transformed by activated KRAS [GeneID=3845]) vs normal cells.

description_full:
  Mutational activation of ras genes is required for the onset and maintenance of different malignancies. Here we show, using a combination of molecular physiology, nutritional perturbations and transcriptional profiling, that full penetrance of phenotypes related to oncogenic Ras activation, including the shift of carbon metabolism towards fermentation and upregulation of key cell cycle regulators, is dependent upon glucose availability. These responses are induced by Ras activation, being specifically reverted by downregulation of the Ras pathway obtained through the expression of a dominant-negative Ras-specific guanine nucleotide exchange protein. Our data allow to link directly to ras activation the alteration in energy metabolism of cancer cells, their fragility towards glucose shortage and ensuing apoptotic death.


systematic_name: M16842
exact_source: Table 1S: DN-wt Down regulated genes
source_species_code: MM
contributor: Lauren Kazmierski
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in reverted NIH3T3 cells (fibroblasts transformed by activated KRAS [GeneID=3845] which then reverted to normal cells upon stable over-expression of a dominant negative form of CDC25 [GeneID=5923]) vs normal fibroblasts.

description_full:
  Mutational activation of ras genes is required for the onset and maintenance of different malignancies. Here we show, using a combination of molecular physiology, nutritional perturbations and transcriptional profiling, that full penetrance of phenotypes related to oncogenic Ras activation, including the shift of carbon metabolism towards fermentation and upregulation of key cell cycle regulators, is dependent upon glucose availability. These responses are induced by Ras activation, being specifically reverted by downregulation of the Ras pathway obtained through the expression of a dominant-negative Ras-specific guanine nucleotide exchange protein. Our data allow to link directly to ras activation the alteration in energy metabolism of cancer cells, their fragility towards glucose shortage and ensuing apoptotic death.


systematic_name: M5686
exact_source: Table 1S
source_species_code: MM
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in MEF cells (embryonic fibroblasts) isolated from RB1 [GeneID=5925] knockout mice: chronic loss of function (LOF) of RB1.

description_full:
  Functional inactivation of the retinoblastoma tumor suppressor gene product (RB) is a common event in human cancers. Classically, RB functions to constrain cellular proliferation, and loss of RB is proposed to facilitate the hyperplastic proliferation associated with tumorigenesis. To understand the repertoire of regulatory processes governed by RB, two models of RB loss were utilized to perform microarray analysis. In murine embryonic fibroblasts harboring germline loss of RB, there was a striking deregulation of gene expression, wherein distinct biological pathways were altered. Specifically, genes involved in cell cycle control and classically associated with E2F-dependent gene regulation were upregulated via RB loss. In contrast, a program of gene expression associated with immune function and response to pathogens was significantly downregulated with the loss of RB. To determine the specific influence of RB loss during a defined period and without the possibility of developmental compensation as occurs in embryonic fibroblasts, a second system was employed wherein Rb was acutely knocked out in adult fibroblasts. This model confirmed the distinct regulation of cell cycle and immune modulatory genes through RB loss. Analyses of cis-elements supported the hypothesis that the majority of those genes upregulated with RB loss are regulated via the E2F family of transcription factors. In contrast, those genes whose expression was reduced with the loss of RB harbored different promoter elements. Consistent with these analyses, we found that disruption of E2F-binding function of RB was associated with the upregulation of gene expression. In contrast, cells harboring an RB mutant protein (RB-750F) that retains E2F-binding activity, but is specifically deficient in the association with LXCXE-containing proteins, failed to upregulate these same target genes. However, downregulation of genes involved in immune function was readily observed with disruption of the LXCXE-binding function of RB. Thus, these studies demonstrate that RB plays a significant role in both the positive and negative regulations of transcriptional programs and indicate that loss of RB has distinct biological effects related to both cell cycle control and immune function.


systematic_name: M15606
exact_source: Table 2S
source_species_code: MM
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in adult fibroblasts with inactivated RB1 [GeneID=5925] by Cre-lox: acute loss of function (LOF) of RB1.

description_full:
  Functional inactivation of the retinoblastoma tumor suppressor gene product (RB) is a common event in human cancers. Classically, RB functions to constrain cellular proliferation, and loss of RB is proposed to facilitate the hyperplastic proliferation associated with tumorigenesis. To understand the repertoire of regulatory processes governed by RB, two models of RB loss were utilized to perform microarray analysis. In murine embryonic fibroblasts harboring germline loss of RB, there was a striking deregulation of gene expression, wherein distinct biological pathways were altered. Specifically, genes involved in cell cycle control and classically associated with E2F-dependent gene regulation were upregulated via RB loss. In contrast, a program of gene expression associated with immune function and response to pathogens was significantly downregulated with the loss of RB. To determine the specific influence of RB loss during a defined period and without the possibility of developmental compensation as occurs in embryonic fibroblasts, a second system was employed wherein Rb was acutely knocked out in adult fibroblasts. This model confirmed the distinct regulation of cell cycle and immune modulatory genes through RB loss. Analyses of cis-elements supported the hypothesis that the majority of those genes upregulated with RB loss are regulated via the E2F family of transcription factors. In contrast, those genes whose expression was reduced with the loss of RB harbored different promoter elements. Consistent with these analyses, we found that disruption of E2F-binding function of RB was associated with the upregulation of gene expression. In contrast, cells harboring an RB mutant protein (RB-750F) that retains E2F-binding activity, but is specifically deficient in the association with LXCXE-containing proteins, failed to upregulate these same target genes. However, downregulation of genes involved in immune function was readily observed with disruption of the LXCXE-binding function of RB. Thus, these studies demonstrate that RB plays a significant role in both the positive and negative regulations of transcriptional programs and indicate that loss of RB has distinct biological effects related to both cell cycle control and immune function.


systematic_name: M1097
exact_source: Online supplement ME-ACells0PercFCS.xls
source_species_code: MM
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in ME-A cells (breast cancer) undergoing apoptosis upon serum starvation (5% to 0% FCS) for 22 hr.

description_full:
  Impairment of the complex regulatory network of cell death and survival is frequently the reason for therapy resistance of breast cancer cells and a major cause of tumor progression. We established two independent cell lines from a fast growing mouse breast tumor (WAP-SVT/t transgenic animal). Cells from one line (ME-A cells) are sensitive to apoptotic stimuli such as growth factor depletion or treatment with antitumor agents (e.g. doxorubicin). Cells from the second line (ME-C cells), which carry a missense mutation at the p53 codon 242, are very insensitive to apoptotic stimuli. Co-cultivation experiments revealed that the ME-C cells mediate cell death resistance to the ME-A cells. Microarray and Western blot analysis showed that osteopontin (OPN) is selectively overexpressed by the ME-C cells. This glycoprotein is the most abundant protein secreted by the ME-C cells and we obtained strong indications that OPN is the main antiapoptotic factor. However, the OPN containing ME-C cell medium does not alter the expression level of pro- or antiapoptotic genes or known inhibitors of apoptosis (IAPs). Its signaling involves mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase (MEK)1/2 as the kinase inhibitor PD98059 restores apoptosis but not the Akt inhibitor. In the ME-A cells, mitochondrial cytochrome c release occurs with and without external apoptotic stimuli. OPN containing ME-C cell medium does not prevent the mitochondrial cytochrome c release and caspase-9 processing. In serum starved ME-A cells, the OPN containing ME-C cell medium prevents caspase-3 activation. However, in doxorubicin-treated cells, although apoptosis is blocked, it does not inhibit caspase-3. This indicates that the ME-A cells distinguish between the initial apoptotic stimuli and that the cells possess a further uncharacterized control element acting downstream from caspase-3.


systematic_name: M1099
exact_source: Online supplement ME-ACells0PercFCSAndMC.xls
source_species_code: MM
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in ME-A cells (breast cancer, sensitive to apoptotic stimuli) upon serum deprivation for 22 hr in the presence of medium concentrate (MC) from ME-C cells (breast cancer, resistant to apoptotic stimuli).

description_full:
  Impairment of the complex regulatory network of cell death and survival is frequently the reason for therapy resistance of breast cancer cells and a major cause of tumor progression. We established two independent cell lines from a fast growing mouse breast tumor (WAP-SVT/t transgenic animal). Cells from one line (ME-A cells) are sensitive to apoptotic stimuli such as growth factor depletion or treatment with antitumor agents (e.g. doxorubicin). Cells from the second line (ME-C cells), which carry a missense mutation at the p53 codon 242, are very insensitive to apoptotic stimuli. Co-cultivation experiments revealed that the ME-C cells mediate cell death resistance to the ME-A cells. Microarray and Western blot analysis showed that osteopontin (OPN) is selectively overexpressed by the ME-C cells. This glycoprotein is the most abundant protein secreted by the ME-C cells and we obtained strong indications that OPN is the main antiapoptotic factor. However, the OPN containing ME-C cell medium does not alter the expression level of pro- or antiapoptotic genes or known inhibitors of apoptosis (IAPs). Its signaling involves mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase (MEK)1/2 as the kinase inhibitor PD98059 restores apoptosis but not the Akt inhibitor. In the ME-A cells, mitochondrial cytochrome c release occurs with and without external apoptotic stimuli. OPN containing ME-C cell medium does not prevent the mitochondrial cytochrome c release and caspase-9 processing. In serum starved ME-A cells, the OPN containing ME-C cell medium prevents caspase-3 activation. However, in doxorubicin-treated cells, although apoptosis is blocked, it does not inhibit caspase-3. This indicates that the ME-A cells distinguish between the initial apoptotic stimuli and that the cells possess a further uncharacterized control element acting downstream from caspase-3.


systematic_name: M1103
exact_source: Online supplement ME-ACellsDoxorubicin.xls
source_species_code: MM
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in ME-A cells (breast cancer) undergoing apoptosis in response to doxorubicin [PubChem=31703].

description_full:
  Impairment of the complex regulatory network of cell death and survival is frequently the reason for therapy resistance of breast cancer cells and a major cause of tumor progression. We established two independent cell lines from a fast growing mouse breast tumor (WAP-SVT/t transgenic animal). Cells from one line (ME-A cells) are sensitive to apoptotic stimuli such as growth factor depletion or treatment with antitumor agents (e.g. doxorubicin). Cells from the second line (ME-C cells), which carry a missense mutation at the p53 codon 242, are very insensitive to apoptotic stimuli. Co-cultivation experiments revealed that the ME-C cells mediate cell death resistance to the ME-A cells. Microarray and Western blot analysis showed that osteopontin (OPN) is selectively overexpressed by the ME-C cells. This glycoprotein is the most abundant protein secreted by the ME-C cells and we obtained strong indications that OPN is the main antiapoptotic factor. However, the OPN containing ME-C cell medium does not alter the expression level of pro- or antiapoptotic genes or known inhibitors of apoptosis (IAPs). Its signaling involves mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase (MEK)1/2 as the kinase inhibitor PD98059 restores apoptosis but not the Akt inhibitor. In the ME-A cells, mitochondrial cytochrome c release occurs with and without external apoptotic stimuli. OPN containing ME-C cell medium does not prevent the mitochondrial cytochrome c release and caspase-9 processing. In serum starved ME-A cells, the OPN containing ME-C cell medium prevents caspase-3 activation. However, in doxorubicin-treated cells, although apoptosis is blocked, it does not inhibit caspase-3. This indicates that the ME-A cells distinguish between the initial apoptotic stimuli and that the cells possess a further uncharacterized control element acting downstream from caspase-3.


systematic_name: M1105
exact_source: Online supplement ME-ACellsDoxorubicin.xls
source_species_code: MM
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in ME-A cells (breast cancer) undergoing apoptosis in response to doxorubicin [PubChem=31703].

description_full:
[cell repeats an earlier one in this file: 1918 characters]


systematic_name: M1106
exact_source: Online supplement ME-ACellsDoxorubicinAndMC.xls
source_species_code: MM
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in ME-A cells (breast cancer, sensitive to apoptotic stimuli) exposed to doxorubicin [PubChem=31703] in the presence of medium concentrate (MC) from ME-C cells (breast cancer, resistant to apoptotic stimuli).

description_full:
[cell repeats an earlier one in this file: 1918 characters]


systematic_name: M1107
exact_source: Online supplement ME-ACellsDoxorubicinAndMC.xls
source_species_code: MM
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in ME-A cells (breast cancer, sensitive to apoptotic stimuli) exposed to doxorubicin [PubChem=31703] in the presence of medium concentrate (MC) from ME-C cells (breast cancer, resistant to apoptotic stimuli).

description_full:
[cell repeats an earlier one in this file: 1918 characters]


systematic_name: M8544
exact_source: Table FS
source_species_code: MM
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Up-regualted genes from the set F (Fig. 5a): specific signature shared by cells expressing AF4-MLL [GeneID=4299;4297] alone and those expressing both AF4-MLL and MLL-AF4 fusion proteins.

description_full:
  The reciprocal chromosomal translocation t(4;11) is correlated with infant, childhood, adult and therapy-related high-risk acute leukemia. Here, we investigated the biological effects of MLL.AF4, AF4.MLL or the combination of both reciprocal fusion proteins in a conditional in vitro cell culture model system. Several parameters like cell growth, cell cycling capacity, apoptotic behavior and growth transformation were investigated under physiological and stress conditions. Co-transfected cells displayed the highest resistance against apoptotic triggers, cell cycling capacity and loss-of-contact inhibition. These analyses were complemented by gene expression profiling experiments and specific gene signatures were established for each of the three cell lines. Interestingly, co-transfected cells strongly upregulate the homeobox gene Nanog. In combination with Oct4, the Nanog homeoprotein is steering maintenance of pluripotency and self-renewal in embryonic stem cells. Transcription of Nanog and other stem cell factors, like Oct4 and Bmi1, was verified in biopsy material of t(4;11) patient cells which express both reciprocal t(4;11) fusion genes. In conclusion, the presence of both reciprocal MLL fusion proteins confers biological properties known from t(4;11) leukemia, suggesting that each of the two fusion proteins contribute specific properties and, in combination, also synergistic effects to the leukemic phenotype.


systematic_name: M18095
exact_source: Table GS
source_species_code: MM
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Up-regulated genes from the set G (Fig. 5a): specific to cells expressing both MLL-AF4 [GeneID=4297;4299] and AF4-MLL fusion proteins.

description_full:
  The reciprocal chromosomal translocation t(4;11) is correlated with infant, childhood, adult and therapy-related high-risk acute leukemia. Here, we investigated the biological effects of MLL.AF4, AF4.MLL or the combination of both reciprocal fusion proteins in a conditional in vitro cell culture model system. Several parameters like cell growth, cell cycling capacity, apoptotic behavior and growth transformation were investigated under physiological and stress conditions. Co-transfected cells displayed the highest resistance against apoptotic triggers, cell cycling capacity and loss-of-contact inhibition. These analyses were complemented by gene expression profiling experiments and specific gene signatures were established for each of the three cell lines. Interestingly, co-transfected cells strongly upregulate the homeobox gene Nanog. In combination with Oct4, the Nanog homeoprotein is steering maintenance of pluripotency and self-renewal in embryonic stem cells. Transcription of Nanog and other stem cell factors, like Oct4 and Bmi1, was verified in biopsy material of t(4;11) patient cells which express both reciprocal t(4;11) fusion genes. In conclusion, the presence of both reciprocal MLL fusion proteins confers biological properties known from t(4;11) leukemia, suggesting that each of the two fusion proteins contribute specific properties and, in combination, also synergistic effects to the leukemic phenotype.


systematic_name: M7514
exact_source: Table 1S: RhoA Fold change < 1 (blue)
source_species_code: MM
GEO_id: GSE5913
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in NIH3T3 cells (fibroblasts) transformed by  expression of contitutively active (Q63L) form of RHOA [GeneID=387] off plasmid vector.

description_full:
  We have used microarray technology to identify the transcriptional targets of Rho subfamily guanosine 5'-triphosphate (GTP)ases in NIH3T3 cells. This analysis indicated that murine fibroblasts transformed by these proteins show similar transcriptomal profiles. Functional annotation of the regulated genes indicate that Rho subfamily GTPases target a wide spectrum of functions, although loci encoding proteins linked to proliferation and DNA synthesis/transcription are upregulated preferentially. Rho proteins promote four main networks of interacting proteins nucleated around E2F, c-Jun, c-Myc and p53. Of those, E2F, c-Jun and c-Myc are essential for the maintenance of cell transformation. Inhibition of Rock, one of the main Rho GTPase targets, leads to small changes in the transcriptome of Rho-transformed cells. Rock inhibition decreases c-myc gene expression without affecting the E2F and c-Jun pathways. Loss-of-function studies demonstrate that c-Myc is important for the blockage of cell-contact inhibition rather than for promoting the proliferation of Rho-transformed cells. However, c-Myc overexpression does not bypass the inhibition of cell transformation induced by Rock blockage, indicating that c-Myc is essential, but not sufficient, for Rock-dependent transformation. These results reveal the complexity of the genetic program orchestrated by the Rho subfamily and pinpoint protein networks that mediate different aspects of the malignant phenotype of Rho-transformed cells.


description_brief: Genes up-regulated during pubertal mammary gland development between weeks 3 and 4.
systematic_name: M13186
exact_source: Table 1S: week 3 to 4 = I
source_species_code: MM
GEO_id: GSE6453
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_full:
  Expression microarray analysis identified over 930 genes regulated during puberty in the mouse mammary gland. Most prominent were genes whose expression increased in parallel with pubertal development and remained high thereafter. Members of the Wnt, transforming growth factor-beta and oestrogen-signalling pathways were significantly overrepresented. Comparison to expression data from CITED1 knockout mice identified a subset of oestrogen-responsive genes displaying altered expression in the absence of CITED1. Included in this subset are stanniocalcin2 (Stc2) and amphiregulin (Areg). Chromatin immunoprecipitation revealed that ERalpha binds to oestrogen response elements in both the Stc2 and Areg genes in the mammary gland during puberty. Additionally, CITED1 and ERalpha localize to the same epithelial cells of the pubertal mammary gland, supporting a role for interaction of these two proteins during normal development. In a human breast cancer data set, expression of Stc2, Areg and CITED1 parallel that of ERalpha. Similar to ERalpha, CITED1 expression correlates with good outcome in breast cancer, implying that potential maintenance of the ERalpha-CITED1 co-regulated signalling pathway in breast tumours can indicate good prognosis.


systematic_name: M1129
exact_source: Fig 2B
source_species_code: MM
GEO_id: GSE6453
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  The 'TEB profile genes': up-regulated during pubertal mammary gland development specifically in the TEB (terminal end bud) structures.

description_full:
[cell repeats an earlier one in this file: 1251 characters]


systematic_name: M1560
exact_source: Supplementary Table A: cluster 6
source_species_code: MM
GEO_id: GSE2118
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Cluster 6: late responding genes activated in ATM [GeneID=472] deficient but not in the wild type tissues.

description_full:
  The ATM protein kinase, functionally missing in patients with the human genetic disorder ataxia-telangiectasia, is a master regulator of the cellular network induced by DNA double-strand breaks. The ATM gene is also frequently mutated in sporadic cancers of lymphoid origin. Here, we applied a functional genomics approach that combined gene expression profiling and computational promoter analysis to obtain global dissection of the transcriptional response to ionizing radiation in murine lymphoid tissue. Cluster analysis revealed a prominent pattern characterizing dozens of genes whose response to irradiation was Atm-dependent. Computational analysis identified significant enrichment of the binding site signatures of NF-kappaB and p53 among promoters of these genes, pointing to the major role of these two transcription factors in mediating the Atm-dependent transcriptional response in the irradiated lymphoid tissue. Examination of the response showed that pro- and antiapoptotic signals were simultaneously induced, with the proapoptotic pathway mediated by p53 targets, and the prosurvival pathway by NF-kappaB targets. These findings further elucidate the molecular network induced by IR, point to novel putative NF-kappaB targets, and suggest a mechanistic model for cellular balancing between pro- and antiapoptotic signals induced by IR in lymphoid tissues, which has implications for cancer management. The emerging model suggests that restoring the p53-mediated apoptotic arm while blocking the NF-kappaB-mediated prosurvival arm could effectively increase the radiosensitivity of lymphoid tumors.


description_brief: Genes down-regulated in non-apoptotic tissues (fetal liver) after MDM4 [GeneID=4194] knockout.
systematic_name: M3395
exact_source: Table 1S: N. Neur = D
source_species_code: MM
GEO_id: E-MEXP-155
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_full:
  The p53 tumour suppressor functions as a transcriptional activator, and several p53-inducible genes that play a critical proapoptotic role have been described. Moreover, p53 regulates the expression of various proteins participating in autoregulatory feedback loops, including proteins that negatively control p53 stability (Mdm2 and Pirh2) or modulate stress-induced phosphorylation of p53 on Ser-46 (p53DINP1 or Wip1), a key event for p53-induced apoptosis. Here, we describe a new systematic analysis of p53 targets using oligonucleotide chips, and report the identification of dapk1 as a novel p53 target. We demonstrate that dapk1 mRNA levels increase in a p53-dependent manner in various cellular settings. Both human and mouse dapk1 genomic loci contain DNA sequences that bind p53 in vitro and in vivo. Since dapk1 encodes a serine/threonine kinase previously shown to suppress oncogene-induced transformation by activating a p19ARF/p53-dependent apoptotic checkpoint, our results suggest that Dapk1 participates in a new positive feedback loop controlling p53 activation and apoptosis.


systematic_name: M1273
exact_source: Table 1S
source_species_code: MM
GEO_id: GSE2127
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Cluster PAM1: genes up-regulated in hepatocellular carcinoma (HCC) vs normal liver tissue from mice deficient for TXNIP [GeneID=10628].

description_full:
  The molecular pathogenesis and the genetic aberrations that lead to the progression of hepatocellular carcinoma (HCC) are largely unknown. Here, we demonstrate that the thioredoxin interacting protein (Txnip) gene is a candidate tumor suppressor gene in vivo. We previously showed that the recombinant inbred congenic strain HcB-19 has a spontaneous mutation of the Txnip gene, and we now show that the strain has dramatically increased incidence of HCC, and that the HCC cosegregates with the Txnip mutation. Approximately 40% of the Txnip-deficient mice developed hepatic tumors with an increased prevalence in male mice. Visible tumors develop as early as 8 months of age. Histological analysis confirmed the morphology of HCC in the Txnip-deficient mice. Molecular markers of HCC, alpha-fetoprotein and p53, were increased in tumors of Txnip-deficient mice. The upregulation of p53 preceded tumor development; however, bromodeoxyuridine (BrdU) labeling of normal hepatic tissue of Txnip-deficient mice did not reveal increased cell proliferation. Finally, microarray analyses of tumor, non-tumor adjacent, and normal tissue of Txnip-deficient mice highlighted the genetic differences leading to the predisposition and onset of HCC. Our findings suggest that Txnip deficiency is sufficient to initiate HCC and suggest novel mechanisms in hepatocarcinogenesis.


systematic_name: M1347
exact_source: Table 1S: logFC < 0
source_species_code: MM
GEO_id: GSE12077
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in the urogenital sinus (UGS) of day E16 females exposed to the androgen dihydrotestosterone [PubChem=10635] for 6 h.

description_full:
  Cancer cells differentiate along specific lineages that largely determine their clinical and biologic behavior. Distinct cancer phenotypes from different cells and organs likely result from unique gene expression repertoires established in the embryo and maintained after malignant transformation. We used comprehensive gene expression analysis to examine this concept in the prostate, an organ with a tractable developmental program and a high propensity for cancer. We focused on gene expression in the murine prostate rudiment at three time points during the first 48 h of exposure to androgen, which initiates proliferation and invasion of prostate epithelial buds into surrounding urogenital sinus mesenchyme. Here, we show that androgen exposure regulates genes previously implicated in prostate carcinogenesis comprising pathways for the phosphatase and tensin homolog (PTEN), fibroblast growth factor (FGF)/mitogen-activated protein kinase (MAPK), and Wnt signaling along with cellular programs regulating such 'hallmarks' of cancer as angiogenesis, apoptosis, migration and proliferation. We found statistically significant evidence for novel androgen-induced gene regulation events that establish and/or maintain prostate cell fate. These include modulation of gene expression through microRNAs, expression of specific transcription factors, and regulation of their predicted targets. By querying public gene expression databases from other tissues, we found that rather than generally characterizing androgen exposure or epithelial budding, the early prostate development program more closely resembles the program for human prostate cancer. Most importantly, early androgen-regulated genes and functional themes associated with prostate development were highly enriched in contrasts between increasingly lethal forms of prostate cancer, confirming a 'reactivation' of embryonic pathways for proliferation and invasion in prostate cancer progression. Among the genes with the most significant links to the development and cancer, we highlight coordinate induction of the transcription factor Sox9 and suppression of the proapoptotic phospholipid-binding protein Annexin A1 that link early prostate development to early prostate carcinogenesis. These results credential early prostate development as a reliable and valid model system for the investigation of genes and pathways that drive prostate cancer.


systematic_name: M1348
exact_source: Table 2S: logFC > 0
source_species_code: MM
GEO_id: GSE12077
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in the urogenital sinus (UGS) of day E16 females exposed to the androgen dihydrotestosterone [PubChem=10635] for 12 h.

description_full:
  Cancer cells differentiate along specific lineages that largely determine their clinical and biologic behavior. Distinct cancer phenotypes from different cells and organs likely result from unique gene expression repertoires established in the embryo and maintained after malignant transformation. We used comprehensive gene expression analysis to examine this concept in the prostate, an organ with a tractable developmental program and a high propensity for cancer. We focused on gene expression in the murine prostate rudiment at three time points during the first 48 h of exposure to androgen, which initiates proliferation and invasion of prostate epithelial buds into surrounding urogenital sinus mesenchyme. Here, we show that androgen exposure regulates genes previously implicated in prostate carcinogenesis comprising pathways for the phosphatase and tensin homolog (PTEN), fibroblast growth factor (FGF)/mitogen-activated protein kinase (MAPK), and Wnt signaling along with cellular programs regulating such 'hallmarks' of cancer as angiogenesis, apoptosis, migration and proliferation. We found statistically significant evidence for novel androgen-induced gene regulation events that establish and/or maintain prostate cell fate. These include modulation of gene expression through microRNAs, expression of specific transcription factors, and regulation of their predicted targets. By querying public gene expression databases from other tissues, we found that rather than generally characterizing androgen exposure or epithelial budding, the early prostate development program more closely resembles the program for human prostate cancer. Most importantly, early androgen-regulated genes and functional themes associated with prostate development were highly enriched in contrasts between increasingly lethal forms of prostate cancer, confirming a 'reactivation' of embryonic pathways for proliferation and invasion in prostate cancer progression. Among the genes with the most significant links to the development and cancer, we highlight coordinate induction of the transcription factor Sox9 and suppression of the proapoptotic phospholipid-binding protein Annexin A1 that link early prostate development to early prostate carcinogenesis. These results credential early prostate development as a reliable and valid model system for the investigation of genes and pathways that drive prostate cancer.


systematic_name: M1350
exact_source: Table 3S: logFC > 0
source_species_code: MM
GEO_id: GSE12077
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in the urogenital sinus (UGS) of day E16 females exposed to the androgen dihydrotestosterone [PubChem=10635] for 48 h.

description_full:
  Cancer cells differentiate along specific lineages that largely determine their clinical and biologic behavior. Distinct cancer phenotypes from different cells and organs likely result from unique gene expression repertoires established in the embryo and maintained after malignant transformation. We used comprehensive gene expression analysis to examine this concept in the prostate, an organ with a tractable developmental program and a high propensity for cancer. We focused on gene expression in the murine prostate rudiment at three time points during the first 48 h of exposure to androgen, which initiates proliferation and invasion of prostate epithelial buds into surrounding urogenital sinus mesenchyme. Here, we show that androgen exposure regulates genes previously implicated in prostate carcinogenesis comprising pathways for the phosphatase and tensin homolog (PTEN), fibroblast growth factor (FGF)/mitogen-activated protein kinase (MAPK), and Wnt signaling along with cellular programs regulating such 'hallmarks' of cancer as angiogenesis, apoptosis, migration and proliferation. We found statistically significant evidence for novel androgen-induced gene regulation events that establish and/or maintain prostate cell fate. These include modulation of gene expression through microRNAs, expression of specific transcription factors, and regulation of their predicted targets. By querying public gene expression databases from other tissues, we found that rather than generally characterizing androgen exposure or epithelial budding, the early prostate development program more closely resembles the program for human prostate cancer. Most importantly, early androgen-regulated genes and functional themes associated with prostate development were highly enriched in contrasts between increasingly lethal forms of prostate cancer, confirming a 'reactivation' of embryonic pathways for proliferation and invasion in prostate cancer progression. Among the genes with the most significant links to the development and cancer, we highlight coordinate induction of the transcription factor Sox9 and suppression of the proapoptotic phospholipid-binding protein Annexin A1 that link early prostate development to early prostate carcinogenesis. These results credential early prostate development as a reliable and valid model system for the investigation of genes and pathways that drive prostate cancer.


systematic_name: M1351
exact_source: Table 3S: logFC < 0
source_species_code: MM
GEO_id: GSE12077
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in the urogenital sinus (UGS) of day E16 females exposed to the androgen dihydrotestosterone [PubChem=10635] for 48 h.

description_full:
[cell repeats an earlier one in this file: 2415 characters]


systematic_name: M6510
exact_source: Table 2S: Z score > 0
source_species_code: MM
GEO_id: GSE9249
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in post-GC, BCL6 [GeneID=604] dependent B cell non-Hodgkin's lymphoma (B-NHL) vs MYC [GeneID=4609] driven pre-GC lymphoma.

description_full:
  Most human B cell non-Hodgkin's lymphomas (B-NHLs) derive from germinal centers (GCs), the structure in which B cells undergo somatic hypermutation (SHM) and class switch recombination (CSR) before being selected for high-affinity antibody production. The pathogenesis of B-NHL is associated with distinct genetic lesions, including chromosomal translocations and aberrant SHM, which arise from mistakes occurring during CSR and SHM. A direct link between these DNA remodeling events and GC lymphoma development, however, has not been demonstrated. Here we have crossed three mouse models of B cell lymphoma driven by oncogenes (Myc, Bcl6 and Myc/Bcl6; refs. 5,6) with mice lacking activation-induced cytidine deaminase (AID), the enzyme required for both CSR and SHM. We show that AID deficiency prevents Bcl6-dependent, GC-derived B-NHL, but has no impact on Myc-driven, pre-GC lymphomas. Accordingly, abrogation of AID is associated with the disappearance of CSR- and SHM-mediated structural alterations. These results show that AID is required for GC-derived lymphomagenesis, supporting the notion that errors in AID-mediated antigen-receptor gene modification processes are principal contributors to the pathogenesis of human B-NHL.


systematic_name: M10914
exact_source: Table 1S: PFC down
source_species_code: MM
GEO_id: GSE10784
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in prefrontal cortex (PFC) of mice carrying a hemizygotic microdeletion in the 22q11.2 region.

description_full:
  Individuals with 22q11.2 microdeletions show behavioral and cognitive deficits and are at high risk of developing schizophrenia. We analyzed an engineered mouse strain carrying a chromosomal deficiency spanning a segment syntenic to the human 22q11.2 locus. We uncovered a previously unknown alteration in the biogenesis of microRNAs (miRNAs) and identified a subset of brain miRNAs affected by the microdeletion. We provide evidence that the abnormal miRNA biogenesis emerges because of haploinsufficiency of the Dgcr8 gene, which encodes an RNA-binding moiety of the 'microprocessor' complex and contributes to the behavioral and neuronal deficits associated with the 22q11.2 microdeletion.


systematic_name: M2388
exact_source: Table 3S
source_species_code: MM
GEO_id: GSE2031
contributor: Jean Junior
contrib_organization: MSigDB Team
description_brief:
  Transcripts in hematopoietic stem cells (HSC) which are trans-regulated (i.e., modulated by a QTL (quantitative trait locus) not in a close proximity to the gene).

description_full:
  We combined large-scale mRNA expression analysis and gene mapping to identify genes and loci that control hematopoietic stem cell (HSC) function. We measured mRNA expression levels in purified HSCs isolated from a panel of densely genotyped recombinant inbred mouse strains. We mapped quantitative trait loci (QTLs) associated with variation in expression of thousands of transcripts. By comparing the physical transcript position with the location of the controlling QTL, we identified polymorphic cis-acting stem cell genes. We also identified multiple trans-acting control loci that modify expression of large numbers of genes. These groups of coregulated transcripts identify pathways that specify variation in stem cells. We illustrate this concept with the identification of candidate genes involved with HSC turnover. We compared expression QTLs in HSCs and brain from the same mice and identified both shared and tissue-specific QTLs. Our data are accessible through WebQTL, a web-based interface that allows custom genetic linkage analysis and identification of coregulated transcripts.


description_brief: Genes defining differentiation potential of the bipotential myeloid cell line FDB.
systematic_name: M1430
exact_source: Table 3S
source_species_code: MM
GEO_id: GSE3333
contributor: Kevin Vogelsang
contrib_organization: MSigDB Team
description_full:
  Mechanisms controlling the balance between proliferation and self-renewal versus growth suppression and differentiation during normal and leukemic myelopoiesis are not understood. We have used the bi-potent FDB1 myeloid cell line model, which is responsive to myelopoietic cytokines and activated mutants of the granulocyte macrophage-colony stimulating factor (GM-CSF) receptor, having differential signaling and leukemogenic activity. This model is suited to large-scale gene-profiling, and we have used a factorial time-course design to generate a substantial and powerful data set. Linear modeling was used to identify gene-expression changes associated with continued proliferation, differentiation, or leukemic receptor signaling. We focused on the changing transcription factor profile, defined a set of novel genes with potential to regulate myeloid growth and differentiation, and demonstrated that the FDB1 cell line model is responsive to forced expression of oncogenes identified in this study. We also identified gene-expression changes associated specifically with the leukemic GM-CSF receptor mutant, V449E. Signaling from this receptor mutant down-regulates CCAAT/enhancer-binding protein alpha (C/EBPalpha) target genes and generates changes characteristic of a specific acute myeloid leukemia signature, defined previously by gene-expression profiling and associated with C/EBPalpha mutations.


description_brief: Genes up-regulated in adipose tissue from obese mouse strains compared to the lean ones.
systematic_name: M1431
exact_source: Table 2
source_species_code: MM
GEO_id: GSE2952
contributor: Kevin Vogelsang
contrib_organization: MSigDB Team
description_full:
  Obesity is strongly correlated with type 2 diabetes mellitus, a common disorder of glucose and lipid metabolism. Although adipocytes are critical in obesity, their role in diabetes has only recently been appreciated. We conducted studies by using DNA microarrays to identify differences in gene expression in adipose tissue from lean, obese, and obese-diabetic mice. The expression level of over 11,000 transcripts was analyzed, and 214 transcripts showed significant differences between lean and obese mice. Surprisingly, the expression of genes normally associated with adipocyte differentiation were down-regulated in obesity. Not all obese individuals will become diabetic; many remain normoglycemic despite profound obesity. Understanding the transition to obesity with concomitant diabetes will provide important clues to the pathogenesis of type 2 diabetes. Therefore, we examined the levels of gene expression in adipose tissue from five groups of obese mice with varying degrees of hyperglycemia, and we identified 88 genes whose expression strongly correlated with diabetes severity. This group included many genes that are known to be involved in signal transduction and energy metabolism as well as genes not previously examined in the context of diabetes. Our data show that a decrease in expression of genes normally involved in adipogenesis is associated with obesity, and we further identify genes important for subsequent development of type 2 diabetes mellitus.


description_brief: Genes changed between developmental stages of Valpha14i natural killer T lymphocyte cells (NKT).
systematic_name: M18517
exact_source: Table 1S
source_species_code: MM
contributor: Kevin Vogelsang
contrib_organization: MSigDB Team
description_full:
  Valpha14i natural killer T (NKT)-cell function has been implicated in a number of disease conditions. The molecular events that drive Valpha14i NKT-cell development remain elusive. We recently showed that T-bet is required for the terminal maturation of these cells. Here we identify some of the genetic targets of T-bet during Valpha14i NKT-cell lineage development. Microarray gene-expression analyses on developing Valpha14i NKT cells were performed and provide a molecular framework to study these maturation events. In vitro ectopic expression of T-bet in immature Valpha14i NKT cells, which do not yet express T-bet, was sufficient to promote Valpha14i NKT-cell maturation, driving the expression of multiple genes, including those that participate in migration, survival, and effector functions. By regulating the expression of T-helper 1 (Th1)-associated cytokines, chemokines, chemokine receptors, and molecules involved in cytolysis, T-bet defines the unique lineage attributes of mature Valpha14i NKT cells and acts to link these attributes to a developmental process.


systematic_name: M14829
exact_source: Table 2S
source_species_code: MM
contributor: Kevin Vogelsang
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in hematopoietic precursor cells conditionally expressing HOXA9 and MEIS1 [GeneID=3205;4211].

description_full:
  Abdominal-type HoxA genes in combination with Meis1 are well-documented on-cogenes in various leukemias but it is unclear how they exert their transforming function. Here we used a system of conditional transformation by an inducible mixed lineage leukemia-eleven-nineteen leukemia (MLL-ENL) oncoprotein to overexpress Hoxa9 and Meis1 in primary hematopoietic cells. Arrays identified c-Myb and a c-Myb target (Gstm1) among the genes with the strongest response to Hoxa9/Meis1. c-Myb overexpression was verified by Northern blot and quantitative reverse transcription-polymerase chain reaction (RT-PCR). Also MLL-ENL activated c-Myb through up-regulation of Hoxa9 and Meis1. Consequently, short-term suppression of c-Myb by small inhibitory RNA (siRNA) efficiently inhibited transformation by MLL-ENL but did not impair transformation by transcription factor E2A-hepatic leukemia factor (E2A-HLF). The anti c-Myb siRNA effect was abrogated by coexpression of a c-Myb derivative with a mutated siRNA target site. The introduction of a dominant-negative c-Myb mutant had a similar but weaker effect on MLL-ENL-mediated transformation. Hematopoietic precursors from mice homozygous for a hypo-morphic c-Myb allele were more severely affected and could be transformed neither by MLL-ENL nor by E2A-HLF. Ectopic expression of c-Myb induced a differentiation block but c-Myb alone was not transforming in a replating assay similar to Hoxa9/Meis1. These results suggest that c-Myb is essential but not sufficient for Hoxa9/Meis1 mediated transformation.


systematic_name: M1484
exact_source: Table 1S
source_species_code: MM
contributor: Kevin Vogelsang
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in pancreatic cells from mice with double knockout of E2F1 [GeneID=1869] and E2F2 [GeneID=1870] compared to wild type.

description_full:
  E2F transcription factors are thought to be key regulators of cell growth control. Here we use mutant mouse strains to investigate the function of E2F1 and E2F2 in vivo. E2F1/E2F2 compound-mutant mice develop nonautoimmune insulin-deficient diabetes and exocrine pancreatic dysfunction characterized by endocrine and exocrine cell dysplasia, a reduction in the number and size of acini and islets, and their replacement by ductal structures and adipose tissue. Mutant pancreatic cells exhibit increased rates of DNA replication but also of apoptosis, resulting in severe pancreatic atrophy. The expression of genes involved in DNA replication and cell cycle control was upregulated in the E2F1/E2F2 compound-mutant pancreas, suggesting that their expression is repressed by E2F1/E2F2 activities and that the inappropriate cell cycle found in the mutant pancreas is likely the result of the deregulated expression of these genes. Interestingly, the expression of ductal cell and adipocyte differentiation marker genes was also upregulated, whereas expression of pancreatic cell marker genes were downregulated. These results suggest that E2F1/E2F2 activity negatively controls growth of mature pancreatic cells and is necessary for the maintenance of differentiated pancreatic phenotypes in the adult.


systematic_name: M3284
exact_source: Table 1S
source_species_code: MM
contributor: Kevin Vogelsang
contrib_organization: MSigDB Team
description_brief:
  Myeloid leukemia model in mice with germ-line MLL-AF9 fusion knock-in [GeneID=4297;4300]: genes changed in comparison among the leukemic, preleukemic and wild-type animals.

description_full:
  Identification of the targets of mixed lineage leukemia (MLL) fusion genes will assist in understanding the biology of MLL fusion gene leukemias and in development of better therapies. Numerous studies have implicated HOXA9 as one of the possible targets of MLL fusion proteins. To determine if HOXA9 was required for leukemia development by MLL fusion genes, we compared the effects of the Mll-AF9 knock-in mutation in mice in the presence or absence of Hoxa9. Both groups of mice showed myeloid expansion at 8 weeks and then developed myeloid leukemia with a similar incidence and time course. The leukemia in the mice lacking Hoxa9 generally displayed a more immature myeloid phenotype than that in the mice that were wild-type for Hoxa9. Gene expression profiling revealed that expression of Mll-AF9 led to overexpression of Hoxa5, Hoxa6, Hoxa7, Hoxa9, and Hoxa10. Thus, genes of the Hox-a cluster are important in defining the phenotype but not the incidence of Mll-AF9 leukemia. These results demonstrate that the Mll-AF9 fusion gene disrupts the expression of several Hox genes, none of which as a single gene is likely to be necessary for development of leukemia. Instead, we propose that the Hox code minimally defined by the Hoxa5-a9 cluster is central to MLL leukemogenesis.


systematic_name: M1606
exact_source: Excel Table 2S: Expression Cluster=Early Progenitors Shared
source_species_code: MM
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Genes in the expression cluster 'Early Progenitors Shared': up-regulated in hematopoietic progenitors from adult bone marrow and from fetal liver.

description_full:
  Mechanisms regulating self-renewal and cell fate decisions in mammalian stem cells are poorly understood. We determined global gene expression profiles for mouse and human hematopoietic stem cells and other stages of the hematopoietic hierarchy. Murine and human hematopoietic stem cells share a number of expressed gene products, which define key conserved regulatory pathways in this developmental system. Moreover, in the mouse, a portion of the genetic program of hematopoietic stem cells is shared with embryonic and neural stem cells. This overlapping set of gene products represents a molecular signature of stem cells.


systematic_name: M11166
exact_source: Excel Table 2S: Expression Cluster=Late Progenitors Shared
source_species_code: MM
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Genes in the expression cluster 'Late Progenitors Shared': up-regulated in hematopoietic late progenitor cells from adult bone marrow and fetal liver.

description_full:
  Mechanisms regulating self-renewal and cell fate decisions in mammalian stem cells are poorly understood. We determined global gene expression profiles for mouse and human hematopoietic stem cells and other stages of the hematopoietic hierarchy. Murine and human hematopoietic stem cells share a number of expressed gene products, which define key conserved regulatory pathways in this developmental system. Moreover, in the mouse, a portion of the genetic program of hematopoietic stem cells is shared with embryonic and neural stem cells. This overlapping set of gene products represents a molecular signature of stem cells.


systematic_name: M16407
exact_source: Excel Table 2S: Expression Cluster=LT-HSC Shared
source_species_code: MM
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Genes in the expression cluster 'LT-HSC Shared': up-regulated in long term hematopoietic stem cells (LT-HSC) from adult bone marrow and fetal liver.

description_full:
  Mechanisms regulating self-renewal and cell fate decisions in mammalian stem cells are poorly understood. We determined global gene expression profiles for mouse and human hematopoietic stem cells and other stages of the hematopoietic hierarchy. Murine and human hematopoietic stem cells share a number of expressed gene products, which define key conserved regulatory pathways in this developmental system. Moreover, in the mouse, a portion of the genetic program of hematopoietic stem cells is shared with embryonic and neural stem cells. This overlapping set of gene products represents a molecular signature of stem cells.


description_brief: Genes depleted in embryonic, neural and hematopoietic stem cells.
systematic_name: M12763
exact_source: Supll. Database
source_species_code: MM
contributor: John Newman
contrib_organization: University of Washington
description_full:
  The transcriptional profiles of mouse embryonic, neural, and hematopoietic stem cells were compared to define a genetic program for stem cells. A total of 216 genes are enriched in all three types of stem cells, and several of these genes are clustered in the genome. When compared to differentiated cell types, stem cells express a significantly higher number of genes (represented by expressed sequence tags) whose functions are unknown. Embryonic and neural stem cells have many similarities at the transcriptional level. These results provide a foundation for a more detailed understanding of stem cell biology.


systematic_name: M4345
exact_source: Table 1S: ko/wt fold 6m >= 2
source_species_code: MM
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Genes up-regulated at 6 months of age in lungs from LIPA [GeneID=3988] knockout mice, which display pulmonary pathology.

description_full:
  The functional roles of neutral lipids in the lung are poorly understood. However, blocking cholesteryl ester and triglyceride metabolism in lysosomal acid lipase gene knockout mice (lal-/-) results in severe pathogenic phenotypes in the lung, including massive neutrophil infiltration, foamy macrophage accumulation, unwanted cell growth, and emphysema. To elucidate the mechanism underlining these pathologies, we performed Affymetrix GeneChip microarray analysis of 1-, 3-, and 6-month-old mice and identified aberrant gene expression that progressed with age. Among changed genes, matrix metalloproteinase (MMP)-12, apoptosis inhibitor 6 (Api-6), erythroblast transformation-specific domain (Ets) transcription factor family member Spi-C, and oncogene MafB were increased 100-, 70-, 40-, and 10-fold, respectively, in lal-/- lungs versus the wild-type lungs. The pathogenic increases of these molecules occurred primarily in alveolar type II epithelial cells. Transcriptional activities of the MMP-12 and Api-6 promoters were stimulated by Spi-C or MafB in respiratory epithelial cells. Treatment with 9-hydroxyoctadecanoic acids and ciglitazone significantly rescued lal-/- pulmonary inflammation and aberrant gene expression. In addition, both compounds as well as peroxisome proliferator-activated receptor gamma inhibited MMP-12 and Api-6 promoter activities. These data suggest that inflammation-triggered cell growth and emphysema during lysosomal acid lipase deficiency are partially caused by peroxisome proliferator-activated receptor-gamma inactivation.


systematic_name: M1533
exact_source: Appendix 1A
source_species_code: MM
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  All significantly down-regulated genes in kidney glomeruli isolated from TCF21 [Gene ID=6943] knockout mice.

description_full:
  Mouse mutations have provided tremendous insights into the molecular basis of renal and glomerular development. However, genes often play important roles during multiple stages of nephrogenesis, making it difficult to determine the role of a gene in a specific cell lineage such as the podocyte. Conditional gene targeting and chimeric analysis are two possible approaches to dissect the function of genes in specific cell populations. However, these are labor-intensive and costly and require the generation, validation, and analysis of additional transgenic lines. For overcoming these shortcomings and, specifically, for studying the role of gene function in developing glomeruli, a technique to isolate and purify glomeruli from murine embryos was developed. Combined with gene expression profiling, this method was used to identify differentially expressed genes in glomeruli from Pod1 knockout (KO) mice that die in the perinatal period with multiple renal defects. Glomeruli from early developing stages (late S-shape/early capillary loop) onward can be isolated successfully from wild-type and KO kidneys at 18.5 d postcoitus, and RNA can readily be obtained and used for genome-wide microarray analysis. With this approach, 3986 genes that are differently expressed between glomeruli from Pod1 KO and wild-type mice were identified, including a four-fold reduction of alpha 8 integrin mRNA in glomeruli from Pod1 KO mice that was confirmed by immunostaining. This procedure may be adapted to any transgenic strain, providing a rapid and efficient method to dissect the function of specific genes in glomerular development.


description_brief: Genes down-regulated in embryonic stem cells from TCEB3 [GeneID=6924] knockout mice.
systematic_name: M1571
exact_source: Table 1S
source_species_code: MM
contributor: John Newman
contrib_organization: University of Washington
description_full:
  Elongin A is a transcription elongation factor that increases the overall rate of mRNA chain elongation by RNA polymerase II. To investigate the function of Elongin A in vivo, the two alleles of the Elongin A gene have been disrupted by homologous recombination in murine embryonic stem (ES) cells. The Elongin A-deficient ES cells are viable, but show a slow growth phenotype because they undergo a delayed mitosis. The cDNA microarray and RNase protection assay using the wild-type and Elongin A-deficient ES cells indicate that the expression of only a small subset of genes is affected in the mutant cells. Taken together, our results suggest that Elongin A regulates transcription of a subset but not all of genes and reveal a linkage between Elongin A function and cell cycle progression.


systematic_name: M16088
exact_source: Table 1S: ko/wt 3m fold >= 2
source_species_code: MM
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Genes up-regulated at 3 months of age in lungs from LIPA [GeneID=3988] knockout mice, which display pulmonary pathology.

description_full:
  The functional roles of neutral lipids in the lung are poorly understood. However, blocking cholesteryl ester and triglyceride metabolism in lysosomal acid lipase gene knockout mice (lal-/-) results in severe pathogenic phenotypes in the lung, including massive neutrophil infiltration, foamy macrophage accumulation, unwanted cell growth, and emphysema. To elucidate the mechanism underlining these pathologies, we performed Affymetrix GeneChip microarray analysis of 1-, 3-, and 6-month-old mice and identified aberrant gene expression that progressed with age. Among changed genes, matrix metalloproteinase (MMP)-12, apoptosis inhibitor 6 (Api-6), erythroblast transformation-specific domain (Ets) transcription factor family member Spi-C, and oncogene MafB were increased 100-, 70-, 40-, and 10-fold, respectively, in lal-/- lungs versus the wild-type lungs. The pathogenic increases of these molecules occurred primarily in alveolar type II epithelial cells. Transcriptional activities of the MMP-12 and Api-6 promoters were stimulated by Spi-C or MafB in respiratory epithelial cells. Treatment with 9-hydroxyoctadecanoic acids and ciglitazone significantly rescued lal-/- pulmonary inflammation and aberrant gene expression. In addition, both compounds as well as peroxisome proliferator-activated receptor gamma inhibited MMP-12 and Api-6 promoter activities. These data suggest that inflammation-triggered cell growth and emphysema during lysosomal acid lipase deficiency are partially caused by peroxisome proliferator-activated receptor-gamma inactivation.


systematic_name: M1579
exact_source: Table 2: cluster 2
source_species_code: MM
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Progressively down-regulated 8-96 h during differentiation of 3T3-L1 cells (fibroblast) into adipocytes.

description_full:
  During cellular differentiation and development, it is recognized that many complex molecular mechanisms as well as precise patterns of differentially expressed genes occur in directing precursor cells toward a given lineage. Using microarray-based technology, we examined gene expression across the course of 3T3-L1 adipocyte differentiation. Total cellular RNA was isolated at times 0, 2, 8, 16, 24, 48, and 96 h following treatment with either standard hormonal inducers of differentiation; insulin, dexamethasone, isobutylmethylxanthine (IDX), or IDX plus trichostatin A (TsA), a histone deacetylase inhibitor and potent adipogenic inhibitor. cRNA was synthesized from cellular RNA and hybridized to high density Affymetrix MG_U74Av2 microarray gene chips containing 12,488 cDNA/Expressed Sequence Tags (ESTs) probe sets. From the IDX-only treated cells, all probe sets that were either unchanged or differentially expressed less than 2-fold throughout differentiation with respect to time 0 preadipocytes were excluded from further analyses. This selection resulted in a net of 1686 transcripts, 859 were increased in expression, and 827 were decreased in expression at least 2-fold across differentiation. To focus in on genes that were more specific to differentiation, the same analysis was performed on IDX plus TsA-treated non-differentiating cells and all probe sets from the IDX-only group that exhibited similar expression profiles in the non-differentiating TsA-treated group were excluded leaving a total of 1016 transcripts that were regulated only under differentiating conditions. Six hundred and thirty-six of these transcripts were elevated at least 2-fold and 380 exhibited a decrease in expression relative to time 0 preadipocytes. This group of genes was further analyzed using hierarchical clustering and self-organizing maps and resulted in the identification of numerous genes not previously known to be regulated during adipocyte differentiation. Many of these genes may well represent novel adipogenic mediators and markers of adipogenesis.


description_brief: Upregulated in the neocortex of aged adult mice (30-month) vs young adult (5-month)
systematic_name: M1590
exact_source: Table 1S
source_species_code: MM
contributor: John Newman
contrib_organization: University of Washington
description_full:
  Ageing of the brain leads to impairments in cognitive and motor skills, and is the major risk factor for several common neurological disorders such as Alzheimer disease (AD) and Parkinson disease (PD). Recent studies suggest that normal brain ageing is associated with subtle morphological and functional alterations in specific neuronal circuits, as opposed to large-scale neuronal loss. In fact, ageing of the central nervous system in diverse mammalian species shares many features, such as atrophy of pyramidal neurons, synaptic atrophy, decrease of striatal dopamine receptors, accumulation of fluorescent pigments, cytoskeletal abnormalities, and reactive astrocytes and microglia. To provide the first global analysis of brain ageing at the molecular level, we used oligonucleotide arrays representing 6,347 genes to determine the gene-expression profile of the ageing neocortex and cerebellum in mice. Ageing resulted in a gene-expression profile indicative of an inflammatory response, oxidative stress and reduced neurotrophic support in both brain regions. At the transcriptional level, brain ageing in mice displays parallels with human neurodegenerative disorders. Caloric restriction, which retards the ageing process in mammals, selectively attenuated the age-associated induction of genes encoding inflammatory and stress responses.


systematic_name: M1626
exact_source: Table 2: Cluster 1
source_species_code: MM
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Cluster 1:  genes progressively down-regulated over 24 h (peak at 0 h timepoint) during differentiation of 3T3-L1 fibroblasts into adipocytes in response to adipogenic hormones.

description_full:
  The molecular mechanisms that regulate cellular differentiation during development and throughout life are complex. It is now recognized that precise patterns of differentially expressed genes ultimately direct a particular cell toward a given lineage and many of these are regulated during the earliest stages of differentiation. Using a microarray-based expression analysis, we have examined gene expression profiles during the first 24 h of 3T3-L1 adipocyte differentiation. RNA was isolated at times 0, 2, 8, 16, and 24 h following stimulation of differentiation and hybridized in duplicate to high density Affymetrix microarray gene chips containing a series of 13,179 cDNA/expressed sequence tag (EST) probe sets. Two hundred and eighty-five cDNA/ESTs were shown to have at least a fivefold change in expression levels during this time course and both hierarchical and self-organizing map clustering analysis was performed to categorize them by expression profiles. Several genes known to be regulated during this time period were confirmed and Western blot analysis of the proteins encoded by some of the identified genes revealed expression profiles similar to their mRNA counterparts. As expected, many of the genes identified have not been examined in such a critical time period during adipogenesis and may well represent novel adipogenic mediators.


systematic_name: M8215
exact_source: Excel Table 2S: Expression Cluster=HSC and Progenitors Shared
source_species_code: MM
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Genes in the expression cluster 'HSC and Progenitors Shared': up-regulated in hematopoietic stem cells (HSC) and progenitors from adult bone marrow and fetal liver.

description_full:
[cell repeats an earlier one in this file: 626 characters]


systematic_name: M1666
exact_source: Table 2: cluster 3
source_species_code: MM
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Strongly down-regulated at 8-96 h during differentiation of 3T3-L1 cells (fibroblast) into adipocytes.

description_full:
  During cellular differentiation and development, it is recognized that many complex molecular mechanisms as well as precise patterns of differentially expressed genes occur in directing precursor cells toward a given lineage. Using microarray-based technology, we examined gene expression across the course of 3T3-L1 adipocyte differentiation. Total cellular RNA was isolated at times 0, 2, 8, 16, 24, 48, and 96 h following treatment with either standard hormonal inducers of differentiation; insulin, dexamethasone, isobutylmethylxanthine (IDX), or IDX plus trichostatin A (TsA), a histone deacetylase inhibitor and potent adipogenic inhibitor. cRNA was synthesized from cellular RNA and hybridized to high density Affymetrix MG_U74Av2 microarray gene chips containing 12,488 cDNA/Expressed Sequence Tags (ESTs) probe sets. From the IDX-only treated cells, all probe sets that were either unchanged or differentially expressed less than 2-fold throughout differentiation with respect to time 0 preadipocytes were excluded from further analyses. This selection resulted in a net of 1686 transcripts, 859 were increased in expression, and 827 were decreased in expression at least 2-fold across differentiation. To focus in on genes that were more specific to differentiation, the same analysis was performed on IDX plus TsA-treated non-differentiating cells and all probe sets from the IDX-only group that exhibited similar expression profiles in the non-differentiating TsA-treated group were excluded leaving a total of 1016 transcripts that were regulated only under differentiating conditions. Six hundred and thirty-six of these transcripts were elevated at least 2-fold and 380 exhibited a decrease in expression relative to time 0 preadipocytes. This group of genes was further analyzed using hierarchical clustering and self-organizing maps and resulted in the identification of numerous genes not previously known to be regulated during adipocyte differentiation. Many of these genes may well represent novel adipogenic mediators and markers of adipogenesis.


systematic_name: M1684
exact_source: Table 1S
source_species_code: MM
GEO_id: GSE10218
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated upon skin specific knockout of FOS [GeneID=2353] by cre-lox in the K5-SOS-F mice (express a constitutively active form of SOS1 [GeneID=6654] in the skin).

description_full:
  Expression and function of the oncogenic transcription factor activator protein (AP-1; mainly composed of Jun and Fos proteins) is required for neoplastic transformation of keratinocytes in vitro and tumor promotion as well as malignant progression in vivo. Here, we describe the identification of 372 differentially expressed genes comparing skin tumor samples of K5-SOS-F transgenic mice (Fos(f/f) SOS(+)) with samples derived from animals with a specific deletion of c-Fos in keratinocytes (Fos(Deltaep) SOS(+)). Fos-dependent transcription of selected genes was confirmed by quantitative real-time PCR analysis using tumor samples and mouse back skin treated with the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). One of the most differentially expressed genes encodes the small mucin-like glycoprotein Podoplanin (Pdpn), whose expression correlates with malignant progression in mouse tumor model systems and human cancer. We found Pdpn and Fos expression in chemically induced mouse skin tumors, and detailed analysis of the Pdpn gene promoter revealed impaired activity in Fos-deficient mouse embryonic fibroblasts, which could be restored by ectopic Fos expression. Direct Fos protein binding to the Pdpn promoter was shown by chromatin immunoprecipitation and a TPA-induced complex at a TPA-responsive element-like motif in the proximal promoter was identified by electrophoretic mobility shift assays. In summary, we could define a Fos-dependent genetic program in a well-established model of skin tumors. Systematic analysis of these novel target genes will guide us in elucidating the molecular mechanisms of AP-1-regulated pathways that are critically implicated in neoplastic transformation and/or malignant progression.


systematic_name: M11891
exact_source: Table 1S: fc(NIR-IR) > 0
source_species_code: MM
GEO_id: GSE11357
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  The postradiation tumor escape signature: genes up-regulated in tumors from irradiated stroma vs those from non-irradiated stroma.

description_full:
  Radiotherapy is widely used to treat human cancer. Patients locally recurring after radiotherapy, however, have increased risk of metastatic progression and poor prognosis. The clinical management of postradiation recurrences remains an unresolved issue. Tumors growing in preirradiated tissues have an increased fraction of hypoxic cells and are more metastatic, a condition known as tumor bed effect. The transcription factor hypoxia inducible factor (HIF)-1 promotes invasion and metastasis of hypoxic tumors, but its role in the tumor bed effect has not been reported. Here, we show that tumor cells derived from SCCVII and HCT116 tumors growing in a preirradiated bed, or selected in vitro through repeated cycles of severe hypoxia, retain invasive and metastatic capacities when returned to normoxia. HIF activity, although facilitating metastatic spreading of tumors growing in a preirradiated bed, is not essential. Through gene expression profiling and gain- and loss-of-function experiments, we identified the matricellular protein CYR61 and alphaVbeta5 integrin as proteins cooperating to mediate these effects. The anti-alphaV integrin monoclonal antibody 17E6 and the small molecular alphaVbeta3/alphaVbeta5 integrin inhibitor EMD121974 suppressed invasion and metastasis induced by CYR61 and attenuated metastasis of tumors growing within a preirradiated field. These results represent a conceptual advance to the understanding of the tumor bed effect and identify CYR61 and alphaVbeta5 integrin as proteins that cooperate to mediate metastasis. They also identify alphaV integrin inhibition as a potential therapeutic approach for preventing metastasis in patients at risk for postradiation recurrences.


systematic_name: M3485
exact_source: Table 1S: fc(NIR-IR) < 0
source_species_code: MM
GEO_id: GSE11357
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  The postradiation tumor escape signature: genes down-regulated in tumors from irradiated stroma vs those from non-irradiated stroma.

description_full:
  Radiotherapy is widely used to treat human cancer. Patients locally recurring after radiotherapy, however, have increased risk of metastatic progression and poor prognosis. The clinical management of postradiation recurrences remains an unresolved issue. Tumors growing in preirradiated tissues have an increased fraction of hypoxic cells and are more metastatic, a condition known as tumor bed effect. The transcription factor hypoxia inducible factor (HIF)-1 promotes invasion and metastasis of hypoxic tumors, but its role in the tumor bed effect has not been reported. Here, we show that tumor cells derived from SCCVII and HCT116 tumors growing in a preirradiated bed, or selected in vitro through repeated cycles of severe hypoxia, retain invasive and metastatic capacities when returned to normoxia. HIF activity, although facilitating metastatic spreading of tumors growing in a preirradiated bed, is not essential. Through gene expression profiling and gain- and loss-of-function experiments, we identified the matricellular protein CYR61 and alphaVbeta5 integrin as proteins cooperating to mediate these effects. The anti-alphaV integrin monoclonal antibody 17E6 and the small molecular alphaVbeta3/alphaVbeta5 integrin inhibitor EMD121974 suppressed invasion and metastasis induced by CYR61 and attenuated metastasis of tumors growing within a preirradiated field. These results represent a conceptual advance to the understanding of the tumor bed effect and identify CYR61 and alphaVbeta5 integrin as proteins that cooperate to mediate metastasis. They also identify alphaV integrin inhibition as a potential therapeutic approach for preventing metastasis in patients at risk for postradiation recurrences.


description_brief: Genes whose promoters are bound by FOXP3 [GeneID=50943] based an a ChIP-chip analysis.
systematic_name: M1741
exact_source: Table 1S
source_species_code: MM
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_full:
  Transcription factor Foxp3 (forkhead box P3), restricted in its expression to a specialized regulatory CD4+ T-cell subset (T(R)) with a dedicated suppressor function, controls T(R) lineage development. In humans and mice, Foxp3 deficiency results in a paucity of T(R) cells and a fatal breach in immunological tolerance, causing highly aggressive multi-organ autoimmune pathology. Here, through genome-wide analysis combining chromatin immunoprecipitation with mouse genome tiling array profiling, we identify Foxp3 binding regions for approximately 700 genes and for an intergenically encoded microRNA. We find that a large number of Foxp3-bound genes are up- or downregulated in Foxp3+ T cells, suggesting that Foxp3 acts as both a transcriptional activator and repressor. Foxp3-mediated regulation unique to the thymus affects, among others, genes encoding nuclear factors that control gene expression and chromatin remodelling. In contrast, Foxp3 target genes shared by the thymic and peripheral T(R) cells encode primarily plasma membrane proteins, as well as cell signalling proteins. Together, our studies suggest that distinct transcriptional sub-programmes implemented by Foxp3 establish T(R) lineage during differentiation and its proliferative and functional competence in the periphery.


systematic_name: M1742
exact_source: Table 2S: stimulated hybridoma cells
source_species_code: MM
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes with promoters bound by FOXP3 [GeneID=50943] in hybridoma cells stimulated by PMA [PubChem=4792] and ionomycin [PubChem=3733].

description_full:
  Foxp3+CD4+CD25+ regulatory T (T(reg)) cells are essential for the prevention of autoimmunity. T(reg) cells have an attenuated cytokine response to T-cell receptor stimulation, and can suppress the proliferation and effector function of neighbouring T cells. The forkhead transcription factor Foxp3 (forkhead box P3) is selectively expressed in T(reg) cells, is required for T(reg) development and function, and is sufficient to induce a T(reg) phenotype in conventional CD4+CD25- T cells. Mutations in Foxp3 cause severe, multi-organ autoimmunity in both human and mouse. FOXP3 can cooperate in a DNA-binding complex with NFAT (nuclear factor of activated T cells) to regulate the transcription of several known target genes. However, the global set of genes regulated directly by Foxp3 is not known and consequently, how this transcription factor controls the gene expression programme for T(reg) function is not understood. Here we identify Foxp3 target genes and report that many of these are key modulators of T-cell activation and function. Remarkably, the predominant, although not exclusive, effect of Foxp3 occupancy is to suppress the activation of target genes on T-cell stimulation. Foxp3 suppression of its targets appears to be crucial for the normal function of T(reg) cells, because overactive variants of some target genes are known to be associated with autoimmune disease.


systematic_name: M1746
exact_source: Table 3S: thymus only
source_species_code: MM
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes with promoters bound by FOXP3 [GeneID=50943] and which are up-regulated only in developing (located in the thymus) regulatory CD4+ [GeneID=920] T lymphocytes.

description_full:
  Transcription factor Foxp3 (forkhead box P3), restricted in its expression to a specialized regulatory CD4+ T-cell subset (T(R)) with a dedicated suppressor function, controls T(R) lineage development. In humans and mice, Foxp3 deficiency results in a paucity of T(R) cells and a fatal breach in immunological tolerance, causing highly aggressive multi-organ autoimmune pathology. Here, through genome-wide analysis combining chromatin immunoprecipitation with mouse genome tiling array profiling, we identify Foxp3 binding regions for approximately 700 genes and for an intergenically encoded microRNA. We find that a large number of Foxp3-bound genes are up- or downregulated in Foxp3+ T cells, suggesting that Foxp3 acts as both a transcriptional activator and repressor. Foxp3-mediated regulation unique to the thymus affects, among others, genes encoding nuclear factors that control gene expression and chromatin remodelling. In contrast, Foxp3 target genes shared by the thymic and peripheral T(R) cells encode primarily plasma membrane proteins, as well as cell signalling proteins. Together, our studies suggest that distinct transcriptional sub-programmes implemented by Foxp3 establish T(R) lineage during differentiation and its proliferative and functional competence in the periphery.


systematic_name: M12595
exact_source: Table 1S: Class NT genes: (N+L)/(T+L) <=1
source_species_code: MM
GEO_id: GSE7348
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Class T (tolerizeable) genes: induced during the first LPS stimulation and either not re-induced or induced to a much lesser degree in tolerant macrophages.

description_full:
  Toll-like receptors (TLRs) induce a multi-component inflammatory response that must be tightly regulated to avoid tissue damage. Most known regulatory mechanisms target TLR signalling pathways and thus broadly inhibit multiple aspects of the inflammatory response. Given the functional diversity of TLR-induced genes, we proposed that additional, gene-specific regulatory mechanisms exist to allow individual aspects of the TLR-induced response to be differentially regulated. Using an in vitro system of lipopolysaccharide tolerance in murine macrophages, we show that TLR-induced genes fall into two categories on the basis of their functions and regulatory requirements. We demonstrate that representatives from the two classes acquire distinct patterns of TLR-induced chromatin modifications. These gene-specific chromatin modifications are associated with transient silencing of one class of genes, which includes pro-inflammatory mediators, and priming of the second class, which includes antimicrobial effectors. These findings illustrate an adaptive response in macrophages and reveal component-specific regulation of inflammation.


description_brief: Up-regulated genes in the 'Field Effect' signature of normal lung tissue adjacent to the tumor.
systematic_name: M13438
exact_source: Table 1: Fold change > 1
source_species_code: MM
GEO_id: GSE7269
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_full:
  One area of intensive investigation is to understand complex cellular and signaling interactions in the tumor microenvironment. Using a novel, although straightforward, microarray approach, we defined a gene expression signature from the lung tumor microenvironment in the murine A/J-urethane model of human lung adenocarcinoma. The tumor microenvironment is reflected by the composition of the cell types present and alterations in mRNA levels, resulting in a Field Effect around the tumor. The genes composing the Field Effect expression signature include proteases and their inhibitors, inflammation markers, and immune signaling molecules. By several criteria, the Field Effect expression signature can be attributed to the macrophage lineage, suggesting a qualitative change in the expression pattern of tumor-associated macrophages (TAM) observed in lung tumors. The protein expression levels for a number of Field Effect genes were verified by Western blot analysis of lung homogenates, and for their expression in macrophages and parenchymal cells outside of the tumors by immunohistochemistry. In addition, the Field Effect expression signature was used to classify bronchoalveolar lavage (BAL) cells from tumor-bearing or age-matched control mice. Using a variety of statistical measures, the Field Effect expression signature correctly classified the BAL cells >94% of the time. Finally, the protein levels for several Field Effect genes were higher in cell-free BAL fluid, indicating they may be secreted by the TAMs. This work suggests that TAMs generate a unique gene expression signature within the tumor microenvironment, and this signature could potentially be used for identifying lung cancer from BAL cells and/or fluid.


systematic_name: M10880
exact_source: Table 1S: AGE
source_species_code: MM
GEO_id: GSE7269
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Down-regulated genes classifying non-tumor lung tissues by age after incution of lung cancer by urethane injection [PubChem=5641]: early (24-26 weeks) vs late (46 weeks).

description_full:
  One area of intensive investigation is to understand complex cellular and signaling interactions in the tumor microenvironment. Using a novel, although straightforward, microarray approach, we defined a gene expression signature from the lung tumor microenvironment in the murine A/J-urethane model of human lung adenocarcinoma. The tumor microenvironment is reflected by the composition of the cell types present and alterations in mRNA levels, resulting in a Field Effect around the tumor. The genes composing the Field Effect expression signature include proteases and their inhibitors, inflammation markers, and immune signaling molecules. By several criteria, the Field Effect expression signature can be attributed to the macrophage lineage, suggesting a qualitative change in the expression pattern of tumor-associated macrophages (TAM) observed in lung tumors. The protein expression levels for a number of Field Effect genes were verified by Western blot analysis of lung homogenates, and for their expression in macrophages and parenchymal cells outside of the tumors by immunohistochemistry. In addition, the Field Effect expression signature was used to classify bronchoalveolar lavage (BAL) cells from tumor-bearing or age-matched control mice. Using a variety of statistical measures, the Field Effect expression signature correctly classified the BAL cells >94% of the time. Finally, the protein levels for several Field Effect genes were higher in cell-free BAL fluid, indicating they may be secreted by the TAMs. This work suggests that TAMs generate a unique gene expression signature within the tumor microenvironment, and this signature could potentially be used for identifying lung cancer from BAL cells and/or fluid.


description_brief: Genes up-regulated in mice with skin specific knockout of RB1 [GeneID=5925] by Cre-lox.
systematic_name: M12224
exact_source: Table 1S: pRb-/-;p53+/+ vs. Control
source_species_code: MM
GEO_id: GSE9144
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_full:
  Squamous cell carcinomas (SCC) represent the most aggressive type of nonmelanoma skin cancer. Although little is known about the causal alterations of SCCs, in organ-transplanted patients the E7 and E6 oncogenes of human papillomavirus, targeting the p53- and pRb-dependent pathways, have been widely involved. Here, we report the functional consequences of the simultaneous elimination of Trp53 and retinoblastoma (Rb) genes in epidermis using Cre-loxP system. Loss of p53, but not pRb, produces spontaneous tumor development, indicating that p53 is the predominant tumor suppressor acting in mouse epidermis. Although the simultaneous inactivation of pRb and p53 does not aggravate the phenotype observed in Rb-deficient epidermis in terms of proliferation and/or differentiation, spontaneous SCC development is severely accelerated in doubly deficient mice. The tumors are aggressive and undifferentiated and display a hair follicle origin. Detailed analysis indicates that the acceleration is mediated by premature activation of the epidermal growth factor receptor/Akt pathway, resulting in increased proliferation in normal and dysplastic hair follicles and augmented tumor angiogenesis. The molecular characteristics of this model provide valuable tools to understand epidermal tumor formation and may ultimately contribute to the development of therapies for the treatment of aggressive squamous cancer.


systematic_name: M15896
exact_source: Table 1S: pRb-/-;p53-/- vs. Control
source_species_code: MM
GEO_id: GSE9144
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in mice with skin specific double knockout of both RB1 and TP53 [GeneID=5925;7157] by Cre-lox.

description_full:
[cell repeats an earlier one in this file: 1411 characters]


systematic_name: M3854
exact_source: Table 1S: pRb-/-;p53-/- vs. Control
source_species_code: MM
GEO_id: GSE9144
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in mice with skin specific double knockout of both RB1 and TP53 [GeneID=5925;7157] by Cre-lox.

description_full:
[cell repeats an earlier one in this file: 1411 characters]


systematic_name: M6315
exact_source: Table 3S: cluster 2
source_species_code: MM
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Cluster 2: genes down-regulated in lung tissue samples from mice with oncogenic form of KRAS [GeneID=3845] and inactivated PTEN [GeneID=5728].

description_full:
  Phosphatase and tensin homologue deleted from chromosome 10 (Pten) is expressed aberrantly in non-small cell lung cancer cells, but the role of Pten in lung neoplasia has not been fully elucidated. In this study, we used a genetic approach to inactivate Pten in the bronchial epithelium of mice. Although, by itself, Pten inactivation had no discernible effect on bronchial epithelial histology, it accelerated lung tumorigenesis initiated by oncogenic K-ras, causing more rapid lethality than that induced by oncogenic K-ras alone (8 weeks versus 24 weeks of median duration of survival, respectively). Lung tumors arose in K-ras mutant, Pten-deficient mice that rapidly obstructed bronchial lumina and replaced alveolar spaces. Relative to K-ras mutant tumors, the K-ras mutant, Pten-deficient tumors exhibited more advanced histologic severity and more prominent inflammation and vascularity. Thus, Pten inactivation cooperated with oncogenic K-ras in promoting lung tumorigenesis.


systematic_name: M15150
exact_source: Table 5S: fold > 1.3
source_species_code: MM
GEO_id: GSE8863
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in cancer stem cells isolated from mammary tumors compared to the non-tumorigenic cells.

description_full:
  Using a syngeneic p53-null mouse mammary gland tumor model that closely mimics human breast cancer, we have identified, by limiting dilution transplantation and in vitro mammosphere assay, a Lin(-)CD29(H)CD24(H) subpopulation of tumor-initiating cells. Upon subsequent transplantation, this subpopulation generated heterogeneous tumors that displayed properties similar to the primary tumor. Analysis of biomarkers suggests the Lin(-)CD29(H)CD24(H) subpopulation may have arisen from a bipotent mammary progenitor. Differentially expressed genes in the Lin(-)CD29(H)CD24(H) mouse mammary gland tumor-initiating cell population include those involved in DNA damage response and repair, as well as genes involved in epigenetic regulation previously shown to be critical for stem cell self-renewal. These studies provide in vitro and in vivo data that support the cancer stem cell (CSC) hypothesis. Furthermore, this p53-null mouse mammary tumor model may allow us to identify new CSC markers and to test the functional importance of these markers.


systematic_name: M1851
exact_source: Table 2: Plasmablastic
source_species_code: MM
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Up-regulated genes that best disciminate plasmablastic plasmacytoma from plasmacytic plasmacytoma tumors.

description_full:
  We have compared histologic features and gene expression profiles of newly identified plasmacytomas from NFS.V(+) congenic mice with plasmacytomas of IL6 transgenic, Fasl mutant, and SJL-beta2M(-/-) mice. NFS.V(+) tumors comprised an overlapping morphologic spectrum of high-grade/anaplastic, intermediate-grade/plasmablastic, and low-grade/plasmacytic cases with similarities to subsets of human multiple myeloma and plasmacytoma. Microarray and immunohistochemical analyses of genes expressed by the most prevalent tumors, plasmablastic plasmacytomas, showed them to be most closely related to immunoblastic lymphomas, less so to plasmacytomas of Fasl mutant and SJL mice, and least to plasmacytic plasmacytomas of IL6 transgenic mice. Plasmablastic tumors seemed to develop in an inflammatory environment associated with gene signatures of T cells, natural killer cells, and macrophages not seen with plasmacytic plasmacytomas. Plasmablastic plasmacytomas from NFS.V(+) and SJL-beta2M(-/-) mice did not have structural alterations in Myc or T(12;15) translocations and did not express Myc at high levels, regular features of transgenic and pristane-induced plasmacytomas. These findings imply that, as for human multiple myeloma, Myc-independent routes of transformation contribute to the pathogenesis of these tumors. These findings suggest that plasma cell neoplasms of mice and humans exhibit similar degrees of complexity. Mouse plasmacytomas, previously considered to be homogeneous, may thus be as diverse as their human counterparts with respect to oncogenic mechanisms of plasma cell transformation. Selecting specific types of mouse plasmacytomas that relate most closely to subtypes of human multiple myeloma may provide new opportunities for preclinical testing of drugs for treatment of the human disease.


systematic_name: M8646
exact_source: Table 5S: Tumor Group=C and D & Fold Change < 0
source_species_code: MM
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated both in group C and D of tumors arising from overexpression of BCL2L1 and MYC [GeneID=598;4609] in plasma cells.

description_full:
  Multiple myeloma is an incurable plasma cell malignancy for which existing animal models are limited. We have previously shown that the targeted expression of the transgenes c-Myc and Bcl-X(L) in murine plasma cells produces malignancy that displays features of human myeloma, such as localization of tumor cells to the bone marrow and lytic bone lesions. We have isolated and characterized in vitro cultures and adoptive transfers of tumors from Bcl-xl/Myc transgenic mice. Tumors have a plasmablastic morphology and variable expression of CD138, CD45, CD38, and CD19. Spectral karyotyping analysis of metaphase chromosomes from primary tumor cell cultures shows that the Bcl-xl/Myc tumors contain a variety of chromosomal abnormalities, including trisomies, translocations, and deletions. The most frequently aberrant chromosomes are 12 and 16. Three sites for recurring translocations were also identified on chromosomes 4D, 12F, and 16C. Gene expression profiling was used to identify differences in gene expression between tumor cells and normal plasma cells (NPC) and to cluster the tumors into two groups (tumor groups C and D), with distinct gene expression profiles. Four hundred and ninety-five genes were significantly different between both tumor groups and NPCs, whereas 124 genes were uniquely different from NPCs in tumor group C and 204 genes were uniquely different from NPCs in tumor group D. Similar to human myeloma, the cyclin D genes are differentially dysregulated in the mouse tumor groups. These data suggest the Bcl-xl/Myc tumors are similar to a subset of plasmablastic human myelomas and provide insight into the specific genes and pathways underlying the human disease.


systematic_name: M5487
exact_source: Suppl. data file 'BMT_356_public.xls': A7 vs S7 P<.01 and FC>2.0
source_species_code: MM
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Hepatic graft versus host disease (GVHD), day 7: up-regulated in allogeneic vs syngeneic bone marrow transplant.

description_full:
  The liver, skin, and gastrointestinal tract are major target organs of acute graft-versus-host disease (GVHD), the major complication of allogeneic bone marrow transplantation (BMT). In order to gain a better understanding of acute GVHD in the liver, we compared the gene expression profiles of livers after experimental allogeneic and syngeneic BMT using oligonucleotide microarray. At 35 days after allogeneic BMT when hepatic GVHD was histologically evident, genes related to cellular effectors and acute-phase proteins were up-regulated, whereas genes largely related to metabolism and endocrine function were down-regulated. At day 7 after BMT before the development of histologic changes in the liver, interferon gamma (IFN-gamma)-inducible genes, major histocompatibility (MHC) class II molecules, and genes related to leukocyte trafficking had been up-regulated. Immunohistochemistry demonstrated that expression of IFN-gamma protein itself was increased in the spleen but not in hepatic tissue. These results suggest that the increased expression of genes associated with the attraction and activation of donor T cells induced by IFN-gamma early after BMT is important in the initiation of hepatic GVHD in this model and provide new potential molecular targets for early detection and intervention of acute GVHD.


systematic_name: M19618
exact_source: Suppl. data file 'BMT_356_public.xls': A35 vs S35 P<.01 and FC>2
source_species_code: MM
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Hepatic graft versus host disease (GVHD), day 35: genes up-regulated in allogeneic vs syngeneic bone marrow transplant.

description_full:
  The liver, skin, and gastrointestinal tract are major target organs of acute graft-versus-host disease (GVHD), the major complication of allogeneic bone marrow transplantation (BMT). In order to gain a better understanding of acute GVHD in the liver, we compared the gene expression profiles of livers after experimental allogeneic and syngeneic BMT using oligonucleotide microarray. At 35 days after allogeneic BMT when hepatic GVHD was histologically evident, genes related to cellular effectors and acute-phase proteins were up-regulated, whereas genes largely related to metabolism and endocrine function were down-regulated. At day 7 after BMT before the development of histologic changes in the liver, interferon gamma (IFN-gamma)-inducible genes, major histocompatibility (MHC) class II molecules, and genes related to leukocyte trafficking had been up-regulated. Immunohistochemistry demonstrated that expression of IFN-gamma protein itself was increased in the spleen but not in hepatic tissue. These results suggest that the increased expression of genes associated with the attraction and activation of donor T cells induced by IFN-gamma early after BMT is important in the initiation of hepatic GVHD in this model and provide new potential molecular targets for early detection and intervention of acute GVHD.


systematic_name: M1887
exact_source: Table 1S
source_species_code: MM
GEO_id: GSE3878
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in gastric mucosal tissue of mice on 2% cholesterol [PubChem=5997] diet and infected with H. pylori vs those infected with H. pylori while on 0% cholesterol diet.

description_full:
  Helicobacter pylori infection causes gastric pathology such as ulcer and carcinoma. Because H. pylori is auxotrophic for cholesterol, we have explored the assimilation of cholesterol by H. pylori in infection. Here we show that H. pylori follows a cholesterol gradient and extracts the lipid from plasma membranes of epithelial cells for subsequent glucosylation. Excessive cholesterol promotes phagocytosis of H. pylori by antigen-presenting cells, such as macrophages and dendritic cells, and enhances antigen-specific T cell responses. A cholesterol-rich diet during bacterial challenge leads to T cell-dependent reduction of the H. pylori burden in the stomach. Intrinsic alpha-glucosylation of cholesterol abrogates phagocytosis of H. pylori and subsequent T cell activation. We identify the gene hp0421 as encoding the enzyme cholesterol-alpha-glucosyltransferase responsible for cholesterol glucosylation. Generation of knockout mutants lacking hp0421 corroborates the importance of cholesteryl glucosides for escaping phagocytosis, T cell activation and bacterial clearance in vivo. Thus, we propose a mechanism regulating the host-pathogen interaction whereby glucosylation of a lipid tips the scales towards immune evasion or response.


systematic_name: M1920
exact_source: Table 3S
source_species_code: MM
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes forming the macrophage-enriched metabolic network (MEMN) claimed to have a causal relationship with the metabolic syndrom traits.

description_full:
  Identifying variations in DNA that increase susceptibility to disease is one of the primary aims of genetic studies using a forward genetics approach. However, identification of disease-susceptibility genes by means of such studies provides limited functional information on how genes lead to disease. In fact, in most cases there is an absence of functional information altogether, preventing a definitive identification of the susceptibility gene or genes. Here we develop an alternative to the classic forward genetics approach for dissecting complex disease traits where, instead of identifying susceptibility genes directly affected by variations in DNA, we identify gene networks that are perturbed by susceptibility loci and that in turn lead to disease. Application of this method to liver and adipose gene expression data generated from a segregating mouse population results in the identification of a macrophage-enriched network supported as having a causal relationship with disease traits associated with metabolic syndrome. Three genes in this network, lipoprotein lipase (Lpl), lactamase beta (Lactb) and protein phosphatase 1-like (Ppm1l), are validated as previously unknown obesity genes, strengthening the association between this network and metabolic disease traits. Our analysis provides direct experimental support that complex traits such as obesity are emergent properties of molecular networks that are modulated by complex genetic loci and environmental factors.


systematic_name: M1613
exact_source: Table 2S: Ps vs CB Fold Change < 0
source_species_code: MM
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Transcripts depleted in pseudopodia of NIH/3T3 cells (fibroblast) in response to the chemotactic migration stimulus by lysophosphatidic acid (LPA) [PubChem=3988].

description_full:
  RNA localization is important for the establishment and maintenance of polarity in multiple cell types. Localized RNAs are usually transported along microtubules or actin filaments and become anchored at their destination to some underlying subcellular structure. Retention commonly involves actin or actin-associated proteins, although cytokeratin filaments and dynein anchor certain RNAs. RNA localization is important for diverse processes ranging from cell fate determination to synaptic plasticity; however, so far there have been few comprehensive studies of localized RNAs in mammalian cells. Here we have addressed this issue, focusing on migrating fibroblasts that polarize to form a leading edge and a tail in a process that involves asymmetric distribution of RNAs. We used a fractionation scheme combined with microarrays to identify, on a genome-wide scale, RNAs that localize in protruding pseudopodia of mouse fibroblasts in response to migratory stimuli. We find that a diverse group of RNAs accumulates in such pseudopodial protrusions. Through their 3' untranslated regions these transcripts are anchored in granules concentrated at the plus ends of detyrosinated microtubules. RNAs in the granules associate with the adenomatous polyposis coli (APC) tumour suppressor and the fragile X mental retardation protein (FMRP). APC is required for the accumulation of transcripts in protrusions. Our results suggest a new type of RNA anchoring mechanism as well as a new, unanticipated function for APC in localizing RNAs.


systematic_name: M12707
exact_source: Table 3S: Ps vs CB Fold Change > 0
source_species_code: MM
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Transcripts enriched in pseudopodia of NIH/3T3 cells (fibroblast) in response to haptotactic migratory stimulus by fibronectin, FN1 [GeneID=2335].

description_full:
  RNA localization is important for the establishment and maintenance of polarity in multiple cell types. Localized RNAs are usually transported along microtubules or actin filaments and become anchored at their destination to some underlying subcellular structure. Retention commonly involves actin or actin-associated proteins, although cytokeratin filaments and dynein anchor certain RNAs. RNA localization is important for diverse processes ranging from cell fate determination to synaptic plasticity; however, so far there have been few comprehensive studies of localized RNAs in mammalian cells. Here we have addressed this issue, focusing on migrating fibroblasts that polarize to form a leading edge and a tail in a process that involves asymmetric distribution of RNAs. We used a fractionation scheme combined with microarrays to identify, on a genome-wide scale, RNAs that localize in protruding pseudopodia of mouse fibroblasts in response to migratory stimuli. We find that a diverse group of RNAs accumulates in such pseudopodial protrusions. Through their 3' untranslated regions these transcripts are anchored in granules concentrated at the plus ends of detyrosinated microtubules. RNAs in the granules associate with the adenomatous polyposis coli (APC) tumour suppressor and the fragile X mental retardation protein (FMRP). APC is required for the accumulation of transcripts in protrusions. Our results suggest a new type of RNA anchoring mechanism as well as a new, unanticipated function for APC in localizing RNAs.


systematic_name: M5314
exact_source: Table 3S: Ps vs CB Fold Change < 0
source_species_code: MM
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Transcripts depleted from pseudopodia of NIH/3T3 cells (fibroblast) in response to haptotactic migratory stimulus by fibronectin, FN1 [GeneID=2335].

description_full:
  RNA localization is important for the establishment and maintenance of polarity in multiple cell types. Localized RNAs are usually transported along microtubules or actin filaments and become anchored at their destination to some underlying subcellular structure. Retention commonly involves actin or actin-associated proteins, although cytokeratin filaments and dynein anchor certain RNAs. RNA localization is important for diverse processes ranging from cell fate determination to synaptic plasticity; however, so far there have been few comprehensive studies of localized RNAs in mammalian cells. Here we have addressed this issue, focusing on migrating fibroblasts that polarize to form a leading edge and a tail in a process that involves asymmetric distribution of RNAs. We used a fractionation scheme combined with microarrays to identify, on a genome-wide scale, RNAs that localize in protruding pseudopodia of mouse fibroblasts in response to migratory stimuli. We find that a diverse group of RNAs accumulates in such pseudopodial protrusions. Through their 3' untranslated regions these transcripts are anchored in granules concentrated at the plus ends of detyrosinated microtubules. RNAs in the granules associate with the adenomatous polyposis coli (APC) tumour suppressor and the fragile X mental retardation protein (FMRP). APC is required for the accumulation of transcripts in protrusions. Our results suggest a new type of RNA anchoring mechanism as well as a new, unanticipated function for APC in localizing RNAs.


systematic_name: M9399
exact_source: Table 3S: Eigengene 1 Score > 0
source_species_code: MM
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Top up-regulated genes from principal component 1 (PCA1) which captures variation between normal plasma cells and tumors arising from aberrant expression of BCL2L1 and MYC [GeneID=598;4609].

description_full:
  Multiple myeloma is an incurable plasma cell malignancy for which existing animal models are limited. We have previously shown that the targeted expression of the transgenes c-Myc and Bcl-X(L) in murine plasma cells produces malignancy that displays features of human myeloma, such as localization of tumor cells to the bone marrow and lytic bone lesions. We have isolated and characterized in vitro cultures and adoptive transfers of tumors from Bcl-xl/Myc transgenic mice. Tumors have a plasmablastic morphology and variable expression of CD138, CD45, CD38, and CD19. Spectral karyotyping analysis of metaphase chromosomes from primary tumor cell cultures shows that the Bcl-xl/Myc tumors contain a variety of chromosomal abnormalities, including trisomies, translocations, and deletions. The most frequently aberrant chromosomes are 12 and 16. Three sites for recurring translocations were also identified on chromosomes 4D, 12F, and 16C. Gene expression profiling was used to identify differences in gene expression between tumor cells and normal plasma cells (NPC) and to cluster the tumors into two groups (tumor groups C and D), with distinct gene expression profiles. Four hundred and ninety-five genes were significantly different between both tumor groups and NPCs, whereas 124 genes were uniquely different from NPCs in tumor group C and 204 genes were uniquely different from NPCs in tumor group D. Similar to human myeloma, the cyclin D genes are differentially dysregulated in the mouse tumor groups. These data suggest the Bcl-xl/Myc tumors are similar to a subset of plasmablastic human myelomas and provide insight into the specific genes and pathways underlying the human disease.


systematic_name: M17163
exact_source: Table 13S: Early/Late Ratio > 1.3
source_species_code: MM
GEO_id: E-MEXP-1853,E-MEXP-1851,E-MEXP-1852
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated at early fetal liver stage (embryonic days  E11.5 - E12.5) compared to the late fetal liver stage (embryonic days E14.5 - E16.5).

description_full:
[cell repeats an earlier one in this file: 854 characters]


systematic_name: M2081
exact_source: Fig. 1S: green in WT
source_species_code: MM
GEO_id: GSE1742
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated by TGFB1 [GeneID=7040] in MEF cells (embryonic fibroblast) via TGFB1R [GeneID=7046].

description_full:
  Transforming growth factor-beta1 (TGF-beta) regulates cellular functions like proliferation, differentiation, and apoptosis. On the cell surface, TGF-beta binds to receptor complexes consisting of TGF-beta receptor type II (TbetaRII) and activin-like kinase receptor-5 (Alk5), and the downstream signaling is transduced by Smad and MAPK proteins. Recent data have shown that alternative receptor combinations aside from the classical pairing of TbetaRII/Alk5 can be relevant for TGF-beta signaling. We have screened for alternative receptors for TGF-beta and also for gene targets of TGF-beta signaling, by performing functional assays and microarray analysis in murine embryonic fibroblast (MEF) cell lines lacking Alk5. Data from TGF-beta-stimulated Alk5(-/-) cells show them to be completely unaffected by TGF-beta. Additionally, 465 downstream targets of Alk5 signaling were identified when comparing Alk5(-/-) or TGF-beta-stimulated Alk5(+/+) MEFs with unstimulated Alk5(+/+) cells. Our results demonstrate that, in MEFs, TGF-beta signals exclusively through complexes involving Alk5, and give insight to its downstream effector genes.


systematic_name: M2086
exact_source: Table 1S: ITNK vs DN3 Ratio > 1
source_species_code: MM
GEO_id: GSE21016
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in ITNK cells (T-lymphocyte progenitors (DN3 cells) reprogrammed to natural killer (NK) cells by ablation of BCL11B [GeneID=64919] gene), compared to the parental DN3 cells.

description_full:
  T cells develop in the thymus and are critical for adaptive immunity. Natural killer (NK) lymphocytes constitute an essential component of the innate immune system in tumor surveillance, reproduction, and defense against microbes and viruses. Here, we show that the transcription factor Bcl11b was expressed in all T cell compartments and was indispensable for T lineage development. When Bcl11b was deleted, T cells from all developmental stages acquired NK cell properties and concomitantly lost or decreased T cell-associated gene expression. These induced T-to-natural killer (ITNK) cells, which were morphologically and genetically similar to conventional NK cells, killed tumor cells in vitro, and effectively prevented tumor metastasis in vivo. Therefore, ITNKs may represent a new cell source for cell-based therapies.


description_brief: Genes up-regulated in immature bone marrow progenitor cells upon knock out of CBFA2T3 [GeneID=863].
systematic_name: M2205
exact_source: Fig. 3S: fold change > 1
source_species_code: MM
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_full:
  While a number of DNA binding transcription factors have been identified that control hematopoietic cell fate decisions, only a limited number of transcriptional corepressors (e.g., the retinoblastoma protein [pRB] and the nuclear hormone corepressor [N-CoR]) have been linked to these functions. Here, we show that the transcriptional corepressor Mtg16 (myeloid translocation gene on chromosome 16), which is targeted by t(16;21) in acute myeloid leukemia, is required for hematopoietic progenitor cell fate decisions and for early progenitor cell proliferation. Inactivation of Mtg16 skewed early myeloid progenitor cells toward the granulocytic/macrophage lineage while reducing the numbers of megakaryocyte-erythroid progenitor cells. In addition, inactivation of Mtg16 impaired the rapid expansion of short-term stem cells, multipotent progenitor cells, and megakaryocyte-erythroid progenitor cells that is required under hematopoietic stress/emergency. This impairment appears to be a failure to proliferate rather than an induction of cell death, as expression of c-Myc, but not Bcl2, complemented the Mtg16(-/-) defect.


systematic_name: M2226
exact_source: Suppl. File: TERcomparison.xls: red
source_species_code: MM
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in erythroid progenitor cells from fetal livers of E13.5 embryos with KLF1 [GeneID=10661] knockout compared to those from the wild type embryos.

description_full:
  Erythroid Krüppel-like factor (EKLF) is a Krüppel-like transcription factor identified as a transcriptional activator and chromatin modifier in erythroid cells. EKLF-deficient (Eklf(-/-)) mice die at day 14.5 of gestation from severe anemia. In this study, we demonstrate that early progenitor cells fail to undergo terminal erythroid differentiation in Eklf(-/-) embryos. To discover potential EKLF target genes responsible for the failure of erythropoiesis, transcriptional profiling was performed with RNA from wild-type and Eklf(-/-) early erythroid progenitor cells. These analyses identified significant perturbation of a network of genes involved in cell cycle regulation, with the critical regulator of the cell cycle, E2f2, at a hub. E2f2 mRNA and protein levels were markedly decreased in Eklf(-/-) early erythroid progenitor cells, which showed a delay in the G(1)-to-S-phase transition. Chromatin immunoprecipitation analysis demonstrated EKLF occupancy at the proximal E2f2 promoter in vivo. Consistent with the role of EKLF as a chromatin modifier, EKLF binding sites in the E2f2 promoter were located in a region of EKLF-dependent DNase I sensitivity in early erythroid progenitor cells. We propose a model in which EKLF-dependent activation and modification of the E2f2 locus is required for cell cycle progression preceding terminal erythroid differentiation.


systematic_name: M2247
exact_source: Table 2S: Found in=WT_III
source_species_code: MM
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Late response genes: differentially expressed only 12 h after UV-C irradiation of MEF cells (embryonic fibroblast).

description_full:
  Phosphorylation is important in p53-mediated DNA damage responses. After UV irradiation, p53 is phosphorylated specifically at murine residue Ser389. Phosphorylation mutant p53.S389A cells and mice show reduced apoptosis and compromised tumor suppression after UV irradiation. We investigated the underlying cellular processes by time-series analysis of UV-induced gene expression responses in wild-type, p53.S389A, and p53(-/-) mouse embryonic fibroblasts. The absence of p53.S389 phosphorylation already causes small endogenous gene expression changes for 2,253, mostly p53-dependent, genes. These genes showed basal gene expression levels intermediate to the wild type and p53(-/-), possibly to readjust the p53 network. Overall, the p53.S389A mutation lifts p53-dependent gene repression to a level similar to that of p53(-/-) but has lesser effect on p53-dependently induced genes. In the wild type, the response of 6,058 genes to UV irradiation was strictly biphasic. The early stress response, from 0 to 3 h, results in the activation of processes to prevent the accumulation of DNA damage in cells, whereas the late response, from 12 to 24 h, relates more to reentering the cell cycle. Although the p53.S389A UV gene response was only subtly changed, many cellular processes were significantly affected. The early response was affected the most, and many cellular processes were phase-specifically lost, gained, or altered, e.g., induction of apoptosis, cell division, and DNA repair, respectively. Altogether, p53.S389 phosphorylation seems essential for many p53 target genes and p53-dependent processes.


systematic_name: M2248
exact_source: Table 2S: Found in=WT_I, WT_III
source_species_code: MM
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Early-late response genes: differentially expressed in the first 3 h and after 12 h following UV-C irradiation of MEF cells (embryonic fibroblast).

description_full:
  Phosphorylation is important in p53-mediated DNA damage responses. After UV irradiation, p53 is phosphorylated specifically at murine residue Ser389. Phosphorylation mutant p53.S389A cells and mice show reduced apoptosis and compromised tumor suppression after UV irradiation. We investigated the underlying cellular processes by time-series analysis of UV-induced gene expression responses in wild-type, p53.S389A, and p53(-/-) mouse embryonic fibroblasts. The absence of p53.S389 phosphorylation already causes small endogenous gene expression changes for 2,253, mostly p53-dependent, genes. These genes showed basal gene expression levels intermediate to the wild type and p53(-/-), possibly to readjust the p53 network. Overall, the p53.S389A mutation lifts p53-dependent gene repression to a level similar to that of p53(-/-) but has lesser effect on p53-dependently induced genes. In the wild type, the response of 6,058 genes to UV irradiation was strictly biphasic. The early stress response, from 0 to 3 h, results in the activation of processes to prevent the accumulation of DNA damage in cells, whereas the late response, from 12 to 24 h, relates more to reentering the cell cycle. Although the p53.S389A UV gene response was only subtly changed, many cellular processes were significantly affected. The early response was affected the most, and many cellular processes were phase-specifically lost, gained, or altered, e.g., induction of apoptosis, cell division, and DNA repair, respectively. Altogether, p53.S389 phosphorylation seems essential for many p53 target genes and p53-dependent processes.


systematic_name: M2259
exact_source: Table 2S: Fold change > 0
source_species_code: MM
GEO_id: GSE8454
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Partial list of genes up-regulated in the kidney of GLIS2 [GeneID=84662] knockout mice compared to the wild type.

description_full:
  To obtain insight into the physiological functions of the Krüppel-like zinc finger protein Gli-similar 2 (Glis2), mice deficient in Glis2 expression were generated. Glis2 mutant (Glis2(mut)) mice exhibit significantly shorter life spans than do littermate wild-type (WT) mice due to the development of progressive chronic kidney disease with features resembling nephronophthisis. Glis2(mut) mice develop severe renal atrophy involving increased cell death and basement membrane thickening in the proximal convoluted tubules. This development is accompanied by infiltration of lymphocytic inflammatory cells and interstitial/glomerular fibrosis. The severity of the fibrosis, inflammatory infiltrates, and glomerular and tubular changes progresses with age. Blood urea nitrogen and creatinine increase, and Glis2(mut) mice develop proteinuria and ultimately die prematurely of renal failure. A comparison of the gene expression profiles of kidneys from 25-day-old/60-day-old WT and Glis2(mut) mice by microarray analysis showed increased expressions of many genes involved in immune responses/inflammation and fibrosis/tissue remodeling in kidneys of Glis2(mut) mice, including several cytokines and adhesion and extracellular matrix proteins. Our data demonstrate that a deficiency in Glis2 expression leads to tubular atrophy and progressive fibrosis, similar to nephronophthisis, that ultimately results in renal failure. Our study indicates that Glis2 plays a critical role in the maintenance of normal kidney architecture and functions.


description_brief: Genes up-regulated in ES (embryonic stem cells) with defficient SUZ12 [GeneID=23512].
systematic_name: M2291
exact_source: Table 1S: FC > 0
source_species_code: MM
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_full:
  Polycomb group (PcG) proteins form multiprotein complexes, called Polycomb repressive complexes (PRCs). PRC2 contains the PcG proteins EZH2, SUZ12, and EED and represses transcription through methylation of lysine (K) 27 of histone H3 (H3). Suz12 is essential for PRC2 activity and its inactivation results in early lethality of mouse embryos. Here, we demonstrate that Suz12(-/-) mouse embryonic stem (ES) cells can be established and expanded in tissue culture. The Suz12(-/-) ES cells are characterized by global loss of H3K27 trimethylation (H3K27me3) and higher expression levels of differentiation-specific genes. Moreover, Suz12(-/-) ES cells are impaired in proper differentiation, resulting in a lack of repression of ES cell markers as well as activation of differentiation-specific genes. Finally, we demonstrate that the PcGs are actively recruited to several genes during ES cell differentiation, which despite an increase in H3K27me3 levels is not always sufficient to prevent transcriptional activation. In summary, we demonstrate that Suz12 is required for the establishment of specific expression programs required for ES cell differentiation. Furthermore, we provide evidence that PcGs have different mechanisms to regulate transcription during cellular differentiation.


description_brief: Genes up-regulated in uterus upon knockout of BMP2 [GeneID=650].
systematic_name: M2324
exact_source: Table 2S
source_species_code: MM
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_full:
  The process of implantation, necessary for all viviparous birth, consists of tightly regulated events, including apposition of the blastocyst, attachment to the uterine lumen, and differentiation of the uterine stroma. In rodents and primates the uterine stroma undergoes a process called decidualization. Decidualization, the process by which the uterine endometrial stroma proliferates and differentiates into large epithelioid decidual cells, is critical to the establishment of fetal-maternal communication and the progression of implantation. The role of bone morphogenetic protein 2 (Bmp2) in regulating the transformation of the uterine stroma during embryo implantation in the mouse was investigated by the conditional ablation of Bmp2 in the uterus using the (PR-cre) mouse. Bmp2 gene ablation was confirmed by real-time PCR analysis in the PR-cre; Bmp2fl/fl (termed Bmp2d/d) uterus. While littermate controls average 0.9 litter of 6.2+/-0.7 pups per month, Bmp2d/d females are completely infertile. Analysis of the infertility indicates that whereas embryo attachment is normal in the Bmp2d/d as in control mice, the uterine stroma is incapable of undergoing the decidual reaction to support further embryonic development. Recombinant human BMP2 can partially rescue the decidual response, suggesting that the observed phenotypes are not due to a developmental consequence of Bmp2 ablation. Microarray analysis demonstrates that ablation of Bmp2 leads to specific gene changes, including disruption of the Wnt signaling pathway, Progesterone receptor (PR) signaling, and the induction of prostaglandin synthase 2 (Ptgs2). Taken together, these data demonstrate that Bmp2 is a critical regulator of gene expression and function in the murine uterus.


systematic_name: M2351
exact_source: Table 4S: Ratio < -1
source_species_code: MM
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in leukemic progenitor cells expressing activated fusion of ESWR1 and FLI1 [GeneID=2130, 2313] compared to normal hematopoetic progenitors.

description_full:
  EWS/FLI-1 is a chimeric oncogene generated by chromosomal translocation in Ewing tumors, a family of poorly differentiated pediatric tumors arising predominantly in bone but also in soft tissue. The fusion gene combines sequences encoding a strong transactivating domain from the EWS protein with the DNA binding domain of FLI-1, an ETS transcription factor. A related fusion, TLS/ERG, has been found in myeloid leukemia. To determine EWS/FLI-1 function in vivo, we engineered mice with Cre-inducible expression of EWS/FLI-1 from the ubiquitous Rosa26 locus. When crossed with Mx1-cre mice, Cre-mediated activation of EWS/FLI-1 resulted in the rapid development of myeloid/erythroid leukemia characterized by expansion of primitive mononuclear cells causing hepatomegaly, splenomegaly, severe anemia, and death. The disease could be transplanted serially into naïve recipients. Gene expression profiles of primary and transplanted animals were highly similar, suggesting that activation of EWS/FLI-1 was the primary event leading to disease in this model. The Cre-inducible EWS/FLI-1 mouse provides a novel model system to study the contribution of this oncogene to malignant disease in vivo.


systematic_name: M2369
exact_source: Suppl. file 2: cluster 3
source_species_code: MM
GEO_id: GSE14406
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated during differentiation of Oli-Neu cells (oligodendroglial precursor) in response to PD174265 [PubChem=4709].

description_full:
  Inadequate remyelination of brain white matter lesions has been associated with a failure of oligodendrocyte precursors to differentiate into mature, myelin-producing cells. In order to better understand which genes play a critical role in oligodendrocyte differentiation, we performed time-dependent, genome-wide gene expression studies of mouse Oli-neu cells as they differentiate into process-forming and myelin basic protein-producing cells, following treatment with three different agents. Our data indicate that different inducers activate distinct pathways that ultimately converge into the completely differentiated state, where regulated gene sets overlap maximally. In order to also gain insight into the functional role of genes that are regulated in this process, we silenced 88 of these genes using small interfering RNA and identified multiple repressors of spontaneous differentiation of Oli-neu, most of which were confirmed in rat primary oligodendrocyte precursors cells. Among these repressors were CNP, a well-known myelin constituent, and three phosphatases, each known to negatively control mitogen-activated protein kinase cascades. We show that a novel inhibitor for one of the identified genes, dual-specificity phosphatase DUSP10/MKP5, was also capable of inducing oligodendrocyte differentiation in primary oligodendrocyte precursors. Oligodendrocytic differentiation feedback loops may therefore yield pharmacological targets to treat disease related to dysfunctional myelin deposition.


description_brief: Genes up-regulated in MEF cells (embryonic fibroblast) with ELAVL1 [GeneID=1994] knocked out.
systematic_name: M2385
exact_source: Table 3b
source_species_code: MM
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_full:
  HuR is an RNA-binding protein implicated in a diverse array of pathophysiological processes due to its effects on the posttranscriptional regulation of AU- and U-rich mRNAs. Here we reveal HuR's requirement in embryonic development through its genetic ablation. Obligatory HuR-null embryos exhibited a stage retardation phenotype and failed to survive beyond midgestation. By means of conditional transgenesis, we restricted HuR's mutation in either embryonic or endothelial compartments to demonstrate that embryonic lethality is consequent to defects in extraembryonic placenta. HuR's absence impaired the invagination of allantoic capillaries into the chorionic trophoblast layer and the differentiation of syncytiotrophoblast cells that control the morphogenesis and vascularization of the placental labyrinth and fetal support. HuR-null embryos rescued from these placental defects proceeded to subsequent developmental stages but displayed defects in skeletal ossification, fusions in limb elements, and asplenia. By coupling gene expression measurements, data meta-analysis, and HuR-RNA association assays, we identified transcription and growth factor mRNAs controlled by HuR, primarily at the posttranscriptional level, to guide morphogenesis, specification, and patterning. Collectively, our data demonstrate the dominant role of HuR in organizing gene expression programs guiding placental labyrinth morphogenesis, skeletal specification patterns, and splenic ontogeny.


description_brief: Genes up-regulated in pancreatic islets upon knockout of HNF1A [GeneID=6927].
systematic_name: M2395
exact_source: Table 2S
source_species_code: MM
GEO_id: E-MEXP-1707
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_full:
  Heterozygous HNF1A mutations cause pancreatic-islet beta-cell dysfunction and monogenic diabetes (MODY3). Hnf1alpha is known to regulate numerous hepatic genes, yet knowledge of its function in pancreatic islets is more limited. We now show that Hnf1a deficiency in mice leads to highly tissue-specific changes in the expression of genes involved in key functions of both islets and liver. To gain insights into the mechanisms of tissue-specific Hnf1alpha regulation, we integrated expression studies of Hnf1a-deficient mice with identification of direct Hnf1alpha targets. We demonstrate that Hnf1alpha can bind in a tissue-selective manner to genes that are expressed only in liver or islets. We also show that Hnf1alpha is essential only for the transcription of a minor fraction of its direct-target genes. Even among genes that were expressed in both liver and islets, the subset of targets showing functional dependence on Hnf1alpha was highly tissue specific. This was partly explained by the compensatory occupancy by the paralog Hnf1beta at selected genes in Hnf1a-deficient liver. In keeping with these findings, the biological consequences of Hnf1a deficiency were markedly different in islets and liver. Notably, Hnf1a deficiency led to impaired large-T-antigen-induced growth and oncogenesis in beta cells yet enhanced proliferation in hepatocytes. Collectively, these findings show that Hnf1alpha governs broad, highly tissue-specific genetic programs in pancreatic islets and liver and reveal key consequences of Hnf1a deficiency relevant to the pathophysiology of monogenic diabetes.


systematic_name: M2419
exact_source: Table 1S_4
source_species_code: MM
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes with promoters bound by PPARG [GeneID=5468] at 8 day time point of adipocyte differentiation of 3T3-L1 cells (preadipocyte).

description_full:
  Control of cell differentiation occurs through transcriptional mechanisms and through epigenetic modification. Using a chromatin immunoprecipitation-on-chip approach, we performed a genome-wide search for target genes of peroxisome proliferator-activated receptor gamma (PPAR gamma) and its partner protein retinoid X receptor alpha during adipogenesis. We show that these two receptors target several genes that encode histone lysine methyltransferase SET domain proteins. The histone H4 Lys 20 (H4K20) monomethyltransferase PR-Set7/Setd8 gene is upregulated by PPAR gamma during adipogenesis, and the knockdown of PR-Set7/Setd8 suppressed adipogenesis. Intriguingly, monomethylated H4K20 (H4K20me1) levels are robustly increased toward the end of differentiation. PR-Set7/Setd8 positively regulates the expression of PPAR gamma and its targets through H4K20 monomethylation. Furthermore, the activation of PPAR gamma transcriptional activity leads to the induction of H4K20me1 modification of PPAR gamma and its targets and thereby promotes adipogenesis. We also show that PPAR gamma targets PPAR gamma2 and promotes its gene expression through H4K20 monomethylation. Our results connect transcriptional regulation and epigenetic chromatin modulation through H4K20 monomethylation during adipogenesis through a feedback loop.


systematic_name: M2437
exact_source: Table 2S: Differentially upregulated genes
source_species_code: MM
GEO_id: GSE16521
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in G1ME cells (megakaryocyte/erythroid progenitor lacking GATA1 [GeneID=2623]) upon knockdown of GATA2 [GeneID=2624] by RNAi.

description_full:
  GATA-2 is an essential transcription factor that regulates multiple aspects of hematopoiesis. Dysregulation of GATA-2 is a hallmark of acute megakaryoblastic leukemia in children with Down syndrome, a malignancy that is defined by the combination of trisomy 21 and a GATA1 mutation. Here, we show that GATA-2 is required for normal megakaryocyte development as well as aberrant megakaryopoiesis in Gata1 mutant cells. Furthermore, we demonstrate that GATA-2 indirectly controls cell cycle progression in GATA-1-deficient megakaryocytes. Genome-wide microarray analysis and chromatin immunoprecipitation studies revealed that GATA-2 regulates a wide set of genes, including cell cycle regulators and megakaryocyte-specific genes. Surprisingly, GATA-2 also negatively regulates the expression of crucial myeloid transcription factors, such as Sfpi1 and Cebpa. In the absence of GATA-1, GATA-2 prevents induction of a latent myeloid gene expression program. Thus, GATA-2 contributes to cell cycle progression and the maintenance of megakaryocyte identity of GATA-1-deficient cells, including GATA-1s-expressing fetal megakaryocyte progenitors. Moreover, our data reveal that overexpression of GATA-2 facilitates aberrant megakaryopoiesis.


systematic_name: M2446
exact_source: Table 3S: 10h TGFB1 treated vs untreated: Fold change < 0
source_species_code: MM
GEO_id: GSE15871
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in MEF cells (embryonic fibroblast) upon stimulation with TGFB1 [GeneID=7040] for 10 h.

description_full:
  Transforming growth factor beta (TGF-beta) and platelet-derived growth factor A (PDGFAlpha) play a central role in tissue morphogenesis and repair, but their interplay remain poorly understood. The nuclear factor I C (NFI-C) transcription factor has been implicated in TGF-beta signaling, extracellular matrix deposition, and skin appendage pathologies, but a potential role in skin morphogenesis or healing had not been assessed. To evaluate this possibility, we performed a global gene expression analysis in NFI-C(-/-) and wild-type embryonic primary murine fibroblasts. This indicated that NFI-C acts mostly to repress gene expression in response to TGF-beta1. Misregulated genes were prominently overrepresented by regulators of connective tissue inflammation and repair. In vivo skin healing revealed a faster inflammatory stage and wound closure in NFI-C(-/-) mice. Expression of PDGFA and PDGF-receptor alpha were increased in wounds of NFI-C(-/-) mice, explaining the early recruitment of macrophages and fibroblasts. Differentiation of fibroblasts to contractile myofibroblasts was also elevated, providing a rationale for faster wound closure. Taken together with the role of TGF-beta in myofibroblast differentiation, our results imply a central role of NFI-C in the interplay of the two signaling pathways and in regulation of the progression of tissue regeneration.


description_brief: Genes requiring MLL [GeneID=4297] for H3K4me3 and expression in MEF cells (embryonic fibroblast).
systematic_name: M2456
exact_source: Table 3S: sheet 1: Expression down (# times)=1 & ChIP-chip down (# times)=1
source_species_code: MM
GEO_id: GSE18258
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_full:
  A common landmark of activated genes is the presence of trimethylation on lysine 4 of histone H3 (H3K4) at promoter regions. Set1/COMPASS was the founding member and is the only H3K4 methylase in Saccharomyces cerevisiae; however, in mammals, at least six H3K4 methylases, Set1A and Set1B and MLL1 to MLL4, are found in COMPASS-like complexes capable of methylating H3K4. To gain further insight into the different roles and functional targets for the H3K4 methylases, we have undertaken a genome-wide analysis of H3K4 methylation patterns in wild-type Mll1(+/+) and Mll1(-)(/)(-) mouse embryonic fibroblasts (MEFs). We found that Mll1 is required for the H3K4 trimethylation of less than 5% of promoters carrying this modification. Many of these genes, which include developmental regulators such as Hox genes, show decreased levels of RNA polymerase II recruitment and expression concomitant with the loss of H3K4 methylation. Although Mll1 is only required for the methylation of a subset of Hox genes, menin, a component of the Mll1 and Mll2 complexes, is required for the overwhelming majority of H3K4 methylation at Hox loci. However, the loss of MLL3/MLL4 and/or the Set1 complexes has little to no effect on the H3K4 methylation of Hox loci or their expression levels in these MEFs. Together these data provide insight into the redundancy and specialization of COMPASS-like complexes in mammals and provide evidence for a possible role for Mll1-mediated H3K4 methylation in the regulation of transcriptional initiation.


description_brief: Genes with DNA sequences bound by RARG [GeneID=5916] in MEF cells (embryonic fibroblast).
systematic_name: M2461
exact_source: Table 1S: RARg-bound in MEF (354)
source_species_code: MM
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_full:
  All-trans retinoic acid (RA) induces transforming growth factor beta (TGF-beta)-dependent autocrine growth of mouse embryonic fibroblasts (MEFs). We have used chromatin immunoprecipitation to map 354 RA receptor (RAR) binding loci in MEFs, most of which were similarly occupied by the RAR alpha and RAR gamma receptors. Only a subset of the genes associated with these loci are regulated by RA, among which are several critical components of the TGF-beta pathway. We also show RAR binding to a novel series of target genes involved in cell cycle regulation, transformation, and metastasis, suggesting new pathways by which RA may regulate proliferation and cancer. Few of the RAR binding loci contained consensus direct-repeat (DR)-type elements. The majority comprised either degenerate DRs or no identifiable DRs but anomalously spaced half sites. Furthermore, we identify 462 RAR target loci in embryonic stem (ES) cells and show that their occupancy is cell type specific. Our results also show that differences in the chromatin landscape regulate the accessibility of a subset of more than 700 identified loci to RARs, thus modulating the repertoire of target genes that can be regulated and the biological effects of RA.


systematic_name: M2464
exact_source: Table 1S: RA-regulation of target genes: Log change > 0
source_species_code: MM
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes bound by RARG [GeneID=5916] and up-regulated by tretinoin (all-trans retinoic acid, ATRA) [PubChem=444795] in MEF cells (embryonic fibroblast).

description_full:
  All-trans retinoic acid (RA) induces transforming growth factor beta (TGF-beta)-dependent autocrine growth of mouse embryonic fibroblasts (MEFs). We have used chromatin immunoprecipitation to map 354 RA receptor (RAR) binding loci in MEFs, most of which were similarly occupied by the RAR alpha and RAR gamma receptors. Only a subset of the genes associated with these loci are regulated by RA, among which are several critical components of the TGF-beta pathway. We also show RAR binding to a novel series of target genes involved in cell cycle regulation, transformation, and metastasis, suggesting new pathways by which RA may regulate proliferation and cancer. Few of the RAR binding loci contained consensus direct-repeat (DR)-type elements. The majority comprised either degenerate DRs or no identifiable DRs but anomalously spaced half sites. Furthermore, we identify 462 RAR target loci in embryonic stem (ES) cells and show that their occupancy is cell type specific. Our results also show that differences in the chromatin landscape regulate the accessibility of a subset of more than 700 identified loci to RARs, thus modulating the repertoire of target genes that can be regulated and the biological effects of RA.


description_brief: Loci bound exclusively by SALL4 [GeneID=57167] isoform b in ES cells (embryonic stem).
systematic_name: M2520
exact_source: Table 1S, 2S: bound by Sall4b but not by Sall4a
source_species_code: MM
GEO_id: GSE21056
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_full:
  Murine embryonic stem (ES) cells are defined by continuous self-renewal and pluripotency. A diverse repertoire of protein isoforms arising from alternative splicing is expressed in ES cells without defined biological roles. Sall4, a transcription factor essential for pluripotency, exists as two isoforms (Sall4a and Sall4b). Both isoforms can form homodimers and a heterodimer with each other, and each can interact with Nanog. By genomewide location analysis, we determined that Sall4a and Sall4b have overlapping, but not identical binding sites within the ES cell genome. In addition, Sall4b, but not Sall4a, binds preferentially to highly expressed loci in ES cells. Sall4a and Sall4b binding sites are distinguished by both epigenetic marks at target loci and their clustering with binding sites of other pluripotency factors. When ES cells expressing a single isoform of Sall4 are generated, Sall4b alone could maintain the pluripotent state, although it could not completely suppress all differentiation markers. Sall4a and Sall4b collaborate in maintenance of the pluripotent state but play distinct roles. Our work is novel in establishing such isoform-specific differences in ES cells.


description_brief: Genes consistently up-regulated in mammary stem cells both in mouse and human species.
systematic_name: M2573
exact_source: Table 1S: Up-regulated in the MaSC-enriched subset
source_species_code: MM
GEO_id: GSE19446
contributor: Daniel Hollern
contrib_organization: Michigan State University
description_full:
  INTRODUCTION: Molecular characterization of the normal epithelial cell types that reside in the mammary gland is an important step toward understanding pathways that regulate self-renewal, lineage commitment, and differentiation along the hierarchy. Here we determined the gene expression signatures of four distinct subpopulations isolated from the mouse mammary gland. The epithelial cell signatures were used to interrogate mouse models of mammary tumorigenesis and to compare with their normal human counterpart subsets to identify conserved genes and networks.METHODS: RNA was prepared from freshly sorted mouse mammary cell subpopulations (mammary stem cell (MaSC)-enriched, committed luminal progenitor, mature luminal and stromal cell) and used for gene expression profiling analysis on the Illumina platform. Gene signatures were derived and compared with those previously reported for the analogous normal human mammary cell subpopulations. The mouse and human epithelial subset signatures were then subjected to Ingenuity Pathway Analysis (IPA) to identify conserved pathways.RESULTS: The four mouse mammary cell subpopulations exhibited distinct gene signatures. Comparison of these signatures with the molecular profiles of different mouse models of mammary tumorigenesis revealed that tumors arising in MMTV-Wnt-1 and p53-/- mice were enriched for MaSC-subset genes, whereas the gene profiles of MMTV-Neu and MMTV-PyMT tumors were most concordant with the luminal progenitor cell signature. Comparison of the mouse mammary epithelial cell signatures with their human counterparts revealed substantial conservation of genes, whereas IPA highlighted a number of conserved pathways in the three epithelial subsets.CONCLUSIONS: The conservation of genes and pathways across species further validates the use of the mouse as a model to study mammary gland development and highlights pathways that are likely to govern cell-fate decisions and differentiation. It is noteworthy that many of the conserved genes in the MaSC population have been considered as epithelial-mesenchymal transition (EMT) signature genes. Therefore, the expression of these genes in tumor cells may reflect basal epithelial cell characteristics and not necessarily cells that have undergone an EMT. Comparative analyses of normal mouse epithelial subsets with murine tumor models have implicated distinct cell types in contributing to tumorigenesis in the different models.


description_brief: Genes up-regulated in the HSC supportive stromal cell lines.
systematic_name: M2581
exact_source: personal communication
source_species_code: MM
contributor: Charles Durand
contrib_organization: Pierre and Marie Curie University
description_full:
  Stromal cell lines represent an exceptional tool to study the role on the microenvironment on hematopoietic stem cell (HSC) activity. We have compared the expression profile of HSC supportive vs non-supportive stromal lines generated from different hematopoietic tissues in the mouse, i.e the aorta-gonad-mesonephros (AGM) region, the fetal liver and the adult bone marrow, sequentially activated during development. In this study, six stromal lines were used with one HSC supportive and one non-supportive for each tissue (triplicate samples for each stromal line). We used Mouse Gene 1.0 ST microrrays in combination with GSEA and statistical analysis to identify lists of genes that segregate HSC supportive from non-supportive stromal lines.


description_brief: Genes down-regulated in preneoplastic mammary tissues and whose expression is maintained in tumors.
systematic_name: M9908
exact_source: Table 1S
source_species_code: MM
GEO_id: GSE3501
contributor: Lauren Kazmierski
contrib_organization: MSigDB Team
description_full:
  Epidemiological studies indicate that parity enhances HER2/ErbB2/Neu-induced breast tumorigenesis. Furthermore, recent studies using multiparous, ErbB2/Neu-overexpressing mouse mammary tumor virus (MMTV-Neu) mice have shown that parity induces a population of cells that are targeted for ErbB2/Neu-induced transformation. Although parity accelerates mammary tumorigenesis, the pattern of tumor development in multiparous MMTV-Neu mice remains stochastic, suggesting that additional events are required for ErbB2/Neu to cause mammary tumors. Whether such events are genetic in nature or reflective of the dynamic hormonal control of the gland that occurs with pregnancy remains unclear. We postulated that young age at pregnancy initiation or chronic trophic maintenance of mammary epithelial cells might provide a cellular environment that significantly increases susceptibility to ErbB2/Neu-induced tumorigenesis. MMTV-Neu mice that were maintained pregnant or lactating beginning at 3 weeks of age demonstrated accelerated tumorigenesis, but this process was still stochastic, indicating that early pregnancy does not provide the requisite events of tumorigenesis. However, bitransgenic mice that were generated by breeding MMTV-Neu mice with a luteinizing hormone-overexpressing mouse model of ovarian hyperstimulation developed multifocal mammary tumors in an accelerated, synchronous manner compared to virgin MMTV-Neu animals. This synchrony of tumor development in the bitransgenic mice suggests that trophic maintenance of the mammary gland provides the additional events required for tumor formation and maintains the population of cells that are targeted by ErbB2/Neu for transformation. Both the synchrony of tumor appearance and the ability to characterize a window of commitment by ovariectomy/palpation studies permitted microarray analysis to evaluate changes in gene expression over a defined timeline that spans the progression from normal to preneoplastic mammary tissue. These approaches led to identification of several candidate genes whose expression changes in the mammary gland with commitment to ErbB2/Neu-induced tumorigenesis, suggesting that they may either be regulated by ErbB2/Neu and/or contribute to tumor formation.


systematic_name: M15891
exact_source: Table 1b
source_species_code: MM
GEO_id: GSE2684
contributor: Lauren Kazmierski
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in MEF cells (embryonic fibroblasts) with TERT [GeneID=7015] knockout, after expression of the gene off a retroviral vector.

description_full:
  Here, we show that ectopic expression of the catalytic subunit of mouse telomerase (mTert) confers a growth advantage to primary murine embryonic fibroblasts (MEFs), which have very long telomeres, as well as facilitates their spontaneous immortalization and increases their colony-forming capacity upon activation of oncogenes. We demonstrate that these telomere length-independent growth-promoting effects of mTert overexpression require catalytically active mTert, as well as the formation of mTert/Terc complexes. The gene expression profile of mTert-overexpressing MEFs indicates that telomerase enhances growth in these cells through the repression of growth-inhibiting genes of the transforming growth factor-beta (TGF-beta) signaling network. We functionally validate this result by showing that mTert abrogates the growth-inhibitory effect of TGF-beta in MEFs, thus demonstrating that telomerase increments the proliferative potential of primary mouse embryonic fibroblasts by targeting the TGF-beta pathway.


systematic_name: M18773
exact_source: Table 3: delta(i) > 0
source_species_code: MM
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in MEF cells (embryonic fibroblasts) isolated from HRAS and NRAS [GeneID=3265;4893] double knockout mice.

description_full:
  We characterized differential gene expression profiles of fibroblast cell lines harboring single or double-homozygous null mutations in H-ras and N-ras. Whereas the expression level of the individual H-, N- and K-ras genes appeared unaffected by the presence or absence of the other ras loci, significant differences were observed between the expression profiles of cells missing N-ras and/or H-ras. Absence of N-ras produced much stronger effects than absence of H-ras over the profile of the cellular transcriptome. N-ras(-/-) and H-ras(-/-) fibroblasts displayed rather antagonistic expression profiles and the transcriptome of H-ras(-/-) cells was significantly closer to that of wild-type fibroblasts than to that of N-ras(-/-) cells. Classifying all differentially expressed genes into functional categories suggested specific roles for H-Ras and N-Ras. It was particularly striking in N-ras(-/-) cells the upregulation of a remarkable number of immunity-related genes, as well as of several loci involved in apoptosis. Reverse-phase protein array assays demonstrated in the same N-ras(-/-) cells the overexpression and nuclear migration of tyrosine phosphorylated signal transducer and activator of transcription 1 (Stat1) which was concomitant with transcriptional activation mediated by interferon-stimulated response elements. Significantly enhanced numbers of apoptotic cells were also detected in cultures of N-ras(-/-) cells. Our data support the notion that different Ras isoforms play functionally distinct cellular roles and indicate that N-Ras is significantly involved in immune modulation/host defense and apoptotic responses.


systematic_name: M18168
exact_source: Table 2: delta(i) > 0
source_species_code: MM
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in MEF cells (embryonic fibroblast) isolated from NRAS [GeneID=4893] knockout mice.

description_full:
  We characterized differential gene expression profiles of fibroblast cell lines harboring single or double-homozygous null mutations in H-ras and N-ras. Whereas the expression level of the individual H-, N- and K-ras genes appeared unaffected by the presence or absence of the other ras loci, significant differences were observed between the expression profiles of cells missing N-ras and/or H-ras. Absence of N-ras produced much stronger effects than absence of H-ras over the profile of the cellular transcriptome. N-ras(-/-) and H-ras(-/-) fibroblasts displayed rather antagonistic expression profiles and the transcriptome of H-ras(-/-) cells was significantly closer to that of wild-type fibroblasts than to that of N-ras(-/-) cells. Classifying all differentially expressed genes into functional categories suggested specific roles for H-Ras and N-Ras. It was particularly striking in N-ras(-/-) cells the upregulation of a remarkable number of immunity-related genes, as well as of several loci involved in apoptosis. Reverse-phase protein array assays demonstrated in the same N-ras(-/-) cells the overexpression and nuclear migration of tyrosine phosphorylated signal transducer and activator of transcription 1 (Stat1) which was concomitant with transcriptional activation mediated by interferon-stimulated response elements. Significantly enhanced numbers of apoptotic cells were also detected in cultures of N-ras(-/-) cells. Our data support the notion that different Ras isoforms play functionally distinct cellular roles and indicate that N-Ras is significantly involved in immune modulation/host defense and apoptotic responses.


systematic_name: M10253
exact_source: Table 5S: RhoAi < 1
source_species_code: MM
GEO_id: GSE5913
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in NIH3T3 cells (fibroblasts) after treatment with Y27632 [PubChem=123862], an inhibitor of ROCK proteins; the changes did not depend on expression of constitutively active (Q63L) form of RHOA [GeneID=387].

description_full:
  We have used microarray technology to identify the transcriptional targets of Rho subfamily guanosine 5'-triphosphate (GTP)ases in NIH3T3 cells. This analysis indicated that murine fibroblasts transformed by these proteins show similar transcriptomal profiles. Functional annotation of the regulated genes indicate that Rho subfamily GTPases target a wide spectrum of functions, although loci encoding proteins linked to proliferation and DNA synthesis/transcription are upregulated preferentially. Rho proteins promote four main networks of interacting proteins nucleated around E2F, c-Jun, c-Myc and p53. Of those, E2F, c-Jun and c-Myc are essential for the maintenance of cell transformation. Inhibition of Rock, one of the main Rho GTPase targets, leads to small changes in the transcriptome of Rho-transformed cells. Rock inhibition decreases c-myc gene expression without affecting the E2F and c-Jun pathways. Loss-of-function studies demonstrate that c-Myc is important for the blockage of cell-contact inhibition rather than for promoting the proliferation of Rho-transformed cells. However, c-Myc overexpression does not bypass the inhibition of cell transformation induced by Rock blockage, indicating that c-Myc is essential, but not sufficient, for Rock-dependent transformation. These results reveal the complexity of the genetic program orchestrated by the Rho subfamily and pinpoint protein networks that mediate different aspects of the malignant phenotype of Rho-transformed cells.


systematic_name: M16834
exact_source: Table 3S: RhoAi > 1 & RhoA < 1
source_species_code: MM
GEO_id: GSE5913
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in NIH3T3 cells (fibroblasts) transformed by  expression of contitutively active (Q63L) form of RHOA [GeneID=387] off plasmid vector; their expression reverted completely after treatment with Y27632 [PubChem=123862], an inhibitor of ROCK proteins.

description_full:
  We have used microarray technology to identify the transcriptional targets of Rho subfamily guanosine 5'-triphosphate (GTP)ases in NIH3T3 cells. This analysis indicated that murine fibroblasts transformed by these proteins show similar transcriptomal profiles. Functional annotation of the regulated genes indicate that Rho subfamily GTPases target a wide spectrum of functions, although loci encoding proteins linked to proliferation and DNA synthesis/transcription are upregulated preferentially. Rho proteins promote four main networks of interacting proteins nucleated around E2F, c-Jun, c-Myc and p53. Of those, E2F, c-Jun and c-Myc are essential for the maintenance of cell transformation. Inhibition of Rock, one of the main Rho GTPase targets, leads to small changes in the transcriptome of Rho-transformed cells. Rock inhibition decreases c-myc gene expression without affecting the E2F and c-Jun pathways. Loss-of-function studies demonstrate that c-Myc is important for the blockage of cell-contact inhibition rather than for promoting the proliferation of Rho-transformed cells. However, c-Myc overexpression does not bypass the inhibition of cell transformation induced by Rock blockage, indicating that c-Myc is essential, but not sufficient, for Rock-dependent transformation. These results reveal the complexity of the genetic program orchestrated by the Rho subfamily and pinpoint protein networks that mediate different aspects of the malignant phenotype of Rho-transformed cells.


systematic_name: M2895
exact_source: Table 1S
source_species_code: MM
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in MEF cells (embryonic fibroblasts) isolated from RB1 [GeneID=5925] knockout mice: chronic loss of function (LOF) of RB1.

description_full:
  Functional inactivation of the retinoblastoma tumor suppressor gene product (RB) is a common event in human cancers. Classically, RB functions to constrain cellular proliferation, and loss of RB is proposed to facilitate the hyperplastic proliferation associated with tumorigenesis. To understand the repertoire of regulatory processes governed by RB, two models of RB loss were utilized to perform microarray analysis. In murine embryonic fibroblasts harboring germline loss of RB, there was a striking deregulation of gene expression, wherein distinct biological pathways were altered. Specifically, genes involved in cell cycle control and classically associated with E2F-dependent gene regulation were upregulated via RB loss. In contrast, a program of gene expression associated with immune function and response to pathogens was significantly downregulated with the loss of RB. To determine the specific influence of RB loss during a defined period and without the possibility of developmental compensation as occurs in embryonic fibroblasts, a second system was employed wherein Rb was acutely knocked out in adult fibroblasts. This model confirmed the distinct regulation of cell cycle and immune modulatory genes through RB loss. Analyses of cis-elements supported the hypothesis that the majority of those genes upregulated with RB loss are regulated via the E2F family of transcription factors. In contrast, those genes whose expression was reduced with the loss of RB harbored different promoter elements. Consistent with these analyses, we found that disruption of E2F-binding function of RB was associated with the upregulation of gene expression. In contrast, cells harboring an RB mutant protein (RB-750F) that retains E2F-binding activity, but is specifically deficient in the association with LXCXE-containing proteins, failed to upregulate these same target genes. However, downregulation of genes involved in immune function was readily observed with disruption of the LXCXE-binding function of RB. Thus, these studies demonstrate that RB plays a significant role in both the positive and negative regulations of transcriptional programs and indicate that loss of RB has distinct biological effects related to both cell cycle control and immune function.


systematic_name: M7094
exact_source: Table 2S
source_species_code: MM
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in adult fibroblasts with inactivated RB1 [GeneID=5925] by Cre-lox: acute loss of function (LOF) of RB1.

description_full:
[cell repeats an earlier one in this file: 2274 characters]


systematic_name: M1098
exact_source: Online supplement ME-ACells0PercFCS.xls
source_species_code: MM
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in ME-A cells (breast cancer) undergoing apoptosis upon serum starvation (5% to 0% FCS) for 22 hr.

description_full:
[cell repeats an earlier one in this file: 1918 characters]


systematic_name: M13715
exact_source: Table 1: Decreased in tumors
source_species_code: MM
GEO_id: GSE2528
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Down-regulated genes from the 65 most significantly changed (p<0.01) genes identified by two analytical methods in the mammary tumors induced by transgenic expression of ERBB2 [GeneID=2064].

description_full:
  Upregulation of HER2/ErbB2/Neu occurs in 15-30% of human breast cancers and correlates with poor prognosis. Identification of ErbB2/Neu transcriptional targets should facilitate development of novel therapeutic approaches. Development of breast cancer is a multistep process; thus, to identify the transcriptomes associated with different stages of progression of tumorigenesis, we compared expression profiles of mammary tumors and preneoplastic mammary tissue from MMTV-Neu transgenic mice to expression profiles of wild-type mammary glands using Affymetrix microarrays. We identified 324 candidate genes that were unique to ErbB2/Neu-induced tumors relative to normal mammary gland tissue from wild-type controls. Expression of a subset of these genes (82) was also changed in the preneoplastic mammary glands compared to wild-type controls, indicating that they may play a pivotal role during early events of ErbB2/Neu-initiated mammary tumorigenesis. Further analysis of the microarray data revealed that expression of several known transforming growth factor (TGF)-beta target genes was altered, suggesting that the TGF-beta signaling cascade is downregulated in ErbB2/Neu-induced tumors. Western blot analysis for TGF-beta-Receptor-I/ALK5 and immunohistochemistry for TGF-beta-Receptor-I/ALK5 and phosphorylated/activated Smad2 confirmed that the Smad-dependent TGF-beta signaling cascade was inactive in these tumors. Although absent in most of the tumor, phosphorylated Smad2 was present in the periphery of tumors. Interestingly, presence of phosphorylated/activated Smad2 correlated with expression of Activin-Receptor-IB/ALK4, suggesting that although Smad-dependent TGF-beta signaling is absent in ErbB2/Neu-induced tumors, Activin signaling may be active at the leading edge of these tumors. Cumulatively, these data indicate that the TGF-beta pathway is intrinsically suppressed in ErbB2/Neu tumors via a mechanism involving loss of TGF-beta-Receptor-I/ALK5.


systematic_name: M13447
exact_source: Table 2: Decreased in adjacent erbB2/neu samples
source_species_code: MM
GEO_id: GSE2528
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Down-regulated genes from top 82 genes out of the 324-gene signature identified in the pre-neoplastic tissue adjacent to the mammary tumors induced by transgenic expression of ERBB2 [GeneID=2064].

description_full:
  Upregulation of HER2/ErbB2/Neu occurs in 15-30% of human breast cancers and correlates with poor prognosis. Identification of ErbB2/Neu transcriptional targets should facilitate development of novel therapeutic approaches. Development of breast cancer is a multistep process; thus, to identify the transcriptomes associated with different stages of progression of tumorigenesis, we compared expression profiles of mammary tumors and preneoplastic mammary tissue from MMTV-Neu transgenic mice to expression profiles of wild-type mammary glands using Affymetrix microarrays. We identified 324 candidate genes that were unique to ErbB2/Neu-induced tumors relative to normal mammary gland tissue from wild-type controls. Expression of a subset of these genes (82) was also changed in the preneoplastic mammary glands compared to wild-type controls, indicating that they may play a pivotal role during early events of ErbB2/Neu-initiated mammary tumorigenesis. Further analysis of the microarray data revealed that expression of several known transforming growth factor (TGF)-beta target genes was altered, suggesting that the TGF-beta signaling cascade is downregulated in ErbB2/Neu-induced tumors. Western blot analysis for TGF-beta-Receptor-I/ALK5 and immunohistochemistry for TGF-beta-Receptor-I/ALK5 and phosphorylated/activated Smad2 confirmed that the Smad-dependent TGF-beta signaling cascade was inactive in these tumors. Although absent in most of the tumor, phosphorylated Smad2 was present in the periphery of tumors. Interestingly, presence of phosphorylated/activated Smad2 correlated with expression of Activin-Receptor-IB/ALK4, suggesting that although Smad-dependent TGF-beta signaling is absent in ErbB2/Neu-induced tumors, Activin signaling may be active at the leading edge of these tumors. Cumulatively, these data indicate that the TGF-beta pathway is intrinsically suppressed in ErbB2/Neu tumors via a mechanism involving loss of TGF-beta-Receptor-I/ALK5.


systematic_name: M1102
exact_source: Online supplement ME-ACells0PercFCSAndMC.xls
source_species_code: MM
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in ME-A cells (breast cancer, sensitive to apoptotic stimuli) upon serum deprivation for 22 hr in the presence of medium concentrate (MC) from ME-C cells (breast cancer, resistant to apoptotic stimuli).

description_full:
[cell repeats an earlier one in this file: 1918 characters]


systematic_name: M16101
exact_source: Table 4S: RhoAi < 1
source_species_code: MM
GEO_id: GSE5913
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in NIH3T3 cells (fibroblasts) transfrormed by expression of constitutively active (Q63L) form of RHOA [GeneID=387] off plasmid vector; their expression did NOT reverted completely after treatment with Y27632 [PubChem=123862], an inhibitor of ROCK proteins.

description_full:
[cell repeats an earlier one in this file: 1498 characters]


systematic_name: M1116
exact_source: Table 1: Regulation=Up
source_species_code: MM
contributor: Lauren Kazmierski
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in MEF cells (embryonic fibroblasts) after knockout of PML [GeneID=5371] and whose promoters were bound by MYC [GeneID=4609].

description_full:
  c-myc is a well-known proto-oncogene encoding for a transcription factor that needs to be tightly regulated in order to preserve cell homeostasis. The Promyelocytic Leukaemia gene product PML plays an important role in cell growth and survival, and resides in discrete subnuclear structures called Nuclear Bodies (NB). We performed comparative analysis of the expression of 40 Myc target genes and of Myc binding to their regulatory regions both in wild-type and PML knockout cells. We demonstrate that if PML is absent, despite Myc binding to the DNA regulatory sequences is unchanged, the expression profile of several Myc target genes is altered. PML is largely involved in gene regulation, via recruitment of several transcription factors and cofactors to the NB. Consistently, we show that Myc partially localizes to the NB and physically interacts with PML, and that this localization depends on Myc expression levels. As deregulation occurs to both activated and repressed Myc target genes, we propose that PML influences Myc transcriptional activity through a mechanism that involves the control of Myc post-translational modifications.


systematic_name: M1117
exact_source: Table 1: Regulation=Down
source_species_code: MM
contributor: Lauren Kazmierski
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in MEF cells (embryonic fibroblasts) after knockout of PML [GeneID=5371] and whose promoters were bound by MYC [GeneID=4609].

description_full:
  c-myc is a well-known proto-oncogene encoding for a transcription factor that needs to be tightly regulated in order to preserve cell homeostasis. The Promyelocytic Leukaemia gene product PML plays an important role in cell growth and survival, and resides in discrete subnuclear structures called Nuclear Bodies (NB). We performed comparative analysis of the expression of 40 Myc target genes and of Myc binding to their regulatory regions both in wild-type and PML knockout cells. We demonstrate that if PML is absent, despite Myc binding to the DNA regulatory sequences is unchanged, the expression profile of several Myc target genes is altered. PML is largely involved in gene regulation, via recruitment of several transcription factors and cofactors to the NB. Consistently, we show that Myc partially localizes to the NB and physically interacts with PML, and that this localization depends on Myc expression levels. As deregulation occurs to both activated and repressed Myc target genes, we propose that PML influences Myc transcriptional activity through a mechanism that involves the control of Myc post-translational modifications.


systematic_name: M8901
exact_source: Table 2S: Fold change: TUvsWT < 1
source_species_code: MM
GEO_id: GSE2528
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Down-regulated genes from the 324 genes identified by two analytical methods as changed in the mammary tumors induced by transgenic expression of ERBB2 [GeneID=2064].

description_full:
  Upregulation of HER2/ErbB2/Neu occurs in 15-30% of human breast cancers and correlates with poor prognosis. Identification of ErbB2/Neu transcriptional targets should facilitate development of novel therapeutic approaches. Development of breast cancer is a multistep process; thus, to identify the transcriptomes associated with different stages of progression of tumorigenesis, we compared expression profiles of mammary tumors and preneoplastic mammary tissue from MMTV-Neu transgenic mice to expression profiles of wild-type mammary glands using Affymetrix microarrays. We identified 324 candidate genes that were unique to ErbB2/Neu-induced tumors relative to normal mammary gland tissue from wild-type controls. Expression of a subset of these genes (82) was also changed in the preneoplastic mammary glands compared to wild-type controls, indicating that they may play a pivotal role during early events of ErbB2/Neu-initiated mammary tumorigenesis. Further analysis of the microarray data revealed that expression of several known transforming growth factor (TGF)-beta target genes was altered, suggesting that the TGF-beta signaling cascade is downregulated in ErbB2/Neu-induced tumors. Western blot analysis for TGF-beta-Receptor-I/ALK5 and immunohistochemistry for TGF-beta-Receptor-I/ALK5 and phosphorylated/activated Smad2 confirmed that the Smad-dependent TGF-beta signaling cascade was inactive in these tumors. Although absent in most of the tumor, phosphorylated Smad2 was present in the periphery of tumors. Interestingly, presence of phosphorylated/activated Smad2 correlated with expression of Activin-Receptor-IB/ALK4, suggesting that although Smad-dependent TGF-beta signaling is absent in ErbB2/Neu-induced tumors, Activin signaling may be active at the leading edge of these tumors. Cumulatively, these data indicate that the TGF-beta pathway is intrinsically suppressed in ErbB2/Neu tumors via a mechanism involving loss of TGF-beta-Receptor-I/ALK5.


systematic_name: M16189
exact_source: Table 1S: RhoA Fold change > 1 (red)
source_species_code: MM
GEO_id: GSE5913
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in NIH3T3 cells (fibroblasts) transformed by  expression of contitutively active (Q63L) form of RHOA [GeneID=387] off plasmid vector.

description_full:
[cell repeats an earlier one in this file: 1498 characters]


description_brief: Genes up-regulated in brain tumors induced by retroviral delivery of PDGFB [GeneID=5155].
systematic_name: M1120
exact_source: Table 1S
source_species_code: MM
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_full:
  Retroviral tagging previously identified putative cancer-causing genes in a mouse brain tumor model where a recombinant Moloney murine leukemia virus encoding the platelet-derived growth factor B-chain (MMLV/PDGFB) was intracerebrally injected in newborn mice. In the present study, expression analysis using cDNA arrays revealed several similarities of virus-induced mouse gliomas with human brain tumors. Brain tumors with short latency contained on average 8.0 retroviral insertions and resembled human glioblastoma multiforme (GBM) whereas long-latency gliomas were of lower grade, similar to human oligodendroglioma (OD) and had 2.3 insertions per tumor. Several known and novel genes of tumor progression or cell markers were differentially expressed between OD- and GBM-like tumors. Array and quantitative real-time PCR analysis demonstrated elevated expression similar to Pdgfralpha of retrovirally tagged genes Abhd2, Ddr1, Fos, Ng2, Ppfibp1, Rad51b and Sulf2 in both glioma types compared to neonatal and adult normal brain. The retrovirally tagged genes Plekhb1, Prex1, Prkg2, Sox10 and 1200004M23Rik were upregulated in the tumors but had a different expression profile than Pdgfralpha whereas Rap1gap, Gli1, Neurl and Camk2b were downregulated in the tumors. The present study accentuates the proposed role of the retrovirally tagged genes in PDGF-driven gliomagenesis and indicates that insertional mutagenesis can promote glioma progression.


systematic_name: M1123
exact_source: Table 1a: Co. vs PAP < 0
source_species_code: MM
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in benign skin tumors (papilloma) induced by treatment with DMBA and TPA [PubChem=6001;4792] chemicals in the two stage skin carcinogenesis model.

description_full:
  Chemically induced mouse skin carcinogenesis represents the most extensively utilized animal model to unravel the multistage nature of tumour development and to design novel therapeutic concepts of human epithelial neoplasia. We combined this tumour model with comprehensive gene expression analysis and could identify a large set of novel tumour-associated genes that have not been associated with epithelial skin cancer development yet. Expression data of selected genes were confirmed by semiquantitative and quantitative RT-PCR as well as in situ hybridization and immunofluorescence analysis on mouse tumour sections. Enhanced expression of genes identified in our screen was also demonstrated in mouse keratinocyte cell lines that form tumours in vivo. Self-organizing map clustering was performed to identify different kinetics of gene expression and coregulation during skin cancer progression. Detailed analysis of differential expressed genes according to their functional annotation confirmed the involvement of several biological processes, such as regulation of cell cycle, apoptosis, extracellular proteolysis and cell adhesion, during skin malignancy. Finally, we detected high transcript levels of ANXA1, LCN2 and S100A8 as well as reduced levels for NDR2 protein in human skin tumour specimens demonstrating that tumour-associated genes identified in the chemically induced tumour model might be of great relevance for the understanding of human epithelial malignancies as well.


systematic_name: M1127
exact_source: Table 1b: Co. vs SCC < 0
source_species_code: MM
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in malignant skin tumors (squamous cell carcinoma, SCC) formed by treatment with DMBA and TPA [PubChem=6001;4792] in the two stage skin carcinogenesis model.

description_full:
  Chemically induced mouse skin carcinogenesis represents the most extensively utilized animal model to unravel the multistage nature of tumour development and to design novel therapeutic concepts of human epithelial neoplasia. We combined this tumour model with comprehensive gene expression analysis and could identify a large set of novel tumour-associated genes that have not been associated with epithelial skin cancer development yet. Expression data of selected genes were confirmed by semiquantitative and quantitative RT-PCR as well as in situ hybridization and immunofluorescence analysis on mouse tumour sections. Enhanced expression of genes identified in our screen was also demonstrated in mouse keratinocyte cell lines that form tumours in vivo. Self-organizing map clustering was performed to identify different kinetics of gene expression and coregulation during skin cancer progression. Detailed analysis of differential expressed genes according to their functional annotation confirmed the involvement of several biological processes, such as regulation of cell cycle, apoptosis, extracellular proteolysis and cell adhesion, during skin malignancy. Finally, we detected high transcript levels of ANXA1, LCN2 and S100A8 as well as reduced levels for NDR2 protein in human skin tumour specimens demonstrating that tumour-associated genes identified in the chemically induced tumour model might be of great relevance for the understanding of human epithelial malignancies as well.


systematic_name: M1141
exact_source: Table 1
source_species_code: MM
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Detoxification pathway genes down-regulated in enterocytes of transgenic mice expressing SV40 T antigen.

description_full:
  Toxic compounds such as carcinogens are removed from the body by the action of a series of detoxifying enzymes and transporters expressed in the liver and the small intestine. We have found that intestinal epithelial cells expressing the SV40 large T antigen (TAg) contain significantly lower levels of mRNAs, encoding several drug metabolizing/detoxifying enzymes and transporters compared to their non-transgenic littermates. In addition, TAg blocks the induction of these mRNAs by xenobiotics. The repression depends on an intact LXCXE motif in TAg, suggesting that inactivation of the retinoblastoma (Rb) family of tumor suppressors plays a role in the process. These results imply that a functional Rb pathway in the intestine is necessary for the expression of the detoxification system used to clear carcinogens, and suggest that loss of this tumor suppressor might alter susceptibility to chemical injury. In addition, the effect of TAg on the detoxification pathway appears to be tissue-specific, as its ectopic expression in the liver failed to suppress the P450 enzymes. The TAg-mediated suppression of drug metabolizing/detoxifying enzymes may have broad implications in the metabolism and mechanism of action of both carcinogens and prescription drugs.


systematic_name: M1157
exact_source: Table 1: induced by E2F3
source_species_code: MM
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in MEF cells (embryonic fibroblasts) at 16 hr after serum stimulation and knockdown of E2F3 [GeneID=1871] by RNAi.

description_full:
  Functions encoded by single genes in lower organisms are often represented by multiple related genes in the mammalian genome. An example is the retinoblastoma and E2F families of proteins that regulate transcription during the cell cycle. Analysis of gene function using germline mutations is often confounded by overlapping function resulting in compensation. Indeed, in cells deleted of the E2F1 or E2F3 genes, there is an increase in the expression of the other family member. To avoid complications of compensatory effects, we have used small-interfering RNAs that target individual E2F proteins to generate a temporary loss of E2F function. We find that both E2F1 and E2F3 are required for cells to enter the S phase from a quiescent state, whereas only E2F3 is necessary for the S phase in growing cells. We also find that the acute loss of E2F3 activity affects the expression of genes encoding DNA replication and mitotic activities, whereas loss of E2F1 affects a limited number of genes that are distinct from those regulated by E2F3. We conclude that the long-term loss of E2F activity does lead to compensation by other family members and that the analysis of acute loss of function reveals specific and distinct roles for these proteins.


systematic_name: M16458
exact_source: Table 1S
source_species_code: MM
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Selected gradually up-regulated genes in the TLX1 [GeneID=3195] Tet On iEBHX15-4 cells (pro-erythroblasts).

description_full:
  Aberrant expression of the human homeobox-containing proto-oncogene TLX1/HOX11 inhibits hematopoietic differentiation programs in a number of murine model systems. Here, we report the establishment of a murine erythroid progenitor cell line, iEBHX1S-4, developmentally arrested by regulatable TLX1 expression. Extinction of TLX1 expression released the iEBHX1S-4 differentiation block, allowing erythropoietin-dependent acquisition of erythroid markers and hemoglobin synthesis. Coordinated activation of erythroid transcriptional networks integrated by the acetyltransferase co-activator CREB-binding protein (CBP) was suggested by bioinformatic analysis of the upstream regulatory regions of several conditionally induced iEBHX1S-4 gene sets. In accord with this notion, CBP-associated acetylation of GATA-1, an essential regulator of erythroid differentiation, increased concomitantly with TLX1 downregulation. Coimmunoprecipitation experiments and glutathione-S-transferase pull-down assays revealed that TLX1 directly binds to CBP, and confocal laser microscopy demonstrated that the two proteins partially colocalize at intranuclear sites in iEBHX1S-4 cells. Notably, the distribution of CBP in conditionally blocked iEBHX1S-4 cells partially overlapped with chromatin marked by a repressive histone methylation pattern, and downregulation of TLX1 coincided with exit of CBP from these heterochromatic regions. Thus, we propose that TLX1-mediated differentiation arrest may be achieved in part through a mechanism that involves redirection of CBP and/or its sequestration in repressive chromatin domains.


systematic_name: M11048
exact_source: Table 2S
source_species_code: MM
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Selected gradually up-regulated genes whose expression profile follows that of CCNE1 [GeneID=898] in the TLX1 [GeneID=3195] Tet On iEBHX15-4 cells (pro-erythroblasts).

description_full:
  Aberrant expression of the human homeobox-containing proto-oncogene TLX1/HOX11 inhibits hematopoietic differentiation programs in a number of murine model systems. Here, we report the establishment of a murine erythroid progenitor cell line, iEBHX1S-4, developmentally arrested by regulatable TLX1 expression. Extinction of TLX1 expression released the iEBHX1S-4 differentiation block, allowing erythropoietin-dependent acquisition of erythroid markers and hemoglobin synthesis. Coordinated activation of erythroid transcriptional networks integrated by the acetyltransferase co-activator CREB-binding protein (CBP) was suggested by bioinformatic analysis of the upstream regulatory regions of several conditionally induced iEBHX1S-4 gene sets. In accord with this notion, CBP-associated acetylation of GATA-1, an essential regulator of erythroid differentiation, increased concomitantly with TLX1 downregulation. Coimmunoprecipitation experiments and glutathione-S-transferase pull-down assays revealed that TLX1 directly binds to CBP, and confocal laser microscopy demonstrated that the two proteins partially colocalize at intranuclear sites in iEBHX1S-4 cells. Notably, the distribution of CBP in conditionally blocked iEBHX1S-4 cells partially overlapped with chromatin marked by a repressive histone methylation pattern, and downregulation of TLX1 coincided with exit of CBP from these heterochromatic regions. Thus, we propose that TLX1-mediated differentiation arrest may be achieved in part through a mechanism that involves redirection of CBP and/or its sequestration in repressive chromatin domains.


description_brief: STAT1 [GeneID=6772] targets in hematopoetic signaling.
systematic_name: M1162
exact_source: Table 2: STAT1
source_species_code: MM
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_full:
  Hematopoiesis is the cumulative result of intricately regulated signaling pathways that are mediated by cytokines and their receptors. Proper culmination of these diverse pathways forms the basis for an orderly generation of different cell types. Recent studies conducted over the past 10-15 years have revealed that hematopoietic cytokine receptor signaling is largely mediated by a family of tyrosine kinases termed Janus kinases (JAKs) and their downstream transcription factors termed STATs (signal transducers and activators of transcription). Aberration in these pathways, such as that caused by the recently identified JAK2V617F mutation, is an underlying cause for diseases such as leukemias and other myeloproliferative disorders. This recent discovery, when coupled with the fact that STATs are activated by oncoproteins such as BCR-ABL, underscores the importance of the JAK-STAT pathway in both normal cellular development and disease states.


systematic_name: M1170
exact_source: Table 2: clusters 1.1-4 and 2.2-4
source_species_code: MM
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Selected genes down-regulated during progression through benign to malignant skin tumors formed by treatment with DMBA and TPA [PubChem=6001;4792] chemicals in the two stage skin carcinogenesis model.

description_full:
  Chemically induced mouse skin carcinogenesis represents the most extensively utilized animal model to unravel the multistage nature of tumour development and to design novel therapeutic concepts of human epithelial neoplasia. We combined this tumour model with comprehensive gene expression analysis and could identify a large set of novel tumour-associated genes that have not been associated with epithelial skin cancer development yet. Expression data of selected genes were confirmed by semiquantitative and quantitative RT-PCR as well as in situ hybridization and immunofluorescence analysis on mouse tumour sections. Enhanced expression of genes identified in our screen was also demonstrated in mouse keratinocyte cell lines that form tumours in vivo. Self-organizing map clustering was performed to identify different kinetics of gene expression and coregulation during skin cancer progression. Detailed analysis of differential expressed genes according to their functional annotation confirmed the involvement of several biological processes, such as regulation of cell cycle, apoptosis, extracellular proteolysis and cell adhesion, during skin malignancy. Finally, we detected high transcript levels of ANXA1, LCN2 and S100A8 as well as reduced levels for NDR2 protein in human skin tumour specimens demonstrating that tumour-associated genes identified in the chemically induced tumour model might be of great relevance for the understanding of human epithelial malignancies as well.


systematic_name: M1171
exact_source: Supplementary Table C
source_species_code: MM
GEO_id: GSE2118
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Known and putative targets of NFKB1 [GeneID=4790] identified among the ATM [GeneID=472] dependent, late responders to ionizing radiation.

description_full:
[cell repeats an earlier one in this file: 1616 characters]


systematic_name: M1239
exact_source: Table 1
source_species_code: MM
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in early vs late brain tumors induced by retroviral delivery of PDGFB [GeneID=5155].

description_full:
  Retroviral tagging previously identified putative cancer-causing genes in a mouse brain tumor model where a recombinant Moloney murine leukemia virus encoding the platelet-derived growth factor B-chain (MMLV/PDGFB) was intracerebrally injected in newborn mice. In the present study, expression analysis using cDNA arrays revealed several similarities of virus-induced mouse gliomas with human brain tumors. Brain tumors with short latency contained on average 8.0 retroviral insertions and resembled human glioblastoma multiforme (GBM) whereas long-latency gliomas were of lower grade, similar to human oligodendroglioma (OD) and had 2.3 insertions per tumor. Several known and novel genes of tumor progression or cell markers were differentially expressed between OD- and GBM-like tumors. Array and quantitative real-time PCR analysis demonstrated elevated expression similar to Pdgfralpha of retrovirally tagged genes Abhd2, Ddr1, Fos, Ng2, Ppfibp1, Rad51b and Sulf2 in both glioma types compared to neonatal and adult normal brain. The retrovirally tagged genes Plekhb1, Prex1, Prkg2, Sox10 and 1200004M23Rik were upregulated in the tumors but had a different expression profile than Pdgfralpha whereas Rap1gap, Gli1, Neurl and Camk2b were downregulated in the tumors. The present study accentuates the proposed role of the retrovirally tagged genes in PDGF-driven gliomagenesis and indicates that insertional mutagenesis can promote glioma progression.


systematic_name: M1259
exact_source: Table 1
source_species_code: MM
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in MEF and REF cells (mouse and rat fibroblasts) but not in TIG3/T cells (human lung fibroblasts expressing TERT [GeneID=7015]) by co-expression of the SV40 early region and the activated HRAS (H-RasV12) [GeneID=3265].

description_full:
  Normal human diploid fibroblasts (HDFs) are refractory to oncogene-mediated transformations in vitro, compared with rodent fibroblasts. As successful oncogene-mediated transformations of normal HDFs have been reported using the human telomerase catalytic subunit, it has been considered that telomerase activity contributes to the species-specific transformability. However, these transformed HDFs are much less malignant compared with those of rodent cells, suggesting the existence of undefined mechanisms that render HDFs resistant to malignant transformation. Here, cDNA microarray analysis identified caveolin-1 as one of the possible cellular factors involved in such mechanisms. The mitogen-activated protein kinases (MAPK) pathway downregulates Caveolin-1 in rodent fibroblasts, transformed by coexpression of the SV40 early region and activated H-Ras. In contrast, the coexpression of these two oncogenes in HDFs failed to reduce the expression level of Caveolin-1. These results strongly suggest the presence of critical differences in events following the phosphorylation of ERK during the activation process of the MAPK signaling pathway between human and rodent cells, as the ERK protein was similarly phosphorylated in both systems. Furthermore, the small interfering RNA-mediated suppression of Caveolin-1 facilitated the oncogene-mediated transformation of normal HDFs, clearly indicating that the differences in the transformability between human and rodent cells are due, at least in part, to the mechanism responsible for the resistance to Ras-induced Caveolin-1 downregulation in HDFs.


systematic_name: M1266
exact_source: Table 2: Fold change < 0
source_species_code: MM
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in preleukemic thymocytes from transgenic mice which overexpress TAL1 [GeneID=6886] in thymus.

description_full:
  Analysis of the INK4A/ARF locus in human T-ALL patients revealed frequent deletions in exon 2, the exon common to both p16(INK4A) and p14(ARF). Other studies have described selective deletion of exon 1beta of p14(ARF) or methylation of the p16(INK4A) promoter. Therefore, it is unclear from these studies whether loss of p16(INK4A) and/or p14(ARF) contributes to the development of T-ALL. To elucidate the relative contribution of the ink4a/arf locus to T-cell leukemogenesis, we mated our tal1 transgenic mice to ink4a/arf-/-, p16(ink4a)-/-, and p19(arf)-/- mice and generated tal1/ink4a/arf+/-, tal1/p16(ink4a)+/-, and tal1/p19(arf)+/- mice. Each of these mice developed T-cell leukemia rapidly, indicating that loss of either p16(ink4a) or p19(arf) cooperates with Tal1 to induce leukemia in mice. Preleukemic studies reveal that Tal1 expression stimulates entry into the cell cycle and thymocyte apoptosis in vivo. Interestingly, mice expressing a DNA-binding mutant of Tal1 do not exhibit increases in S phase cells. The S phase induction is accompanied by an increase in thymocyte apoptosis in tal1 transgenic mice. Whereas apoptosis is reduced to wild-type levels in tal1/ink4a/arf-/- mice, S phase induction remains unaffected. Thus, Tal1 stimulates cell cycle entry independent of the ink4a/arf locus, but its ability to induce apoptosis is Ink4a/Arf-dependent.


systematic_name: M1280
exact_source: Table 4S
source_species_code: MM
GEO_id: GSE2127
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Cluster PAM4: genes down-regulated in hepatocellular carcinoma (HCC) vs normal liver tissue from mice deficient for TXNIP [GeneID=10628].

description_full:
  The molecular pathogenesis and the genetic aberrations that lead to the progression of hepatocellular carcinoma (HCC) are largely unknown. Here, we demonstrate that the thioredoxin interacting protein (Txnip) gene is a candidate tumor suppressor gene in vivo. We previously showed that the recombinant inbred congenic strain HcB-19 has a spontaneous mutation of the Txnip gene, and we now show that the strain has dramatically increased incidence of HCC, and that the HCC cosegregates with the Txnip mutation. Approximately 40% of the Txnip-deficient mice developed hepatic tumors with an increased prevalence in male mice. Visible tumors develop as early as 8 months of age. Histological analysis confirmed the morphology of HCC in the Txnip-deficient mice. Molecular markers of HCC, alpha-fetoprotein and p53, were increased in tumors of Txnip-deficient mice. The upregulation of p53 preceded tumor development; however, bromodeoxyuridine (BrdU) labeling of normal hepatic tissue of Txnip-deficient mice did not reveal increased cell proliferation. Finally, microarray analyses of tumor, non-tumor adjacent, and normal tissue of Txnip-deficient mice highlighted the genetic differences leading to the predisposition and onset of HCC. Our findings suggest that Txnip deficiency is sufficient to initiate HCC and suggest novel mechanisms in hepatocarcinogenesis.


systematic_name: M1291
exact_source: Table 1
source_species_code: MM
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Candidate mammary tumorigenesis genes from the common insertion sites (CIS) of MMTV virus that induced breast tumors in mice.

description_full:
  We performed a high-throughput retroviral insertional mutagenesis screen in mouse mammary tumor virus (MMTV)-induced mammary tumors and identified 33 common insertion sites, of which 17 genes were previously not known to be associated with mammary cancer and 13 had not previously been linked to cancer in general. Although members of the Wnt and fibroblast growth factors (Fgf) families were frequently tagged, our exhaustive screening for MMTV insertion sites uncovered a new repertoire of candidate breast cancer oncogenes. We validated one of these genes, Rspo3, as an oncogene by overexpression in a p53-deficient mammary epithelial cell line. The human orthologs of the candidate oncogenes were frequently deregulated in human breast cancers and associated with several tumor parameters. Computational analysis of all MMTV-tagged genes uncovered specific gene families not previously associated with cancer and showed a significant overrepresentation of protein domains and signaling pathways mainly associated with development and growth factor signaling. Comparison of all tagged genes in MMTV and Moloney murine leukemia virus-induced malignancies showed that both viruses target mostly different genes that act predominantly in distinct pathways.


systematic_name: M1292
exact_source: Table 6S
source_species_code: MM
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes uniquely up-regulated in SEND cells (skin endothelium) at hypoxia after knockdown of HIF1A [GeneID=3091] by RNAi.

description_full:
  The ternary complex factor Net/Elk3 is downregulated in hypoxia and participates in the induction by hypoxia of several genes, including c-fos, vascular endothelial growth factor and egr-1. However, the global role of Net in hypoxia remains to be elucidated. We have identified, in a large-scale analysis of RNA expression using microarrays, more than 370 genes that are regulated by Net in hypoxia. In order to gain insights into the role of Net in hypoxia, we have analysed in parallel the genes regulated by HIF-1alpha, the classical factor involved in the response to hypoxia. We identified about 190 genes that are regulated by HIF-1alpha in hypoxia. Surprisingly, when we compare the genes induced by hypoxia that require either Net or HIF-1alpha, the majority are the same (75%), suggesting that the functions of both factors are closely linked. Interestingly, in hypoxia, Net regulates the expression of several genes known to control HIF-1alpha stability, including PHD2, PHD3 and Siah2, suggesting that Net regulates the stability of HIF-1alpha. We found that inhibition of Net by RNAi leads to decreased HIF-1alpha expression at the protein level in hypoxia. These results indicate that Net participates in the transcriptional response to hypoxia by regulation of HIF-1alpha protein stability.


systematic_name: M1294
exact_source: Table 2
source_species_code: MM
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Angiogenic genes up-regulated in A17 carcinomas (high vascularization) compared to the syngeneic BB1 and spontaneous tumors (little vascularization).

description_full:
  Tumor microenvironment in carcinomas recruits mesenchymal cells with an abnormal proangiogenic and invasive phenotype. It is not clear whether mesenchymal tumor cells (MTCs) derive from the activation of mature fibroblasts or from their stem cell precursors. However, stromal cell activation in tumors resembles in several aspects the mesenchymal rearrangement which normally occurs during reparative processes such as wound healing. Mesenchymal stem cells (MSCs) play a crucial role in developmental and reparative processes and have extraordinary proangiogenic potential, on the basis of which they are thought to show great promise for the treatment of ischemic disorders. Here, we show that MTCs have proangiogenic potential and that they share the transcriptional expression of the best-known proangiogenic factors with MSCs. We also found that MTCs and MSCs have the same molecular signature for stemness-related genes, and that when co-implanted with cancer cells in syngeneic animals MSCs determine early tumor appearance, probably by favoring the angiogenic switch. Our data (1) reveal crucial aspects of the proangiogenic phenotype of MTCs, (2) strongly suggest their stem origin and (3) signal the risk of therapeutic use of MSCs in tumor-promoting conditions.


systematic_name: M1299
exact_source: Table 1S: Fold Change < 0
source_species_code: MM
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in SEND cells (skin endothelium) at normal oxygen (normoxia) conditions after knockdown of ELK3 [GeneID=2004] by RNAi.

description_full:
[cell repeats an earlier one in this file: 1304 characters]


systematic_name: M1303
exact_source: Table 2S: Fold Change > 0
source_species_code: MM
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in SEND cells (skin endothelium) at hypoxia with ELK3 [GeneID=2004] knockdown by RNAi.

description_full:
[cell repeats an earlier one in this file: 1304 characters]


systematic_name: M1304
exact_source: Table 2S: Fold Change < 0
source_species_code: MM
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in SEND cells (skin endothelium) at hypoxia with ELK3 [GeneID=2004] knockdown by RNAi.

description_full:
[cell repeats an earlier one in this file: 1304 characters]


systematic_name: M1309
exact_source: Table 4S: Fold Change < 0
source_species_code: MM
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in SEND cells (skin endothelium) at hypoxia after knockdown of HIF1A [GeneID=3091] by RNAi.

description_full:
[cell repeats an earlier one in this file: 1304 characters]


systematic_name: M1316
exact_source: Table 5S: FC siNetH / FC siNetN < 0
source_species_code: MM
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes specifically down-regulated in SEND cells (skin endothelium) at hypoxia after knockdown of ELK3 [GeneID=2004] by RNAi.

description_full:
[cell repeats an earlier one in this file: 1304 characters]


systematic_name: M1317
exact_source: Table 7S
source_species_code: MM
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in SEND cells (skin endothelium) at hypoxia after knockdown of ELK3 [GeneID=2004] and HIF1A [GeneID=3091] by RNAi.

description_full:
[cell repeats an earlier one in this file: 1304 characters]


systematic_name: M1318
exact_source: Table 7S
source_species_code: MM
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in SEND cells (skin endothelium) at hypoxia after knockdown of ELK3 [GeneID=2004] and HIF1A [GeneID=3091] by RNAi.

description_full:
[cell repeats an earlier one in this file: 1304 characters]


systematic_name: M1373
exact_source: Fig 4, 5: red
source_species_code: MM
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in MMH-RT cells (hepatocytes displaying an invasive, metastatic phenotype) during epithelial to mesenchymal transition (EMT).

description_full:
  Polarized hepatocytes expressing hyperactive Ha-Ras adopt an invasive and metastatic phenotype in cooperation with transforming growth factor (TGF)-beta. This dramatic increase in malignancy is displayed by an epithelial to mesenchymal transition (EMT), which mimics the TGF-beta-mediated progression of human hepatocellular carcinomas. In culture, hepatocellular EMT occurs highly synchronously, facilitating the analysis of molecular events underlying the various stages of this process. Here, we show that in response to TGF-beta, phosphorylated Smads rapidly translocated into the nucleus and activated transcription of target genes such as E-cadherin repressors of the Snail superfamily, causing loss of cell adhesion. Within the TGF-beta superfamily of cytokines, TGF-beta1, -beta2 and -beta3 were specific for the induction of hepatocellular EMT. Expression profiling of EMT kinetics revealed 78 up- and 235 downregulated genes, which preferentially modulate metabolic activities, extracellular matrix composition, transcriptional activities and cell survival. Independent of the genetic background, platelet-derived growth factor (PDGF)-A ligand and both PDGF receptor subunits were highly elevated, together with autocrine secretion of bioactive PDGF. Interference with PDGF signalling by employing hepatocytes expressing the dominant-negative PDGF-alpha receptor revealed decreased TGF-beta-induced migration in vitro and efficient suppression of tumour growth in vivo. In conclusion, these results provide evidence for a crucial role of PDGF in TGF-beta-mediated tumour progression of hepatocytes and suggest PDGF as a target for therapeutic intervention in liver cancer.


systematic_name: M1376
exact_source: Fig 4, 5: blue
source_species_code: MM
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in MMH-RT cells (hepatocytes displaying an invasive, metastatic phenotype) during epithelial to mesenchymal transition (EMT).

description_full:
  Polarized hepatocytes expressing hyperactive Ha-Ras adopt an invasive and metastatic phenotype in cooperation with transforming growth factor (TGF)-beta. This dramatic increase in malignancy is displayed by an epithelial to mesenchymal transition (EMT), which mimics the TGF-beta-mediated progression of human hepatocellular carcinomas. In culture, hepatocellular EMT occurs highly synchronously, facilitating the analysis of molecular events underlying the various stages of this process. Here, we show that in response to TGF-beta, phosphorylated Smads rapidly translocated into the nucleus and activated transcription of target genes such as E-cadherin repressors of the Snail superfamily, causing loss of cell adhesion. Within the TGF-beta superfamily of cytokines, TGF-beta1, -beta2 and -beta3 were specific for the induction of hepatocellular EMT. Expression profiling of EMT kinetics revealed 78 up- and 235 downregulated genes, which preferentially modulate metabolic activities, extracellular matrix composition, transcriptional activities and cell survival. Independent of the genetic background, platelet-derived growth factor (PDGF)-A ligand and both PDGF receptor subunits were highly elevated, together with autocrine secretion of bioactive PDGF. Interference with PDGF signalling by employing hepatocytes expressing the dominant-negative PDGF-alpha receptor revealed decreased TGF-beta-induced migration in vitro and efficient suppression of tumour growth in vivo. In conclusion, these results provide evidence for a crucial role of PDGF in TGF-beta-mediated tumour progression of hepatocytes and suggest PDGF as a target for therapeutic intervention in liver cancer.


description_brief: Cluster 1 of genes distinguishing among different B lymphocyte neoplasms.
systematic_name: M1383
exact_source: Table 2S: Cluster = 1
source_species_code: MM
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_full:
  Aside from Myc-activating translocations characteristic of plasmacytomas (PCT), little is known about genetic factors and signaling pathways responsible for the development of spontaneous B-cell lineage lymphomas of mice. Here, we characterized the transcriptional profiles of PCT, centroblastic diffuse large B-cell lymphomas (CBL), and high-grade splenic marginal zone B-cell lymphoma (MZL++) using high-throughput quantitative reverse transcription-PCR. Expression profiles of CBL and MZL++ were strikingly similar and quite unlike that of PCT. Among the genes expressed at significantly higher levels by PCT were a number involved in NOTCH signaling, a finding supported by gene set enrichment analyses of microarray data. To investigate the importance of this pathway, NOTCH signaling was blocked in PCT cell lines by treatment with a gamma-secretase inhibitor (GSI) or transduction of a dominant-negative mutant of MAML1. These treatments resulted in reduced expression of NOTCH transcriptional targets in association with impaired proliferation and increased apoptosis. GSI treatment of transformed plasma cells in a primary PCT also induced apoptosis. These results integrate NOTCH activation with oncogenic signaling pathways downstream of translocated Myc in the pathogenesis of mouse PCT, two signaling pathways also implicated in development of human multiple myeloma and T-cell lymphoblastic lymphoma.


systematic_name: M1395
exact_source: Table 4S: Pre-BI
source_species_code: MM
GEO_id: GSE7897
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Up-regulated genes in the B lymphocyte developmental signature, based on expression profiling of lymphomas from the Emu-myc transgenic mice: the Pre-BI stage.

description_full:
  The Emu-myc transgenic mouse has provided a valuable model for the study of B-cell lymphoma. Making use of gene expression analysis and, in particular, expression signatures of cell signaling pathway activation, we now show that several forms of B lymphoma can be identified in the Emu-myc mice associated with time of tumor onset. Furthermore, one form of Emu-myc tumor with pre-B character is shown to resemble human Burkitt lymphoma, whereas others exhibit more differentiated B-cell characteristics and show similarity with human diffuse large B-cell lymphoma in the pattern of gene expression, as well as oncogenic pathway activation. Importantly, we show that signatures of oncogenic pathway activity provide further dissection of the spectrum of diffuse large B-cell lymphoma, identifying a subset of patients who have very poor prognosis and could benefit from more aggressive or novel therapeutic strategies. Taken together, these studies provide insight into the complexity of the oncogenic process and a novel strategy for dissecting the heterogeneity of B lymphoma.


systematic_name: M19287
exact_source: Table 4S: Large Pre-BII
source_species_code: MM
GEO_id: GSE7897
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Up-regulated genes in the B lymphocyte developmental signature, based on expression profiling of lymphomas from the Emu-myc transgenic mice: the  Large Pre-BII stage.

description_full:
  The Emu-myc transgenic mouse has provided a valuable model for the study of B-cell lymphoma. Making use of gene expression analysis and, in particular, expression signatures of cell signaling pathway activation, we now show that several forms of B lymphoma can be identified in the Emu-myc mice associated with time of tumor onset. Furthermore, one form of Emu-myc tumor with pre-B character is shown to resemble human Burkitt lymphoma, whereas others exhibit more differentiated B-cell characteristics and show similarity with human diffuse large B-cell lymphoma in the pattern of gene expression, as well as oncogenic pathway activation. Importantly, we show that signatures of oncogenic pathway activity provide further dissection of the spectrum of diffuse large B-cell lymphoma, identifying a subset of patients who have very poor prognosis and could benefit from more aggressive or novel therapeutic strategies. Taken together, these studies provide insight into the complexity of the oncogenic process and a novel strategy for dissecting the heterogeneity of B lymphoma.


systematic_name: M18917
exact_source: Table 4S: Immature B
source_species_code: MM
GEO_id: GSE7897
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Down-regulated genes in the B lymphocyte developmental signature based on expression profiling of lymphomas from the Emu-myc transgenic mice: the immature B stage.

description_full:
  The Emu-myc transgenic mouse has provided a valuable model for the study of B-cell lymphoma. Making use of gene expression analysis and, in particular, expression signatures of cell signaling pathway activation, we now show that several forms of B lymphoma can be identified in the Emu-myc mice associated with time of tumor onset. Furthermore, one form of Emu-myc tumor with pre-B character is shown to resemble human Burkitt lymphoma, whereas others exhibit more differentiated B-cell characteristics and show similarity with human diffuse large B-cell lymphoma in the pattern of gene expression, as well as oncogenic pathway activation. Importantly, we show that signatures of oncogenic pathway activity provide further dissection of the spectrum of diffuse large B-cell lymphoma, identifying a subset of patients who have very poor prognosis and could benefit from more aggressive or novel therapeutic strategies. Taken together, these studies provide insight into the complexity of the oncogenic process and a novel strategy for dissecting the heterogeneity of B lymphoma.


systematic_name: M15148
exact_source: Table 2S: DEC ALL
source_species_code: MM
contributor: Kate Stafford
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in P14 nerves of transgenic mice having hypomorhic (reduced function) allele of EGR2 [GeneID=1959].

description_full:
  Egr2 is a transcription factor required for peripheral nerve myelination in rodents, and mutations in Egr2 are associated with congenital hypomyelinating neuropathy (CHN) in humans. To further study its role in myelination, we generated mice harboring a hypomorphic Egr2 allele (Egr2Lo) that survive for up to 3 weeks postnatally, a period of active myelination in rodents. These Egr2Lo/Lo mice provided the opportunity to study the molecular effects of Egr2 deficiency on Schwann cell biology, an analysis that was not possible previously, because of the perinatal lethality of Egr2-null mice. Egr2Lo/Lo mice phenocopy CHN, as evidenced by the severe hypomyelination and increased numbers of proliferating Schwann cells of the peripheral nerves. Comparison of sciatic nerve gene expression profiles during development and after crush injury with those of Egr2Lo/Lo Schwann cells revealed that they are developmentally arrested, with down-regulation of myelination-related genes and up-regulation of genes associated with immature and promyelinating Schwann cells. One of the abnormally elevated genes in Egr2Lo/Lo Schwann cells, Sox2, encodes a transcription factor that is crucial for maintenance of neural stem cell pluripotency. Wild-type Schwann cells infected with Sox2 adenovirus or lentivirus inhibited expression of myelination-associated genes (e.g., myelin protein zero; Mpz), and failed to myelinate axons in vitro, but had an enhanced proliferative response to beta-neuregulin. The characterization of a mouse model of CHN has provided insight into Schwann cell differentiation and allowed the identification of Sox2 as a negative regulator of myelination.


systematic_name: M17138
exact_source: Fig. 4
source_species_code: MM
GEO_id: GSE2031
contributor: Jean Junior
contrib_organization: MSigDB Team
description_brief:
  Genes that physically map to the hematopoietic stem cell (HSC) proliferation QTL (quantitative trait locus) Scp2.

description_full:
  We combined large-scale mRNA expression analysis and gene mapping to identify genes and loci that control hematopoietic stem cell (HSC) function. We measured mRNA expression levels in purified HSCs isolated from a panel of densely genotyped recombinant inbred mouse strains. We mapped quantitative trait loci (QTLs) associated with variation in expression of thousands of transcripts. By comparing the physical transcript position with the location of the controlling QTL, we identified polymorphic cis-acting stem cell genes. We also identified multiple trans-acting control loci that modify expression of large numbers of genes. These groups of coregulated transcripts identify pathways that specify variation in stem cells. We illustrate this concept with the identification of candidate genes involved with HSC turnover. We compared expression QTLs in HSCs and brain from the same mice and identified both shared and tissue-specific QTLs. Our data are accessible through WebQTL, a web-based interface that allows custom genetic linkage analysis and identification of coregulated transcripts.


systematic_name: M2637
exact_source: Table 2S
source_species_code: MM
contributor: Kate Stafford
contrib_organization: MSigDB Team
description_brief:
  Molecular timetable composed of 96 time-indicating genes (103 probes) in the central (suprachiasmatic nucleus (SCN)) clock.

description_full:
  Detection of individual body time (BT) via a single-time-point assay has been a longstanding unfulfilled dream in medicine, because BT information can be exploited to maximize potency and minimize toxicity during drug administration and thus will enable highly optimized medication. To achieve this dream, we created a molecular timetable composed of >100 time-indicating genes, whose gene expression levels can represent internal BT. Here we describe a robust method called the molecular-timetable method for BT detection from a single-time-point expression profile. The power of this method is demonstrated by the sensitive and accurate detection of BT and the sensitive diagnosis of rhythm disorders. These results demonstrate the feasibility of BT detection based on single-time-point sampling, suggest the potential for expression-based diagnosis of rhythm disorders, and may translate functional genomics into chronotherapy and personalized medicine.


description_brief: Genes known to modulate ROS or whose expression changes in response to ROS
systematic_name: M6891
exact_source: unknown
source_species_code: MM
contributor: Nick Houstis
contrib_organization: Broad Institute
description_full:
  Insulin resistance is a cardinal feature of type 2 diabetes and is characteristic of a wide range of other clinical and experimental settings. Little is known about why insulin resistance occurs in so many contexts. Do the various insults that trigger insulin resistance act through a common mechanism? Or, as has been suggested, do they use distinct cellular pathways? Here we report a genomic analysis of two cellular models of insulin resistance, one induced by treatment with the cytokine tumour-necrosis factor-alpha and the other with the glucocorticoid dexamethasone. Gene expression analysis suggests that reactive oxygen species (ROS) levels are increased in both models, and we confirmed this through measures of cellular redox state. ROS have previously been proposed to be involved in insulin resistance, although evidence for a causal role has been scant. We tested this hypothesis in cell culture using six treatments designed to alter ROS levels, including two small molecules and four transgenes; all ameliorated insulin resistance to varying degrees. One of these treatments was tested in obese, insulin-resistant mice and was shown to improve insulin sensitivity and glucose homeostasis. Together, our findings suggest that increased ROS levels are an important trigger for insulin resistance in numerous settings.


systematic_name: M1406
exact_source: Table 2
source_species_code: MM
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated during epithelial to mesenchymal transition (EMT) induced by TGFB1 [GeneID=7040] in the EpH4 cells (mammary epithelium cell line transformed by HRAS [GeneID=3265]).

description_full:
  Epithelial-to-mesenchymal transition (EMT), a switch of polarized epithelial cells to a migratory, fibroblastoid phenotype, is increasingly considered as an important event during malignant tumor progression and metastasis. To identify molecular players involved in EMT and metastasis, we performed expression profiling of a set of combined in vitro/in vivo cellular models, based on clonal, fully polarized mammary epithelial cells. Seven closely related cell pairs were used, which were modified by defined oncogenes and/or external factors and showed specific aspects of epithelial plasticity relevant to cell migration, local invasion and metastasis. Since mRNA levels do not necessarily reflect protein levels in cells, we used an improved expression profiling method based on polysome-bound RNA, suitable to analyse global gene expression on Affymetrix chips. A substantial fraction of all regulated genes was found to be exclusively controlled at the translational level. Furthermore, profiling of the above multiple cell pairs allowed one to identify small numbers of genes by cluster analysis, specifically correlating gene expression with EMT, metastasis, scattering and/or oncogene function. A small set of genes specifically regulated during EMT was identified, including key regulators and signaling pathways involved in cell proliferation, epithelial polarity, survival and trans-differentiation to mesenchymal-like cells with invasive behavior.


systematic_name: M1407
exact_source: Fig. 2
source_species_code: MM
GEO_id: GSE628
contributor: Jean-Pierre Bourquin
contrib_organization: Dana-Farber Cancer Institute
description_brief:
  Genes up-regulated after GATA1 [GeneID=2623] activation in G1E-ER4 cells (erythroid precursors engineered to express GATA1 upon addition of estradiol [PubChem=5757]).

description_full:
  Transcription factor GATA-1 is required for erythropoiesis, yet its full actions are unknown. We performed transcriptome analysis of G1E-ER4 cells, a GATA-1-null erythroblast line that undergoes synchronous erythroid maturation when GATA-1 activity is restored. We interrogated more than 9000 transcripts at 6 time points representing the transition from late burst forming unit-erythroid (BFU-E) to basophilic erythroblast stages. Our findings illuminate several new aspects of GATA-1 function. First, the large number of genes responding quickly to restoration of GATA-1 extends the repertoire of its potential targets. Second, many transcripts were rapidly down-regulated, highlighting the importance of GATA-1 in gene repression. Third, up-regulation of some known GATA-1 targets was delayed, suggesting that auxiliary factors are required. For example, induction of the direct GATA-1 target gene beta major globin was late and, surprisingly, required new protein synthesis. In contrast, the gene encoding Fog1, which cooperates with GATA-1 in beta globin transcription, was rapidly induced independently of protein synthesis. Guided by bioinformatic analysis, we demonstrated that selected regions of the Fog1 gene exhibit enhancer activity and in vivo occupancy by GATA-1. These findings define a regulatory loop for beta globin expression and, more generally, demonstrate how transcriptome analysis can be used to generate testable hypotheses regarding transcriptional networks.


systematic_name: M12498
exact_source: Table 1S
source_species_code: MM
contributor: Kate Stafford
contrib_organization: MSigDB Team
description_brief:
  Molecular timetable composed of 162 time-indicating genes (182 probes) in the peripheral (liver) clock.

description_full:
  Detection of individual body time (BT) via a single-time-point assay has been a longstanding unfulfilled dream in medicine, because BT information can be exploited to maximize potency and minimize toxicity during drug administration and thus will enable highly optimized medication. To achieve this dream, we created a molecular timetable composed of >100 time-indicating genes, whose gene expression levels can represent internal BT. Here we describe a robust method called the molecular-timetable method for BT detection from a single-time-point expression profile. The power of this method is demonstrated by the sensitive and accurate detection of BT and the sensitive diagnosis of rhythm disorders. These results demonstrate the feasibility of BT detection based on single-time-point sampling, suggest the potential for expression-based diagnosis of rhythm disorders, and may translate functional genomics into chronotherapy and personalized medicine.


systematic_name: M15964
exact_source: text on page 235
source_species_code: MM
contributor: Jean Junior
contrib_organization: MSigDB Team
description_brief:
  Neurologically relevant genes modulated in brain tissue by a trans-regulatory QTL (quantitative trait locus) near D6Mit150 marker.

description_full:
  Patterns of gene expression in the central nervous system are highly variable and heritable. This genetic variation among normal individuals leads to considerable structural, functional and behavioral differences. We devised a general approach to dissect genetic networks systematically across biological scale, from base pairs to behavior, using a reference population of recombinant inbred strains. We profiled gene expression using Affymetrix oligonucleotide arrays in the BXD recombinant inbred strains, for which we have extensive SNP and haplotype data. We integrated a complementary database comprising 25 years of legacy phenotypic data on these strains. Covariance among gene expression and pharmacological and behavioral traits is often highly significant, corroborates known functional relations and is often generated by common quantitative trait loci. We found that a small number of major-effect quantitative trait loci jointly modulated large sets of transcripts and classical neural phenotypes in patterns specific to each tissue. We developed new analytic and graph theoretical approaches to study shared genetic modulation of networks of traits using gene sets involved in neural synapse function as an example. We built these tools into an open web resource called WebQTL that can be used to test a broad array of hypotheses.


systematic_name: M1417
exact_source: Table 3
source_species_code: MM
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated during epithelial to mesenchymal transition (EMT) induced by TGFB1 [GeneID=7040] in the EpH4 cells (mammary epithelium cell line transformed by HRAS [GeneID=3265]).

description_full:
  Epithelial-to-mesenchymal transition (EMT), a switch of polarized epithelial cells to a migratory, fibroblastoid phenotype, is increasingly considered as an important event during malignant tumor progression and metastasis. To identify molecular players involved in EMT and metastasis, we performed expression profiling of a set of combined in vitro/in vivo cellular models, based on clonal, fully polarized mammary epithelial cells. Seven closely related cell pairs were used, which were modified by defined oncogenes and/or external factors and showed specific aspects of epithelial plasticity relevant to cell migration, local invasion and metastasis. Since mRNA levels do not necessarily reflect protein levels in cells, we used an improved expression profiling method based on polysome-bound RNA, suitable to analyse global gene expression on Affymetrix chips. A substantial fraction of all regulated genes was found to be exclusively controlled at the translational level. Furthermore, profiling of the above multiple cell pairs allowed one to identify small numbers of genes by cluster analysis, specifically correlating gene expression with EMT, metastasis, scattering and/or oncogene function. A small set of genes specifically regulated during EMT was identified, including key regulators and signaling pathways involved in cell proliferation, epithelial polarity, survival and trans-differentiation to mesenchymal-like cells with invasive behavior.


systematic_name: M12804
exact_source: Table 2S: INC ALL
source_species_code: MM
contributor: Kate Stafford
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in P14 nerves of transgenic mice having hypomorhic (reduced function) allele of EGR2 [GeneID=1959].

description_full:
  Egr2 is a transcription factor required for peripheral nerve myelination in rodents, and mutations in Egr2 are associated with congenital hypomyelinating neuropathy (CHN) in humans. To further study its role in myelination, we generated mice harboring a hypomorphic Egr2 allele (Egr2Lo) that survive for up to 3 weeks postnatally, a period of active myelination in rodents. These Egr2Lo/Lo mice provided the opportunity to study the molecular effects of Egr2 deficiency on Schwann cell biology, an analysis that was not possible previously, because of the perinatal lethality of Egr2-null mice. Egr2Lo/Lo mice phenocopy CHN, as evidenced by the severe hypomyelination and increased numbers of proliferating Schwann cells of the peripheral nerves. Comparison of sciatic nerve gene expression profiles during development and after crush injury with those of Egr2Lo/Lo Schwann cells revealed that they are developmentally arrested, with down-regulation of myelination-related genes and up-regulation of genes associated with immature and promyelinating Schwann cells. One of the abnormally elevated genes in Egr2Lo/Lo Schwann cells, Sox2, encodes a transcription factor that is crucial for maintenance of neural stem cell pluripotency. Wild-type Schwann cells infected with Sox2 adenovirus or lentivirus inhibited expression of myelination-associated genes (e.g., myelin protein zero; Mpz), and failed to myelinate axons in vitro, but had an enhanced proliferative response to beta-neuregulin. The characterization of a mouse model of CHN has provided insight into Schwann cell differentiation and allowed the identification of Sox2 as a negative regulator of myelination.


systematic_name: M1435
exact_source: Tables 3-5
source_species_code: MM
contributor: Kevin Vogelsang
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in macrophages by aerolysin-related cytotoxic enterotoxin (Act) from Aeromonas hydrophila.

description_full:
  A cytotoxic enterotoxin (Act) of Aeromonas hydrophila possesses several biological activities, and it induces an inflammatory response in the host. In this study, we used microarrays to gain a global and molecular view of the cellular transcriptional responses to Act and to identify important genes up-regulated by this toxin. Total RNA was isolated at 0, 2, and 12 h from Act-treated macrophages and applied to Affymetrix MGU74 arrays, and the data were processed using a multi-analysis approach to identify genes that might be critical in the inflammatory process evoked by Act. Seventy-six genes were significantly and consistently up-regulated. Many of these genes were immune-related, and several were transcription factors, adhesion molecules, and cytokines. Additionally, we identified several apoptosis-associated genes that were significantly up-regulated in Act-treated macrophages. Act-induced apoptosis of macrophages was confirmed by annexin V staining and DNA laddering. Quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay were used to verify increased expression of some inflammatory and apoptosis-associated genes identified by the microarray analysis. To further confirm Act-induced increases in gene expression, real-time RT-PCR was also used for selected genes. Taken together, the array data provided for the first time a global view of Act-mediated signal transduction and clearly demonstrated an inflammatory response and apoptosis mediated by this toxin in host cells at the molecular level.


description_brief: Genes up-regulated in B cell lymphoma tumors expressing an activated form of MYC [GeneID=4609].
systematic_name: M1249
exact_source: Table 1
source_species_code: MM
contributor: Kevin Vogelsang
contrib_organization: MSigDB Team
description_full:
  The involvement of the c-Myc transcription factor in neoplastic transformation is well documented. However, which of its numerous target genes are crucial for tumorigenesis remains a frequently contested issue. We have recently established a non-transgenic murine model for B-cell lymphoma based on neoplastic conversion of p53-null bone marrow cells by conditionally active Myc. Using this model, we have identified a number of genes whose expression levels are affected by Myc during B-lymphomagenesis. Here we discuss their possible roles in neoplastic processes and describe an experimental approach allowing in vivo validation of these roles. We demonstrate that lymphoma cells overexpressing one of the Myc targets, the interleukin-10 receptor gene, have a very strong selective advantage over low IL10R expressors. Furthermore, Mcl1, a presumptive IL10R effector, also confers selective advantages when overexpressed in Myc-transformed hematopoietic cells. Thus, both IL10R and Mcl1 might be amenable to therapeutic interventions, and new targets can be identified and validated using the selection approach.


systematic_name: M1448
exact_source: Table 1: LPS/Control
source_species_code: MM
contributor: Kevin Vogelsang
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in RAW 264.7 cells (macrophage) 3 hr after stimulation with bacterial lipopolysaccharide (LPS).

description_full:
  Adenosine is released into the extracellular space from nerve terminals and cells subjected to ischemic stress. This nucleoside modulates a plethora of cellular functions via occupancy of specific receptors. Adenosine is also an important endogenous regulator of macrophage function, because it suppresses the production of a number of proinflammatory cytokines by these cells. However, the mechanisms of this anti-inflammatory effect have not been well characterized. We hypothesized that adenosine may exert some of its anti-inflammatory effects by decreasing activation of the transcription factor nuclear factor-kappaB (NF-kappaB), because gene expression of most of the proinflammatory cytokines inhibited by adenosine is dependent on NF-kappaB activation. Using bacterial lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages, we found that adenosine as well as adenosine receptor agonists decreased the production of tumor necrosis factor (TNF)-alpha, a typical NF-kappaB-regulated cytokine. This effect of adenosine was not due to an action on the process of TNF-alpha release, because adenosine suppressed also the intracellular levels of TNF-alpha. However, cDNA microarray analysis revealed that mRNA levels of neither TNF-alpha nor other cytokines were altered by adenosine in either LPS-activated or quiescent macrophages. In addition, although LPS induced expression of a number of other, noncytokine genes, including the adenosine A2b receptor, adenosine did not affect the expression of these genes. Furthermore, adenosine as well as adenosine receptor agonists failed to decrease LPS-induced NF-kappaB DNA binding, NF-kappaB promoter activity, p65 nuclear translocation, and inhibitory kappaB degradation. Together, our results suggest that the anti-inflammatory effects of adenosine are independent of NF-kappaB.


systematic_name: M1452
exact_source: Table 2: Control/LPS
source_species_code: MM
contributor: Kevin Vogelsang
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in RAW 264.7 cells (macrophage) 3 hr after stimulation with bacterial lipopolysaccharide (LPS).

description_full:
  Adenosine is released into the extracellular space from nerve terminals and cells subjected to ischemic stress. This nucleoside modulates a plethora of cellular functions via occupancy of specific receptors. Adenosine is also an important endogenous regulator of macrophage function, because it suppresses the production of a number of proinflammatory cytokines by these cells. However, the mechanisms of this anti-inflammatory effect have not been well characterized. We hypothesized that adenosine may exert some of its anti-inflammatory effects by decreasing activation of the transcription factor nuclear factor-kappaB (NF-kappaB), because gene expression of most of the proinflammatory cytokines inhibited by adenosine is dependent on NF-kappaB activation. Using bacterial lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages, we found that adenosine as well as adenosine receptor agonists decreased the production of tumor necrosis factor (TNF)-alpha, a typical NF-kappaB-regulated cytokine. This effect of adenosine was not due to an action on the process of TNF-alpha release, because adenosine suppressed also the intracellular levels of TNF-alpha. However, cDNA microarray analysis revealed that mRNA levels of neither TNF-alpha nor other cytokines were altered by adenosine in either LPS-activated or quiescent macrophages. In addition, although LPS induced expression of a number of other, noncytokine genes, including the adenosine A2b receptor, adenosine did not affect the expression of these genes. Furthermore, adenosine as well as adenosine receptor agonists failed to decrease LPS-induced NF-kappaB DNA binding, NF-kappaB promoter activity, p65 nuclear translocation, and inhibitory kappaB degradation. Together, our results suggest that the anti-inflammatory effects of adenosine are independent of NF-kappaB.


systematic_name: M12338
exact_source: Table 1S
source_species_code: MM
GEO_id: GSE2188
contributor: Kevin Vogelsang
contrib_organization: MSigDB Team
description_brief:
  Genes changed in NIH 3T3 cells (embryonic fibroblast) by expression of one or more of C/EBP proteins: CEBPA, CEBPB, CEBPG,  and CEBPD [GeneID=1050;1051;1054;1052].

description_full:
  CCAAT/enhancer-binding proteins (C/EBPs) are a family of transcription factors that regulate cell growth and differentiation in numerous cell types. To identify novel C/EBP-target genes, we performed transcriptional profiling using inducible NIH 3T3 cell lines expressing 1 of 4 members of the C/EBP family. Functional analysis revealed a previously unknown link between C/EBP proteins and circadian clock genes. Our microarray data showed that the expression levels of 2 core components of the circadian network, Per2 and Rev-Erbalpha, were significantly altered by C/EBPs. Recent studies suggested that Per2 behaves as a tumor suppressor gene in mice. Therefore, we focused our additional studies on Per2. We showed that Per2 expression is up-regulated by C/EBPalpha and C/EBPepsilon. Per2 levels were reduced in lymphoma cell lines and in acute myeloid leukemia (AML) patient samples. In addition, we generated stable K562 cells that expressed an inducible Per2 gene. Induction of Per2 expression resulted in growth inhibition, cell cycle arrest, apoptosis, and loss of clonogenic ability. These results suggest that Per2 is a downstream C/EBPalpha-target gene involved in AML, and its disruption might be involved in initiation and/or progression of AML.


description_brief: Genes up-regulated in MEF cells (embryonic fibroblast) expressing ~25% of YY1 [GeneID=7528].
systematic_name: M1466
exact_source: Table 1S
source_species_code: MM
contributor: Kevin Vogelsang
contrib_organization: MSigDB Team
description_full:
  Constitutive ablation of the Yin Yang 1 (YY1) transcription factor in mice results in peri-implantation lethality. In this study, we used homologous recombination to generate knockout mice carrying yy1 alleles expressing various amounts of YY1. Phenotypic analysis of yy1 mutant embryos expressing approximately 75%, approximately 50%, and approximately 25% of the normal complement of YY1 identified a dosage-dependent requirement for YY1 during late embryogenesis. Indeed, reduction of YY1 levels impairs embryonic growth and viability in a dose-dependent manner. Analysis of the corresponding mouse embryonic fibroblast cells also revealed a tight correlation between YY1 dosage and cell proliferation, with a complete ablation of YY1 inducing cytokinesis failure and cell cycle arrest. Consistently, RNA interference-mediated inhibition of YY1 in HeLa cells prevents cytokinesis, causes proliferative arrest, and increases cellular sensitivity to various apoptotic agents. Genome-wide expression profiling identified a plethora of YY1 target genes that have been implicated in cell growth, proliferation, cytokinesis, apoptosis, development, and differentiation, suggesting that YY1 coordinates multiple essential biological processes through a complex transcriptional network. These data not only shed new light on the molecular basis for YY1 developmental roles and cellular functions, but also provide insight into the general mechanisms controlling eukaryotic cell proliferation, apoptosis, and differentiation.


systematic_name: M1319
exact_source: Table 1S
source_species_code: MM
contributor: Kevin Vogelsang
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in hematopoietic precursor cells conditionally expressing HOXA9 and MEIS1 [GeneID=3205;4211].

description_full:
  Abdominal-type HoxA genes in combination with Meis1 are well-documented on-cogenes in various leukemias but it is unclear how they exert their transforming function. Here we used a system of conditional transformation by an inducible mixed lineage leukemia-eleven-nineteen leukemia (MLL-ENL) oncoprotein to overexpress Hoxa9 and Meis1 in primary hematopoietic cells. Arrays identified c-Myb and a c-Myb target (Gstm1) among the genes with the strongest response to Hoxa9/Meis1. c-Myb overexpression was verified by Northern blot and quantitative reverse transcription-polymerase chain reaction (RT-PCR). Also MLL-ENL activated c-Myb through up-regulation of Hoxa9 and Meis1. Consequently, short-term suppression of c-Myb by small inhibitory RNA (siRNA) efficiently inhibited transformation by MLL-ENL but did not impair transformation by transcription factor E2A-hepatic leukemia factor (E2A-HLF). The anti c-Myb siRNA effect was abrogated by coexpression of a c-Myb derivative with a mutated siRNA target site. The introduction of a dominant-negative c-Myb mutant had a similar but weaker effect on MLL-ENL-mediated transformation. Hematopoietic precursors from mice homozygous for a hypo-morphic c-Myb allele were more severely affected and could be transformed neither by MLL-ENL nor by E2A-HLF. Ectopic expression of c-Myb induced a differentiation block but c-Myb alone was not transforming in a replating assay similar to Hoxa9/Meis1. These results suggest that c-Myb is essential but not sufficient for Hoxa9/Meis1 mediated transformation.


description_brief: Putative targets or partners of EZH2 [GeneID=2146] in hematopoietic stem cells.
systematic_name: M1486
exact_source: Table 1
source_species_code: MM
contributor: Kevin Vogelsang
contrib_organization: MSigDB Team
description_full:
  The molecular mechanism responsible for a decline of stem cell functioning after replicative stress remains unknown. We used mouse embryonic fibroblasts (MEFs) and hematopoietic stem cells (HSCs) to identify genes involved in the process of cellular aging. In proliferating and senescent MEFs one of the most differentially expressed transcripts was Enhancer of zeste homolog 2 (Ezh2), a Polycomb group protein (PcG) involved in histone methylation and deacetylation. Retroviral overexpression of Ezh2 in MEFs resulted in bypassing of the senescence program. More importantly, whereas normal HSCs were rapidly exhausted after serial transplantations, overexpression of Ezh2 completely conserved long-term repopulating potential. Animals that were reconstituted with 3 times serially transplanted control bone marrow cells all died due to hematopoietic failure. In contrast, similarly transplanted Ezh2-overexpressing stem cells restored stem cell quality to normal levels. In a genetic genomics screen, we identified novel putative Ezh2 target or partner stem cell genes that are associated with chromatin modification. Our data suggest that stabilization of the chromatin structure preserves HSC potential after replicative stress.


description_brief: Genes up-regulated in pre-B lymphocytes upon Cre-Lox knockout of E2A [GeneID=6929].
systematic_name: M1490
exact_source: Table 1
source_species_code: MM
contributor: Kevin Vogelsang
contrib_organization: MSigDB Team
description_full:
  The transcription factors encoded by the E2A gene have been shown to play essential roles in the initiation and progression of lymphocyte development. However, there is still a lack of comprehensive understanding of E2A downstream genes in B-cell development. We previously developed a gene tagging-based chromatin immunoprecipitation (ChIP) system to directly evaluate E2A target genes in B-cell development. Here, we have improved this ChIP strategy and used it in conjunction with microarray analysis on E2A-deficient pre-B-cell lines to determine E2A target genes in lymphocyte development. Both microarray data and ChIP studies confirmed that E2A directly controls IgH gene expression. The microarray assay also revealed genes that were significantly up-regulated after E2A disruption. ChIP analysis showed that E2A was most likely to be directly involved in repression of some of these target genes such as Nfil3 and FGFR2. An inducible E2A reconstitution system further demonstrated that E2A-mediated repression of Nfil3 and FGFR2 was reversible. Collectively, these findings indicate that E2A is a positive regulator for one set of genes and a negative regulator for another set of genes in developing B lymphocytes.


systematic_name: M1498
exact_source: Table 1 & 2: Methotrexate
source_species_code: MM
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Genes down-regulated in  FL5.12 cells (pro-B lymphocyte) in response to methotrexate [PubChem=4112].

description_full:
  DNA microarrays are powerful tools for the analysis of gene expression on a genomic scale. The importance of individual regulatory events for the process under study can however not be deduced unequivocally without additional experiments. We devised a strategy to identify central regulators of cancer drug responses by combining the results of microarray experiments with efficient methods for phenotypic testing of candidate genes. We exposed murine FL5.12 pro-B cells to cisplatin, camptothecin, methotrexate or paclitaxel, respectively and analysed the patterns of gene expression with cDNA microarrays. Drug-specific regulatory events as well as intersections between different apoptotic pathways, including previously studied responses to staurosporine and interleukin-3 (IL-3) deprivation, were identified. Genes shared by at least three pathways were chosen for further analysis. Ectopic expression of three such genes, TEAP, GP49B, and Lipin1 was found to have an anti-proliferative effect on pro-B cells. Interestingly, we identified hemoglobin alpha as a strong pro-apoptotic regulator. While hemoglobin-expressing cells were growing normally in the presence of IL-3, they displayed accelerated apoptosis with similar kinetics as Bax overexpressing cells upon IL-3 removal. The pro-apoptotic effect of hemoglobin was suppressed by Bcl-2 and was characterized by enhanced stimulation of caspase activity.


systematic_name: M1500
exact_source: Table 2: cluster 4
source_species_code: MM
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Strongly down-regulated at 8-48 h during differentiation of 3T3-L1 cells (fibroblast) into adipocytes.

description_full:
  During cellular differentiation and development, it is recognized that many complex molecular mechanisms as well as precise patterns of differentially expressed genes occur in directing precursor cells toward a given lineage. Using microarray-based technology, we examined gene expression across the course of 3T3-L1 adipocyte differentiation. Total cellular RNA was isolated at times 0, 2, 8, 16, 24, 48, and 96 h following treatment with either standard hormonal inducers of differentiation; insulin, dexamethasone, isobutylmethylxanthine (IDX), or IDX plus trichostatin A (TsA), a histone deacetylase inhibitor and potent adipogenic inhibitor. cRNA was synthesized from cellular RNA and hybridized to high density Affymetrix MG_U74Av2 microarray gene chips containing 12,488 cDNA/Expressed Sequence Tags (ESTs) probe sets. From the IDX-only treated cells, all probe sets that were either unchanged or differentially expressed less than 2-fold throughout differentiation with respect to time 0 preadipocytes were excluded from further analyses. This selection resulted in a net of 1686 transcripts, 859 were increased in expression, and 827 were decreased in expression at least 2-fold across differentiation. To focus in on genes that were more specific to differentiation, the same analysis was performed on IDX plus TsA-treated non-differentiating cells and all probe sets from the IDX-only group that exhibited similar expression profiles in the non-differentiating TsA-treated group were excluded leaving a total of 1016 transcripts that were regulated only under differentiating conditions. Six hundred and thirty-six of these transcripts were elevated at least 2-fold and 380 exhibited a decrease in expression relative to time 0 preadipocytes. This group of genes was further analyzed using hierarchical clustering and self-organizing maps and resulted in the identification of numerous genes not previously known to be regulated during adipocyte differentiation. Many of these genes may well represent novel adipogenic mediators and markers of adipogenesis.


systematic_name: M11205
exact_source: Excel Table 2S: Expression Cluster=MBC Shared
source_species_code: MM
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Genes in the expression cluster 'MBC Shared': up-regulated in mature blood cell populations from adult bone marrow and fetal liver.

description_full:
[cell repeats an earlier one in this file: 626 characters]


systematic_name: M1504
exact_source: Table 1: Fold-TGZ >= 1.1
source_species_code: MM
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Adipocyte abundant genes up-regulated in 3T3-L1 cells (fibroblasts induced to differentiate to adipocytes) in response to troglitazone [PubChem=5591].

description_full:
  Troglitazone (TGZ), a member of the thiazolidinedione class of anti-diabetic compounds and a peroxisome proliferator activator receptor-gamma (PPAR-gamma) agonist, restores systemic insulin sensitivity and improves the full insulin resistance syndrome in vivo. The mechanisms underlying its in vivo function are not understood. Here we investigated the potential functional interaction between PPAR-gamma and NF-kappaB in adipocytes. We show that TGZ selectively blocked tumor necrosis factor-alpha-induced and NF-kappaB-dependent repression of multiple adipocyte-specific genes and induction of growth phase and other genes. This occurs without interfering with NF-kappaB expression, activation, nuclear translocation, or DNA binding and without suppressing NF-kappaB-dependent survival signals. Notably, the expressions of some tumor necrosis factor-alpha-induced genes in adipocytes were unaffected by PPAR-gamma activation. In reporter gene assays in HeLa cells, ectopic expression of PPAR-gamma abolished induction of a NF-kappaB-responsive reporter gene by the p65 subunit (RelA) of NF-kappaB, and the inhibition was further enhanced in the presence of TGZ. Conversely, overexpression of p65 inhibited induction of a PPAR-gamma-responsive reporter gene by activated PPAR-gamma in a dose-dependent manner. The inhibitory effect was independent of the presence of NF-kappaB-binding sites in the promoter region. Other NF-kappaB family members, p50 and c-Rel as well as the S276A mutant of p65, blocked PPAR-gamma-mediated gene transcription less effectively. Thus, p65 antagonizes the transcriptional regulatory activity of PPAR-gamma in adipocytes, and PPAR-gamma activation can at least partially override the inhibitory effects of p65 on the expression of key adipocyte genes. Our data suggest that inhibition of NF-kappaB activity is a mechanism by which PPAR-gamma agonists improve insulin sensitivity in vivo and that adipocyte NF-kappaB is a potential therapeutic target for obesity-linked type 2 diabetes.


description_brief: Up-regulated in hepatocytes upon expression of NOS2 [GeneID=4843].
systematic_name: M1507
exact_source: Table 1, 3-14: Increase
source_species_code: MM
contributor: John Newman
contrib_organization: University of Washington
description_full:
  Nitric oxide (NO) can modulate numerous genes directly; however, some genes may be modulated only in the presence of the inflammatory stimuli that increase the expression of the inducible nitric oxide synthase (iNOS). One method by which to examine changes in NO-mediated gene expression is to carry out a gene array analysis on NO-nai;ve cells. Herein, we report a gene array analysis on mRNA from iNOS-null (iNOS(-/-)) mouse hepatocytes harvested from mice exposed to NO by infection with an adenovirus expressing human iNOS (Ad-iNOS). Of the 6500 genes on this array, only approximately 200 were modulated either up or down by the increased iNOS activity according to our criteria for significance. Several clearly defined families of genes were modulated, including genes coding for proinflammatory transcription factors, cytokines, cytokine receptors, proteins associated with cell proliferation and cellular energetics, as well as proteins involved in apoptosis. Our results suggest that iNOS has a generally anti-inflammatory and anti-apoptotic role in hepatocytes but also acts to suppress proliferation and protein synthesis. The expression of iNOS results in increased expression of stress-related proteins, including heme oxygenase-1 (HO-1). We used HO-1 to confirm that a significant change identified by an analysis could be demonstrated as significant in cells and tissues. The elevation of HO-1 was confirmed at the protein level in hepatocytes in vitro. Furthermore, iNOS(-/-) mice experienced greatly increased liver injury subsequent to intestinal ischemia/reperfusion injury, associated with an inability to upregulate HO-1. This is the first study to address the global gene changes induced by iNOS in any cell type, and the findings presented herein may have clinical relevance for conditions such as septic or hemorrhagic shock in which hepatocytes, NO, and HO-1 play a crucial role.


systematic_name: M1522
exact_source: Table 1
source_species_code: MM
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Genes up-regulated in MEF cells (embryonic fibroblast) lacking TP53 and BRCA1 [GeneID=7157;672] by expression of TP53; most genes are further up-regulated by simultaneous expression of BRCA1.

description_full:
  The tumor suppressor protein BRCA1 has been shown to enhance p53 transcription, whereas activated p53 represses BRCA1 transcription. To further understand the functional interaction of these proteins, we investigated the role of BRCA1 in p53-induced phenotypes. We found that BRCA1 when subjected to forced expression acts synergistically with wild-type p53, resulting in irreversible growth arrest, as shown by VhD mouse fibroblast cells expressing a temperature-sensitive mutant of p53. Furthermore, reintroduction of both BRCA1 and p53 into BRCA1(-/-)/p53(-/-) mouse embryonic fibroblasts markedly increased the senescence phenotype compared to that induced by p53 alone. In particular, we found that BRCA1 expression attenuated p53-mediated cell death in response to gamma-irradiation. Moreover, microarray screening of 11 000 murine genes demonstrated that a set of genes upregulated by p53 is enhanced by coexpression of BRCA1 and p53, suggesting that BRCA1 and p53 exert a promoter selectivity leading to a specific phenotype. Taken together, our results provide evidence that BRCA1 is involved in p53-mediated growth suppression rather than apoptosis.


systematic_name: M1524
exact_source: Table 1: Fold-TNFa-TGZ =< -1.3
source_species_code: MM
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Adipocyte abundant genes down-regulated in 3T3-L1 cells (fibroblasts induced to differentiate to adipocytes) in response to troglitazone [PubChem=5591] and TNF [GeneID=7124].

description_full:
  Troglitazone (TGZ), a member of the thiazolidinedione class of anti-diabetic compounds and a peroxisome proliferator activator receptor-gamma (PPAR-gamma) agonist, restores systemic insulin sensitivity and improves the full insulin resistance syndrome in vivo. The mechanisms underlying its in vivo function are not understood. Here we investigated the potential functional interaction between PPAR-gamma and NF-kappaB in adipocytes. We show that TGZ selectively blocked tumor necrosis factor-alpha-induced and NF-kappaB-dependent repression of multiple adipocyte-specific genes and induction of growth phase and other genes. This occurs without interfering with NF-kappaB expression, activation, nuclear translocation, or DNA binding and without suppressing NF-kappaB-dependent survival signals. Notably, the expressions of some tumor necrosis factor-alpha-induced genes in adipocytes were unaffected by PPAR-gamma activation. In reporter gene assays in HeLa cells, ectopic expression of PPAR-gamma abolished induction of a NF-kappaB-responsive reporter gene by the p65 subunit (RelA) of NF-kappaB, and the inhibition was further enhanced in the presence of TGZ. Conversely, overexpression of p65 inhibited induction of a PPAR-gamma-responsive reporter gene by activated PPAR-gamma in a dose-dependent manner. The inhibitory effect was independent of the presence of NF-kappaB-binding sites in the promoter region. Other NF-kappaB family members, p50 and c-Rel as well as the S276A mutant of p65, blocked PPAR-gamma-mediated gene transcription less effectively. Thus, p65 antagonizes the transcriptional regulatory activity of PPAR-gamma in adipocytes, and PPAR-gamma activation can at least partially override the inhibitory effects of p65 on the expression of key adipocyte genes. Our data suggest that inhibition of NF-kappaB activity is a mechanism by which PPAR-gamma agonists improve insulin sensitivity in vivo and that adipocyte NF-kappaB is a potential therapeutic target for obesity-linked type 2 diabetes.


systematic_name: M1527
exact_source: Table 1
source_species_code: MM
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Genes up-regulated in the mouse model of acute lung injury induced by inhaling nickel sulfate [PubChem=24586].

description_full:
  The role of nitric oxide (NO) in acute lung injury remains controversial. Although inhaled NO increases oxygenation in clinical trials, inhibiting NO-synthase (NOS) can be protective. To examine the latter, nickel-exposed mice were treated with saline or NOS inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME). Initial microarray analysis of nickel-induced gene expression of saline-treated mice revealed increased inflammatory mediator, matrix injury-repair, and hypoxia-induced factor-mediated sequences and decreased lung-specific (e.g., surfactant-associated protein B and C) sequences. Compared with saline control, L-NAME-treated mice had enhanced survival with attenuated serum nitrate/nitrite, endothelial NOS activity, and lavage neutrophils and protein. Although initial cytokine (i.e., interferon-gamma, interleukins-1beta and -6, macrophage inflammatory protein-2, monocyte chemotactic protein-1, and tumor necrosis factor-alpha) gene expression was similar between groups, subsequent larger cytokine increases only occurred in saline-treated mice. Similarly, surfactant protein gene expression decreased initially in both groups yet was restored subsequently with L-NAME treatment. Interestingly, the role of inducible NOS (iNOS) in these responses seems minimal. iNOS gene expression was unaltered, iNOS activity and nitrotyrosine residues were undetectable, and an iNOS antagonist, aminoguanidine, failed to increase survival. Rather, systemic L-NAME treatment appears to attenuate pulmonary endothelial NOS activity, subsequent cytokine expression, inflammation, and protein permeability, and thereby restores surfactant gene expression and increases survival.


systematic_name: M1531
exact_source: Table 3
source_species_code: MM
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Genes most consistently regulated at 24 h by all six genotoxins tested: cisplatin, methyl methanesulfonate, mitomycin C, taxol, hydroxyurea and etoposide [PubChem=2767;4156;5746;4666;3657;36462].

description_full:
  During the safety evaluation process of new drugs and chemicals, a battery of genotoxicity tests is conducted starting with in vitro genotoxicity assays. Obtaining positive results in in vitro genotoxicity tests is not uncommon. Follow-up studies to determine the biological relevance of positive genotoxicity results are costly, time consuming, and utilize animals. More efficient methods, especially for identifying a putative mode of action like an indirect mechanism of genotoxicity (where DNA molecules are not the initial primary targets), would greatly improve the risk assessment for genotoxins. To this end, we are participating in an International Life Sciences Institute (ILSI) project involving studies of gene expression changes caused by model genotoxins. The purpose of the work is to evaluate gene expression tools in general, and specifically for discriminating genotoxins that are direct-acting from indirect-acting. Our lab has evaluated gene expression changes as well as micronuclei (MN) in L5178Y TK(+/-) mouse lymphoma cells treated with six compounds. Direct-acting genotoxins (where DNA is the initial primary target) that were evaluated included the DNA crosslinking agents, mitomycin C (MMC) and cisplatin (CIS), and an alkylating agent, methyl methanesulfonate (MMS). Indirect-acting genotoxins included hydroxyurea (HU), a ribonucleotide reductase inhibitor, taxol (TXL), a microtubule inhibitor, and etoposide (ETOP), a DNA topoisomerase II inhibitor. Microarray gene expression analysis was conducted using Affymetrix mouse oligonucleotide arrays on RNA samples derived from cells which were harvested immediately after the 4 h chemical treatment, and 20 h after the 4 h chemical treatment. The evaluation of these experimental results yields evidence of differentially regulated genes at both 4 and 24 h time points that appear to have discriminating power for direct versus indirect genotoxins, and therefore may serve as a fingerprint for classifying chemicals when their mechanism of action is unknown.


systematic_name: M7883
exact_source: Table 2
source_species_code: MM
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Genes most strongly up-regulated in kidney glomeruli isolated from TCF21 [GeneID=6943] knockout mice.

description_full:
  Mouse mutations have provided tremendous insights into the molecular basis of renal and glomerular development. However, genes often play important roles during multiple stages of nephrogenesis, making it difficult to determine the role of a gene in a specific cell lineage such as the podocyte. Conditional gene targeting and chimeric analysis are two possible approaches to dissect the function of genes in specific cell populations. However, these are labor-intensive and costly and require the generation, validation, and analysis of additional transgenic lines. For overcoming these shortcomings and, specifically, for studying the role of gene function in developing glomeruli, a technique to isolate and purify glomeruli from murine embryos was developed. Combined with gene expression profiling, this method was used to identify differentially expressed genes in glomeruli from Pod1 knockout (KO) mice that die in the perinatal period with multiple renal defects. Glomeruli from early developing stages (late S-shape/early capillary loop) onward can be isolated successfully from wild-type and KO kidneys at 18.5 d postcoitus, and RNA can readily be obtained and used for genome-wide microarray analysis. With this approach, 3986 genes that are differently expressed between glomeruli from Pod1 KO and wild-type mice were identified, including a four-fold reduction of alpha 8 integrin mRNA in glomeruli from Pod1 KO mice that was confirmed by immunostaining. This procedure may be adapted to any transgenic strain, providing a rapid and efficient method to dissect the function of specific genes in glomerular development.


description_brief: Genes up-regulated in NIH-3T3 cells (fibroblast) after knockdown of PRMT5 [GeneID=10419] by RNAi.
systematic_name: M10688
exact_source: Table 1S
source_species_code: MM
contributor: John Newman
contrib_organization: University of Washington
description_full:
  Protein arginine methyltransferases (PRMTs) have been implicated in transcriptional activation and repression, but their role in controlling cell growth and proliferation remains obscure. We have recently shown that PRMT5 can interact with flag-tagged BRG1- and hBRM-based hSWI/SNF chromatin remodelers and that both complexes can specifically methylate histones H3 and H4. Here we report that PRMT5 can be found in association with endogenous hSWI/SNF complexes, which can methylate H3 and H4 N-terminal tails, and show that H3 arginine 8 and H4 arginine 3 are preferred sites of methylation by recombinant and hSWI/SNF-associated PRMT5. To elucidate the role played by PRMT5 in gene regulation, we have established a PRMT5 antisense cell line and determined by microarray analysis that more genes are derepressed when PRMT5 levels are reduced. Among the affected genes, we show that suppressor of tumorigenicity 7 (ST7) and nonmetastatic 23 (NM23) are direct targets of PRMT5-containing BRG1 and hBRM complexes. Furthermore, we demonstrate that expression of ST7 and NM23 is reduced in a cell line that overexpresses PRMT5 and that this decrease in expression correlates with H3R8 methylation, H3K9 deacetylation, and increased transformation of NIH 3T3 cells. These findings suggest that the BRG1- and hBRM-associated PRMT5 regulates cell growth and proliferation by controlling expression of genes involved in tumor suppression.


description_brief: Top genes down-regulated in liver tissue from mice with knockout of ZMPSTE24 [GeneID=10269].
systematic_name: M5958
exact_source: Table 1S: Face1-liver change=D
source_species_code: MM
contributor: John Newman
contrib_organization: University of Washington
description_full:
  Zmpste24 (also called FACE-1) is a metalloproteinase involved in the maturation of lamin A (Lmna), an essential component of the nuclear envelope. Both Zmpste24- and Lmna-deficient mice exhibit profound nuclear architecture abnormalities and multiple histopathological defects that phenocopy an accelerated ageing process. Similarly, diverse human progeroid syndromes are caused by mutations in ZMPSTE24 or LMNA genes. To elucidate the molecular mechanisms underlying these devastating diseases, we have analysed the transcriptional alterations occurring in tissues from Zmpste24-deficient mice. We demonstrate that Zmpste24 deficiency elicits a stress signalling pathway that is evidenced by a marked upregulation of p53 target genes, and accompanied by a senescence phenotype at the cellular level and accelerated ageing at the organismal level. These phenotypes are largely rescued in Zmpste24-/-Lmna+/- mice and partially reversed in Zmpste24-/-p53-/- mice. These findings provide evidence for the existence of a checkpoint response activated by the nuclear abnormalities caused by prelamin A accumulation, and support the concept that hyperactivation of the tumour suppressor p53 may cause accelerated ageing.


description_brief: Genes down-regulated in C2AS12 cells (myoblast) by IGF1 [GeneID=3479] vs PDGFB [GeneID=5155].
systematic_name: M14780
exact_source: Table 2
source_species_code: MM
contributor: John Newman
contrib_organization: University of Washington
description_full:
  Peptide growth factors regulate cell fate by activating distinct signal transduction pathways that ultimately influence gene expression. Insulin-like growth factors (IGFs) play central roles in controlling somatic growth and participate in skeletal muscle development and regeneration. In cultured muscle cells, IGF action is critical both for maintaining viability during the transition from proliferating to differentiating myoblasts and for facilitating differentiation. By contrast, platelet-derived growth factor (PDGF) can sustain cell survival but inhibits differentiation. Here we examine the genetic programs that accompany IGF and PDGF action in myoblasts. Through analysis of high-density oligonucleotide arrays containing approximately 36,000 mouse probe sets, we identify 90 transcripts differentially induced by IGF-I, including 28 muscle-specific genes and 33 previously unannotated mRNAs, and 55 transcripts specifically stimulated by PDGF, including 14 unknowns. Detailed study of one IGF-induced mRNA shows that it encodes a protein related to a recently characterized repulsive guidance molecule postulated to regulate neuronal targeting during development. Our results demonstrate the power of transcriptional profiling for gene discovery and provide opportunities for investigating new proteins potentially involved in different aspects of growth factor action in muscle.


systematic_name: M1555
exact_source: Table 1: Fold-TNFa =< -1.4
source_species_code: MM
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Adipocyte abundant genes down-regulated in 3T3-L1 cells (fibroblasts induced to differentiate to adipocytes) in response to TNF [GeneID=7124].

description_full:
  Troglitazone (TGZ), a member of the thiazolidinedione class of anti-diabetic compounds and a peroxisome proliferator activator receptor-gamma (PPAR-gamma) agonist, restores systemic insulin sensitivity and improves the full insulin resistance syndrome in vivo. The mechanisms underlying its in vivo function are not understood. Here we investigated the potential functional interaction between PPAR-gamma and NF-kappaB in adipocytes. We show that TGZ selectively blocked tumor necrosis factor-alpha-induced and NF-kappaB-dependent repression of multiple adipocyte-specific genes and induction of growth phase and other genes. This occurs without interfering with NF-kappaB expression, activation, nuclear translocation, or DNA binding and without suppressing NF-kappaB-dependent survival signals. Notably, the expressions of some tumor necrosis factor-alpha-induced genes in adipocytes were unaffected by PPAR-gamma activation. In reporter gene assays in HeLa cells, ectopic expression of PPAR-gamma abolished induction of a NF-kappaB-responsive reporter gene by the p65 subunit (RelA) of NF-kappaB, and the inhibition was further enhanced in the presence of TGZ. Conversely, overexpression of p65 inhibited induction of a PPAR-gamma-responsive reporter gene by activated PPAR-gamma in a dose-dependent manner. The inhibitory effect was independent of the presence of NF-kappaB-binding sites in the promoter region. Other NF-kappaB family members, p50 and c-Rel as well as the S276A mutant of p65, blocked PPAR-gamma-mediated gene transcription less effectively. Thus, p65 antagonizes the transcriptional regulatory activity of PPAR-gamma in adipocytes, and PPAR-gamma activation can at least partially override the inhibitory effects of p65 on the expression of key adipocyte genes. Our data suggest that inhibition of NF-kappaB activity is a mechanism by which PPAR-gamma agonists improve insulin sensitivity in vivo and that adipocyte NF-kappaB is a potential therapeutic target for obesity-linked type 2 diabetes.


systematic_name: M1557
exact_source: Table 1S: Fold Change Due to MyoD >= 2
source_species_code: MM
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Genes up-regulated in NIH 3T3 cells (fibroblasts) 24 h after inducing MyoD [GeneID=4654] differentiation program.

description_full:
  The activation of muscle-specific gene expression requires the coordinated action of muscle regulatory proteins and chromatin-remodeling enzymes. Microarray analysis performed in the presence or absence of a dominant-negative BRG1 ATPase demonstrated that approximately one-third of MyoD-induced genes were highly dependent on SWI/SNF enzymes. To understand the mechanism of activation, we performed chromatin immunoprecipitations analyzing the myogenin promoter. We found that H4 hyperacetylation preceded Brg1 binding in a MyoD-dependent manner but that MyoD binding occurred subsequent to H4 modification and Brg1 interaction. In the absence of functional SWI/SNF enzymes, muscle regulatory proteins did not bind to the myogenin promoter, thereby providing evidence for SWI/SNF-dependent activator binding. We observed that the homeodomain factor Pbx1, which cooperates with MyoD to stimulate myogenin expression, is constitutively bound to the myogenin promoter in a SWI/SNF-independent manner, suggesting a two-step mechanism in which MyoD initially interacts indirectly with the myogenin promoter and attracts chromatin-remodeling enzymes, which then facilitate direct binding by MyoD and other regulatory proteins.


