# gene_set_details

description_brief: Genes down-regulated in MCF7 cells (breast cancer) at 6 h of estradiol [PubChem=5757] treatment.
systematic_name: M2154
exact_source: Table 2S
source_species_code: HS
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_full:
  Alternative promoters (AP) occur in >30% protein-coding genes and contribute to proteome diversity. However, large-scale analyses of AP regulation are lacking, and little is known about their potential physiopathologic significance. To better understand the transcriptomic effect of estrogens, which play a major role in breast cancer, we analyzed gene and AP regulation by estradiol in MCF7 cells using pan-genomic exon arrays. We thereby identified novel estrogen-regulated genes (ERG) and determined the regulation of AP-encoded transcripts in 150 regulated genes. In <30% cases, APs were regulated in a similar manner by estradiol, whereas in >70% cases, they were regulated differentially. The patterns of AP regulation correlated with the patterns of estrogen receptor alpha (ERalpha) and CCCTC-binding factor (CTCF) binding sites at regulated gene loci. Interestingly, among genes with differentially regulated (DR) APs, we identified cases where estradiol regulated APs in an opposite manner, sometimes without affecting global gene expression levels. This promoter switch was mediated by the DDX5/DDX17 family of ERalpha coregulators. Finally, genes with DR promoters were preferentially involved in specific processes (e.g., cell structure and motility, and cell cycle). We show, in particular, that isoforms encoded by the NET1 gene APs, which are inversely regulated by estradiol, play distinct roles in cell adhesion and cell cycle regulation and that their expression is differentially associated with prognosis in ER(+) breast cancer. Altogether, this study identifies the patterns of AP regulation in ERGs and shows the contribution of AP-encoded isoforms to the estradiol-regulated transcriptome as well as their physiopathologic significance in breast cancer.


systematic_name: M2221
exact_source: Table 3S: fold change (log2) > 0
source_species_code: HS
GEO_id: E-MEXP-1772
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in K562 cells (lymphoblast) by MYC [GeneID=4609] in the presence of CKN1B [GeneID=1027].

description_full:
  Inhibition of differentiation has been proposed as an important mechanism for Myc-induced tumorigenesis, but the mechanisms involved are unclear. We have established a genetically defined differentiation model in human leukemia K562 cells by conditional expression of the cyclin-dependent kinase (Cdk) inhibitor p27 (inducible by Zn(2+)) and Myc (activatable by 4-hydroxy-tamoxifen). Induction of p27 resulted in erythroid differentiation, accompanied by Cdk inhibition and G(1) arrest. Interestingly, activation of Myc inhibited p27-mediated erythroid differentiation without affecting p27-mediated proliferation arrest. Microarray-based gene expression indicated that, in the presence of p27, Myc blocked the upregulation of several erythroid-cell-specific genes, including NFE2, JUNB, and GATA1 (transcription factors with a pivotal role in erythropoiesis). Moreover, Myc also blocked the upregulation of Mad1, a transcriptional antagonist of Myc that is able to induce erythroid differentiation. Cotransfection experiments demonstrated that Myc-mediated inhibition of differentiation is partly dependent on the repression of Mad1 and GATA1. In conclusion, this model demonstrates that Myc-mediated inhibition of differentiation depends on the regulation of a specific gene program, whereas it is independent of p27-mediated cell cycle arrest. Our results support the hypothesis that differentiation inhibition is an important Myc tumorigenic mechanism that is independent of cell proliferation.


systematic_name: M2232
exact_source: Table 5S: # of WTE2 near gene > 0
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes bound by ESR1 [GeneID=2099] and down-regulated by estradiol [PubChem=5757] in MCF-7 cells (breast cancer).

description_full:
  Estrogen regulates several biological processes through estrogen receptor alpha (ERalpha) and ERbeta. ERalpha-estrogen signaling is additionally controlled by extracellular signal activated kinases such as AKT. In this study, we analyzed the effect of AKT on genome-wide ERalpha binding in MCF-7 breast cancer cells. Parental and AKT-overexpressing cells displayed 4,349 and 4,359 ERalpha binding sites, respectively, with approximately 60% overlap. In both cell types, approximately 40% of estrogen-regulated genes associate with ERalpha binding sites; a similar percentage of estrogen-regulated genes are differentially expressed in two cell types. Based on pathway analysis, these differentially estrogen-regulated genes are linked to transforming growth factor beta (TGF-beta), NF-kappaB, and E2F pathways. Consistent with this, the two cell types responded differently to TGF-beta treatment: parental cells, but not AKT-overexpressing cells, required estrogen to overcome growth inhibition. Combining the ERalpha DNA-binding pattern with gene expression data from primary tumors revealed specific effects of AKT on ERalpha binding and estrogen-regulated expression of genes that define prognostic subgroups and tamoxifen sensitivity of ERalpha-positive breast cancer. These results suggest a unique role of AKT in modulating estrogen signaling in ERalpha-positive breast cancers and highlights how extracellular signal activated kinases can change the landscape of transcription factor binding to the genome.


systematic_name: M2235
exact_source: Table 6S: # of AKTE2 near gene > 0
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes bound by ESR1 [GeneID=2099] and down-regulated by estradiol [PubChem=5757] in MCF-7 cells (breast cancer) expressing constitutevly active form of AKT1 [GeneID=207].

description_full:
  Estrogen regulates several biological processes through estrogen receptor alpha (ERalpha) and ERbeta. ERalpha-estrogen signaling is additionally controlled by extracellular signal activated kinases such as AKT. In this study, we analyzed the effect of AKT on genome-wide ERalpha binding in MCF-7 breast cancer cells. Parental and AKT-overexpressing cells displayed 4,349 and 4,359 ERalpha binding sites, respectively, with approximately 60% overlap. In both cell types, approximately 40% of estrogen-regulated genes associate with ERalpha binding sites; a similar percentage of estrogen-regulated genes are differentially expressed in two cell types. Based on pathway analysis, these differentially estrogen-regulated genes are linked to transforming growth factor beta (TGF-beta), NF-kappaB, and E2F pathways. Consistent with this, the two cell types responded differently to TGF-beta treatment: parental cells, but not AKT-overexpressing cells, required estrogen to overcome growth inhibition. Combining the ERalpha DNA-binding pattern with gene expression data from primary tumors revealed specific effects of AKT on ERalpha binding and estrogen-regulated expression of genes that define prognostic subgroups and tamoxifen sensitivity of ERalpha-positive breast cancer. These results suggest a unique role of AKT in modulating estrogen signaling in ERalpha-positive breast cancers and highlights how extracellular signal activated kinases can change the landscape of transcription factor binding to the genome.


systematic_name: M2239
exact_source: Table 2S: Dec. in 2 x 3D exps
source_species_code: HS
GEO_id: GSE9747
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated upon overexpression of PARVB [GeneID=29780] in MDA-MB-231 cells (breast cancer) cultured in 3D collagen I and 3D Matrigel only.

description_full:
  Parvin-beta is a focal adhesion protein downregulated in human breast cancer cells. Loss of Parvin-beta contributes to increased integrin-linked kinase activity, cell-matrix adhesion, and invasion through the extracellular matrix in vitro. The effect of ectopic Parvin-beta expression on the transcriptional profile of MDA-MB-231 breast cancer cells, which normally do not express Parvin-beta, was evaluated. Particular emphasis was placed upon propagating MDA-MB-231 breast cancer cells in three-dimensional culture matrices. Interestingly, Parvin-beta reexpression in MDA-MB-231 cells increased the mRNA expression, serine 82 phosphorylation (mediated by CDK9), and activity of the nuclear hormone receptor peroxisome proliferator-activated receptor gamma (PPARgamma), and there was a concomitant increase in lipogenic gene expression as a downstream effector of PPARgamma. Importantly, Parvin-beta suppressed breast cancer growth in vivo, with associated decreased proliferation. These data suggest that Parvin-beta might influence breast cancer progression.


systematic_name: M2240
exact_source: Table 2S: Inc. in 3D Mat only
source_species_code: HS
GEO_id: GSE9747
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated upon overexpression of PARVB [GeneID=29780] in MDA-MB-231 cells (breast cancer) cultured in 3D Matrigel only.

description_full:
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systematic_name: M2241
exact_source: Table 2S: Dec. in 3D Mat only
source_species_code: HS
GEO_id: GSE9747
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated upon overexpression of PARVB [GeneID=29780] in MDA-MB-231 cells (breast cancer) cultured in 3D Matrigel only.

description_full:
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systematic_name: M2244
exact_source: Table 1S: category WTG vs SAG = CatB
source_species_code: MM
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Category B genes: p53-dependent genes whose expression in the absence of S389 phosphorylation is dissimilar to loss of TP53 [GeneID=7157] in MEF (embryonic fibroblast) cells in response to UV-C irradiation.

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: M2256
exact_source: Table 2S
source_species_code: HS
GEO_id: GSE8596,GSE8665
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes commonly down-regulated in UET-13 cells (mesenchymal progenitor) by expression of EWSR1 [GeneID=2130] fusions with ETS transcription factors FLI1 and ERG [GeneID=2313 ,2078].

description_full:
  Ewing's family tumor (EFT) is a rare pediatric tumor of unclear origin that occurs in bone and soft tissue. Specific chromosomal translocations found in EFT cause EWS to fuse to a subset of ets transcription factor genes (ETS), generating chimeric EWS/ETS proteins. These proteins are believed to play a crucial role in the onset and progression of EFT. However, the mechanisms responsible for the EWS/ETS-mediated onset remain unclear. Here we report the establishment of a tetracycline-controlled EWS/ETS-inducible system in human bone marrow-derived mesenchymal progenitor cells (MPCs). Ectopic expression of both EWS/FLI1 and EWS/ERG proteins resulted in a dramatic change of morphology, i.e., from a mesenchymal spindle shape to a small round-to-polygonal cell, one of the characteristics of EFT. EWS/ETS also induced immunophenotypic changes in MPCs, including the disappearance of the mesenchyme-positive markers CD10 and CD13 and the up-regulation of the EFT-positive markers CD54, CD99, CD117, and CD271. Furthermore, a prominent shift from the gene expression profile of MPCs to that of EFT was observed in the presence of EWS/ETS. Together with the observation that EWS/ETS enhances the ability of cells to invade Matrigel, these results suggest that EWS/ETS proteins contribute to alterations of cellular features and confer an EFT-like phenotype to human MPCs.


systematic_name: M2313
exact_source: Table 1: DLD23 24 hours; red
source_species_code: HS
GEO_id: E-MEXP-721
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in DL23 cells (colon cancer) upon expression of an activated form of FOXO3 [GeneID=2309].

description_full:
  Forkhead transcription factors of the O class (FOXOs) are important targets of the phosphatidylinositol 3-kinase (PI3-kinase)/Akt pathway. FOXOs have been implicated in the regulation of cell cycle progression, oxidative stress resistance, and apoptosis. Using DNA microarrays, we analyzed the transcriptional response to FOXO3a activation by gene expression analysis in DLD-1 colon cancer cells stably expressing a FOXO3a.A3-ER fusion protein. We found that activation of FOXO3a resulted in repression of a number of previously identified Myc target genes. Furthermore, FOXO3a activation induced expression of several members of the Mad/Mxd family of transcriptional repressors, most notably Mxi1. The induction of Mxi1 by FOXO3a was specific to the Mxi1-SR alpha isoform and was mediated by three highly conserved FOXO binding sites within the first intron of the gene. Activation of FOXO3a in response to inhibition of Akt also resulted in activation of Mxi1-SR alpha expression. Silencing of Mxi1 by small interfering RNA (siRNA) reduced FOXO3a-mediated repression of a number of Myc target genes. We also observed that FOXO3a activation induced a switch in promoter occupancy from Myc to Mxi1 on the E-box containing promoter regions of two Myc target genes, APEX and FOXM1. siRNA-mediated transient silencing of Mxi1 or all Mad/Mxd proteins reduced exit from S phase in response to FOXO3a activation, and stable silencing of Mxi1 or Mad1 reduced the growth inhibitory effect of FOXO3a. We conclude that induction of Mad/Mxd proteins contributes to the inhibition of proliferation in response to FOXO3a activation. Our results provide evidence of direct regulation of Mxi1 by FOXO3a and imply an additional mechanism through which the PI3-kinase/Akt/FOXO pathway can modulate Myc function.


systematic_name: M2340
exact_source: Table 1
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Top genes up-regulated in HEK293 cells (fibroblast) in response to trichostatin A (TSA) [PubChem=5562].

description_full:
  A hallmark of vertebrate genes is that actively transcribed genes are hypomethylated in critical regulatory sequences. However, the mechanisms that link gene transcription and DNA hypomethylation are unclear. Using a trichostatin A (TSA)-induced replication-independent demethylation assay with HEK 293 cells, we show that RNA transcription is required for DNA demethylation. Histone acetylation precedes but is not sufficient to trigger DNA demethylation. Following histone acetylation, RNA polymerase II (RNAP II) interacts with the methylated promoter. Inhibition of RNAP II transcription with actinomycin D, alpha-amanitin, or CDK7-specific small interfering RNA inhibits DNA demethylation. H3 trimethyl lysine 4 methylation, a marker of actively transcribed genes, was associated with the cytomegalovirus promoter only after demethylation. TSA-induced demethylation of the endogenous cancer testis gene GAGE follows a similar sequence of events and is dependent on RNA transcription as well. These data suggest that DNA demethylation follows rather than precedes early transcription and point towards a novel function for DNA demethylation as a memory of actively transcribed genes.


description_brief: Genes up-regulated in intestinal crypt cells upon deletion of CTNNB1 [GeneID=1499].
systematic_name: M2342
exact_source: Table 1S
source_species_code: HS
GEO_id: GSE8818
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_full:
  The Wnt signaling pathway is deregulated in over 90% of human colorectal cancers. beta-Catenin, the central signal transducer of the Wnt pathway, can directly modulate gene expression by interacting with transcription factors of the TCF/LEF family. In the present study we investigate the role of Wnt signaling in the homeostasis of intestinal epithelium by using tissue-specific, inducible beta-catenin gene ablation in adult mice. Block of Wnt/beta-catenin signaling resulted in rapid loss of transient-amplifying cells and crypt structures. Importantly, intestinal stem cells were induced to terminally differentiate upon deletion of beta-catenin, resulting in a complete block of intestinal homeostasis and fatal loss of intestinal function. Transcriptional profiling of mutant crypt mRNA isolated by laser capture microdissection confirmed those observations and allowed us to identify genes potentially responsible for the functional preservation of intestinal stem cells. Our data demonstrate an essential requirement of Wnt/beta-catenin signaling for the maintenance of the intestinal epithelium in the adult organism. This challenges attempts to target aberrant Wnt signaling as a new therapeutic strategy to treat colorectal cancer.


systematic_name: M2356
exact_source: Table 2S
source_species_code: HS
GEO_id: GSE11710
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes with promoters occupied by SMAD2 or SMAD3 [GeneID=4087, 4088] in HaCaT cells (keratinocyte) according to a ChIP-chip analysis.

description_full:
  The Smad2 and Smad3 (Smad2/3) proteins are principally involved in the transmission of transforming growth factor beta (TGF-beta) signaling from the plasma membrane to the nucleus. Many transcription factors have been shown to cooperate with the Smad2/3 proteins in regulating the transcription of target genes, enabling appropriate gene expression by cells. Here we identified 1,787 Smad2/3 binding sites in the promoter regions of over 25,500 genes by chromatin immunoprecipitation on microarray in HaCaT keratinocytes. Binding elements for the v-ets erythroblastosis virus E26 oncogene homolog (ETS) and transcription factor AP-2 (TFAP2) were significantly enriched in Smad2/3 binding sites, and knockdown of either ETS1 or TFAP2A resulted in overall alteration of TGF-beta-induced transcription, suggesting general roles for ETS1 and TFAP2A in the transcription induced by TGF-beta-Smad pathways. We identified novel Smad binding sites in the CDKN1A gene where Smad2/3 binding was regulated by ETS1 and TFAP2A. Moreover, we showed that small interfering RNAs for ETS1 and TFAP2A affected TGF-beta-induced cytostasis. We also analyzed Smad2- or Smad3-specific target genes regulated by TGF-beta and found that their specificity did not appear to be solely determined by the amounts of the Smad2/3 proteins bound to the promoters. These findings reveal novel regulatory mechanisms of Smad2/3-induced transcription and provide an essential resource for understanding their roles.


systematic_name: M2367
exact_source: Table 3S: down-regulated
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in HEK-293 cells (fibroblast) upon knockdown of CTBP1 but not of SATB1 [GeneID=1487, 6304] by RNAi.

description_full:
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systematic_name: M2413
exact_source: Table 1S: Probeset average sheet: Only 611-60h regulated
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes regulated in MCF7 cells (breast cancer) by expression of the truncated (611-CTF) form of ERBB2 [GeneID=2064] at 60 h time point.

description_full:
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systematic_name: M2414
exact_source: Fig. 11S
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in MCF7 cells (breast cancer) more than three-fold by the truncated form 611-CTF of ERBB2 [GeneID=2064] and less than two-fold by the full-length ERBB2 [GeneID=2064].

description_full:
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systematic_name: M2469
exact_source: Table 2S: list 3
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes induced under hypoxia independently of KDM3A [GeneID=55818] in RCC4 cells (renal carcinoma) expressing VHL [GeneID=7428].

description_full:
  The hypoxia-inducible transcription factors (HIFs) directly and indirectly mediate cellular adaptation to reduced oxygen tensions. Recent studies have shown that the histone demethylase genes JMJD1A, JMJD2B, and JARID1B are HIF targets, suggesting that HIFs indirectly influence gene expression at the level of histone methylation under hypoxia. In this study, we identify a subset of hypoxia-inducible genes that are dependent on JMJD1A in both renal cell and colon carcinoma cell lines. JMJD1A regulates the expression of adrenomedullin (ADM) and growth and differentiation factor 15 (GDF15) under hypoxia by decreasing promoter histone methylation. In addition, we demonstrate that loss of JMJD1A is sufficient to reduce tumor growth in vivo, demonstrating that histone demethylation plays a significant role in modulating growth within the tumor microenvironment. Thus, hypoxic regulation of JMJD1A acts as a signal amplifier to facilitate hypoxic gene expression, ultimately enhancing tumor growth.


description_brief: Genes up-regulated hT-RPE cells (immortalized retinal pigment epithelium) by MYC [GeneID=4609].
systematic_name: M2477
exact_source: Table 1S
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_full:
  It has been proposed that c-Myc proapoptotic activity accounts for most of its restraint of tumor formation. We established a telomerase-immortalized human epithelial cell line expressing an activatable c-Myc protein. We found that c-Myc activation induces, in addition to increased sensitivity to apoptosis, reductions in cell motility and invasiveness. Transcriptome analysis revealed that urokinase (uPA) and uPA receptor (uPAR) were strongly downregulated by c-Myc. Evidence is provided that the repression of uPA and uPAR may account for most of the antimigratory and proapoptotic activities of c-Myc. c-Myc is known to cooperate with Ras in cellular transformation. We therefore investigated if this cooperation could converge in the control of uPA/uPAR expression. We found that Ras is able to block the effects of c-Myc activation on apoptosis and cellular motility but not on cell invasiveness. Accordingly, the activation of c-Myc in the context of Ras expression had only minor influence on uPAR expression but still had a profound repressive effect on uPA expression. Thus, the differential regulation of uPA and uPAR by c-Myc and Ras correlates with the effects of these two oncoproteins on cell motility, invasiveness, and survival. In conclusion, we have discovered a novel link between c-Myc and uPA/uPAR. We propose that reductions of cell motility and invasiveness could contribute to the inhibition of tumorigenesis by c-Myc and that the regulation of uPA and uPAR expression may be a component of the ability of c-Myc to reduce motility and invasiveness.


systematic_name: M2488
exact_source: Table 3S: sheet: Downregulated
source_species_code: HS
GEO_id: GSE20753
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in HeLa cells (cervical carcinoma) upon knockdown of PHF8 [GeneID=23133] by RNAi.

description_full:
  Mutations in PHF8 are associated with X-linked mental retardation and cleft lip/cleft palate. PHF8 contains a plant homeodomain (PHD) in its N terminus and is a member of a family of JmjC domain-containing proteins. While PHDs can act as methyl lysine recognition motifs, JmjC domains can catalyze lysine demethylation. Here, we show that PHF8 is a histone demethylase that removes repressive histone H3 dimethyl lysine 9 marks. Our biochemical analysis revealed specific association of the PHF8 PHD with histone H3 trimethylated at lysine 4 (H3K4me3). Chromatin immunoprecipitation followed by high-throughput sequencing indicated that PHF8 is enriched at the transcription start sites of many active or poised genes, mirroring the presence of RNA polymerase II (RNAPII) and of H3K4me3-bearing nucleosomes. We show that PHF8 can act as a transcriptional coactivator and that its activation function largely depends on binding of the PHD to H3K4me3. Furthermore, we present evidence for direct interaction of PHF8 with the C-terminal domain of RNAPII. Importantly, a PHF8 disease mutant was defective in demethylation and in coactivation. This is the first demonstration of a chromatin-modifying enzyme that is globally recruited to promoters through its association with H3K4me3 and RNAPII.


systematic_name: M2494
exact_source: Table 3S
source_species_code: HS
GEO_id: GSE16908
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in primary LEC cells (lymphatic endothelum) upon overexpression of MIR31 [GeneID=407035].

description_full:
  The lymphatic vascular system maintains tissue fluid homeostasis, helps mediate afferent immune responses, and promotes cancer metastasis. To address the role microRNAs (miRNAs) play in the development and function of the lymphatic vascular system, we defined the in vitro miRNA expression profiles of primary human lymphatic endothelial cells (LECs) and blood vascular endothelial cells (BVECs) and identified four BVEC signature and two LEC signature miRNAs. Their vascular lineage-specific expression patterns were confirmed in vivo by quantitative real-time PCR and in situ hybridization. Functional characterization of the BVEC signature miRNA miR-31 identified a novel BVEC-specific posttranscriptional regulatory mechanism that inhibits the expression of lymphatic lineage-specific transcripts in vitro. We demonstrate that suppression of lymphatic differentiation is partially mediated via direct repression of PROX1, a transcription factor that functions as a master regulator of lymphatic lineage-specific differentiation. Finally, in vivo studies of Xenopus and zebrafish demonstrated that gain of miR-31 function impaired venous sprouting and lymphatic vascular development, thus highlighting the importance of miR-31 as a negative regulator of lymphatic development. Collectively, our findings identify miR-31 is a potent regulator of vascular lineage-specific differentiation and development in vertebrates.


systematic_name: M2500
exact_source: Table 2S: p38i LY79754 response=complete
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes whose expression changes in Calu-6 cells (lung cancer) by TNF [GeneID=7124] were blocked completely by p38 inhibitor LY479754.

description_full:
  p38 mitogen-activated protein kinase (MAPK) is rapidly activated by stresses and is believed to play an important role in the stress response. While Chk1 is known to mediate G(2) DNA damage checkpoint control, p38 was also reported to have an essential function in this checkpoint control. Here, we have investigated further the roles of p38 and Chk1 in the G(2) DNA damage checkpoint in cancer cells. We find that although p38 activation is strongly induced by DNA damage, its activity is not required for the G(2) DNA damage checkpoint. In contrast, Chk1 kinase is responsible for the execution of G(2) DNA damage checkpoint control in p53-deficient cells. The inhibition of p38 activity has no effect on Chk1 activation and gamma-H2AX expression. Global gene expression profiling of cancer cells in response to tumor necrosis factor alpha (TNF-alpha) revealed that p38 plays a strong prosurvival role through the coordinated downregulation of proapoptotic genes and upregulation of prosurvival genes. We show that the inhibition of p38 activity during G(2) DNA damage checkpoint arrest triggers apoptosis in a p53-independent manner with a concurrent decrease in the level of Bcl2 family proteins. Our results suggest that although p38 MAPK is not required for the G(2) DNA damage checkpoint function, it plays an important prosurvival role during the G(2) DNA damage checkpoint response through the upregulation of the Bcl2 family proteins.


systematic_name: M2535
exact_source: Table 1S: sheet=hNMSC-signature; D in all 3 pools
source_species_code: HS
GEO_id: GSE18931
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  The '3/3 signature': genes consistently down-regulated in all three pools of normal mammary stem cells (defined by their ability to retain the dye PKH26).

description_full:
  Pathways that govern stem cell (SC) function are often subverted in cancer. Here, we report the isolation to near purity of human normal mammary SCs (hNMSCs), from cultured mammospheres, on the basis of their ability to retain the lipophilic dye PKH26 as a consequence of their quiescent nature. PKH26-positive cells possess all the characteristics of hNMSCs. The transcriptional profile of PKH26-positive cells (hNMSC signature) was able to predict biological and molecular features of breast cancers. By using markers of the hNMSC signature, we prospectively isolated SCs from the normal gland and from breast tumors. Poorly differentiated (G3) cancers displayed higher content of prospectively isolated cancer SCs (CSCs) than did well-differentiated (G1) cancers. By comparing G3 and G1 tumors in xenotransplantation experiments, we directly demonstrated that G3s are enriched in CSCs. Our data support the notion that the heterogeneous phenotypical and molecular traits of human breast cancers are a function of their CSC content.


systematic_name: M7581
exact_source: Table 1
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in pancreatic cancer cells grown in orthotopic xenograft tumors compared to those grown in vitro.

description_full:
[cell repeats an earlier one in this file: 1002 characters]


systematic_name: M2427
exact_source: Table 2
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in pancreatic cancer cells grown in orthotopic xenograft tumors compared to those grown in vitro.

description_full:
[cell repeats an earlier one in this file: 1002 characters]


systematic_name: M7738
exact_source: Table 3: t statistic > 0
source_species_code: HS
GEO_id: GSE6791
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Up-regulated genes in cervical carcinoma and head and neck tumors positive for human papilloma virus (HPV) compared to those negative for HPV.

description_full:
  Human papillomaviruses (HPV) are associated with nearly all cervical cancers, 20% to 30% of head and neck cancers (HNC), and other cancers. Because HNCs also arise in HPV-negative patients, this type of cancer provides unique opportunities to define similarities and differences of HPV-positive versus HPV-negative cancers arising in the same tissue. Here, we describe genome-wide expression profiling of 84 HNCs, cervical cancers, and site-matched normal epithelial samples in which we used laser capture microdissection to enrich samples for tumor-derived versus normal epithelial cells. This analysis revealed that HPV(+) HNCs and cervical cancers differed in their patterns of gene expression yet shared many changes compared with HPV(-) HNCs. Some of these shared changes were predicted, but many others were not. Notably, HPV(+) HNCs and cervical cancers were found to be up-regulated in their expression of a distinct and larger subset of cell cycle genes than that observed in HPV(-) HNC. Moreover, HPV(+) cancers overexpressed testis-specific genes that are normally expressed only in meiotic cells. Many, although not all, of the hallmark differences between HPV(+) HNC and HPV(-) HNC were a direct consequence of HPV and in particular the viral E6 and E7 oncogenes. This included a novel association of HPV oncogenes with testis-specific gene expression. These findings in primary human tumors provide novel biomarkers for early detection of HPV(+) and HPV(-) cancers, and emphasize the potential value of targeting E6 and E7 function, alone or combined with radiation and/or traditional chemotherapy, in the treatment of HPV(+) cancers.


systematic_name: M16975
exact_source: Table 1S
source_species_code: HS
GEO_id: GSE7824
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Up-regulated genes in peripheral zone of human pancreatic cancer growing in the pancreas of nude mice compared to that of the tumor from the central zone.

description_full:
  Using Affymetrix HG-U133 Plus 2.0 array and laser capture microdissection techniques, we determined whether different zones of the same pancreatic tumor exhibited differential expression of genes. Human L3.6pl pancreatic cancer cells were implanted into the pancreas of nude mice. Three weeks later when tumors were 7 to 9 mm in diameter, gene expression patterns in tumor cells within the central and peripheral zones were compared, and 1,222 genes showed statistically significant differences. Bioinformatic functional analysis revealed that 346 up-regulated genes in the peripheral zone were related to cytoskeleton organization and biogenesis, cell cycle, cell adhesion, cell motility, DNA replication, localization, integrin-mediated signaling pathway, development, morphogenesis, and IkappaB kinase/nuclear factor-kappaB cascade; 876 up-regulated genes in the central zone were related to regulation of cell proliferation, regulation of transcription, transmembrane receptor protein tyrosine kinase signaling pathways, response to stress, small GTPase-mediated signal transduction, hexose metabolism, cell death, response to external stimulus, carbohydrate metabolism, and response to wounding. The reliability of the microarray results were confirmed by in situ hybridization analysis of the expression of two genes. Collectively, the data showed zonal heterogeneity for gene expression profiles in tumors and suggest that characterization of zonal gene expression profiles is essential if microarray analyses of genetic profiles are to produce reproducible data, predict disease prognosis, and allow design of specific therapeutics.


systematic_name: M4752
exact_source: Table 1S: non-responders / responders < 1
source_species_code: HS
GEO_id: GSE3493
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in rectal cancer patients resistant to radiotherapy (non-responders) relative to the sensitive ones (responders).

description_full:
  Preoperative radiotherapy has been widely used to improve local control of disease and to improve survival in the treatment of rectal cancer. However, the response to radiotherapy differs among individual tumors. Our objective here was to identify a set of discriminating genes that can be used for characterization and prediction of response to radiotherapy in rectal cancer. Fifty-two rectal cancer patients who underwent preoperative radiotherapy were studied. Biopsy specimens were obtained from rectal cancer before preoperative radiotherapy. Response to radiotherapy was determined by histopathologic examination of surgically resected specimens and classified as responders or nonresponders. By determining gene expression profiles using human U95Av2 Gene Chip, we identified 33 novel discriminating genes of which the expression differed significantly between responders and nonresponders. Using this gene set, we were able to establish a new model to predict response to radiotherapy in rectal cancer with an accuracy of 82.4%. The list of discriminating genes included growth factor, apoptosis, cell proliferation, signal transduction, or cell adhesion-related genes. Among 33 discriminating genes, apoptosis inducers (lumican, thrombospondin 2, and galectin-1) showed higher expression in responders whereas apoptosis inhibitors (cyclophilin 40 and glutathione peroxidase) showed higher expression in nonresponders. The present study suggested the possibility that gene expression profiling may be useful in predicting response to radiotherapy to establish an individualized tailored therapy for rectal cancer. Global expression profiles of responders and nonresponders may provide insights into the development of novel therapeutic targets.


systematic_name: M7012
exact_source: Table 3S
source_species_code: HS
GEO_id: GSE3893
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in invasive ductal carcinoma (IDC) relative to ductal carcinoma in situ (DCIS, non-invasive).

description_full:
  Becoming invasive is a crucial step in breast cancer oncogenesis. At this point, a lesion carries the potential for spreading and metastasis--a process, whose molecular characteristics still remain poorly understood. In this article, we describe a matched-pair analysis of ductal carcinoma in situ (DCIS) and invasive ductal carcinoma (IDC) of nine breast ductal carcinomas to identify novel molecular markers characterizing the transition from DCIS to IDC. The purpose of this study was to better understand the molecular biology of this transition and to identify candidate genes whose products might serve as prognostic markers and/or as molecular targets for treatment. To obtain cellular-based gene expression profiles from epithelial tumor cells, we combined laser capture microdissection with a T7-based two-round RNA amplification and Affymetrix oligonucleotide microarray analysis. Altogether, a set of 24 tumor samples was analyzed, comprised of nine matched DCIS/IDC and replicate DCIS/IDC preparations from three of the nine tumors. Cluster analysis on expression data shows the robustness and reproducibility of the techniques we established. Using multiple statistical methods, 546 significantly differentially expressed probe sets were identified. Eighteen candidate genes were evaluated by RT-PCR. Examples of genes already known to be associated with breast cancer invasion are BPAG1, LRRC15, MMP11, and PLAU. The expression of BPAG1, DACT1, GREM1, MEF2C, SART2, and TNFAIP6 was localized to epithelial tumor cells by in situ hybridization and/or immunohistochemistry, confirming the accuracy of laser capture microdissection sampling and microarray analysis.


systematic_name: M659
exact_source: Table 1: Down-regulated genes
source_species_code: HS
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in H1975 cells (non-small cell lung cancer, NSCLC) resistant to gefitinib [PubChem=123631] after treatment with EGFR inhibitor CL-387785 [PubChem=2776] for 6h.

description_full:
  Activating mutations in the epidermal growth factor receptor (EGFR) tyrosine kinase domain determine responsiveness to EGFR tyrosine kinase inhibitors in patients with advanced non-small cell lung cancer (NSCLC). The modulation of transcriptional pathways by mutant EGFR signaling is not fully understood. Previously, we and others identified a single base pair change leading to a threonine to methionine (T790M) amino acid alteration in the ATP-binding pocket of the EGFR as a common mechanism of acquired resistance. The gefitinib-resistant, T790M-mutant H1975 NSCLC cell line undergoes prominent growth arrest and apoptosis when treated with the irreversible EGFR inhibitor, CL-387,785. We did a transcriptional profiling study of mutant EGFR target genes that are differentially expressed in the resistant gefitinib-treated and the sensitive CL387,785-treated H1975 cells to identify the pivotal transcriptional changes in NSCLC with EGFR-activating mutations. We identified a small subset of early gene changes, including significant reduction of cyclin D1 as a result of EGFR inhibition by CL-387,785 but not by gefitinib. The reduction in cyclin D1 transcription was associated with subsequent suppression of E2F-responsive genes, consistent with proliferation arrest. Furthermore, cyclin D1 expression was higher in EGFR-mutant lung cancer cells compared with cells with wild-type EGFR. EGFR-mutant cells were routinely sensitive to the cyclin-dependent kinase inhibitor flavopiridol, confirming the functional relevance of the cyclin D axis. These studies suggest that cyclin D1 may contribute to the emergence of EGFR-driven tumorigenesis and can be an alternative target of therapy.


systematic_name: M3766
exact_source: Table 1S: d-stat > 0
source_species_code: HS
GEO_id: GSE2990
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Up-regulated genes whose expression correlated with histologic grade of invasive breast cancer tumors: comparison of grade 1 vs grade 3.

description_full:
  BACKGROUND: Histologic grade in breast cancer provides clinically important prognostic information. However, 30%-60% of tumors are classified as histologic grade 2. This grade is associated with an intermediate risk of recurrence and is thus not informative for clinical decision making. We examined whether histologic grade was associated with gene expression profiles of breast cancers and whether such profiles could be used to improve histologic grading. METHODS: We analyzed microarray data from 189 invasive breast carcinomas and from three published gene expression datasets from breast carcinomas. We identified differentially expressed genes in a training set of 64 estrogen receptor (ER)-positive tumor samples by comparing expression profiles between histologic grade 3 tumors and histologic grade 1 tumors and used the expression of these genes to define the gene expression grade index. Data from 597 independent tumors were used to evaluate the association between relapse-free survival and the gene expression grade index in a Kaplan-Meier analysis. All statistical tests were two-sided. RESULTS: We identified 97 genes in our training set that were associated with histologic grade; most of these genes were involved in cell cycle regulation and proliferation. In validation datasets, the gene expression grade index was strongly associated with histologic grade 1 and 3 status; however, among histologic grade 2 tumors, the index spanned the values for histologic grade 1-3 tumors. Among patients with histologic grade 2 tumors, a high gene expression grade index was associated with a higher risk of recurrence than a low gene expression grade index (hazard ratio = 3.61, 95% confidence interval = 2.25 to 5.78; P < .001, log-rank test). CONCLUSIONS: Gene expression grade index appeared to reclassify patients with histologic grade 2 tumors into two groups with high versus low risks of recurrence. This approach may improve the accuracy of tumor grading and thus its prognostic value.


systematic_name: M14024
exact_source: Table 1S: E population: f.ch.>0
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in erythroid progenitor cells isolated from bone marrow of patients with Diamond-Blackfan anemia (DBA) and mutated RPS19 [GeneID=6223].

description_full:
[cell repeats an earlier one in this file: 1452 characters]


systematic_name: M3045
exact_source: Table 1S
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in CD4+ [GeneID=920] T lymphocytes after stimulation with prostaglandin E2 [PubChem=5280360].

description_full:
  Many tumors, including Hodgkin's lymphoma, are associated with decreased cellular immunity and elevated levels of prostaglandin E(2) (PGE(2)), a known inhibitor of CD4+ T cell activation, suggested to be involved in immune deviation in cancer. To address the molecular mechanisms tumor-derived PGE(2) might have on primary human CD4+ T cells, we used a whole genome-based transcriptional approach and show that PGE(2) severely limited changes of gene expression induced by signaling through the T cell receptor and CD28. This data suggests an interference of PGE(2) at an early step of T cell receptor signaling: indeed, PGE(2) stimulation of T cells leads to inactivation of lck and reduced phosphorylation of ZAP70. Antiapoptotic genes escaped PGE(2)-induced inhibition resulting in partial protection from apoptosis in response to irradiation or Fas-mediated signaling. As a functional consequence, PGE(2)-treated CD4+ T cells are arrested in the cell cycle associated with up-regulation of the cyclin/cyclin-dependent kinase inhibitor p27(kip1). Most importantly, CD4+ T cells in Hodgkin's lymphoma show similar regulation of genes that were altered in vitro by PGE(2) in T cells from healthy individuals. These data strongly suggest that PGE(2) is an important factor leading to CD4+ T cell impairment observed in Hodgkin's lymphoma.


systematic_name: M2214
exact_source: Table 1S
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in CD4+ [GeneID=920] T lymphocytes after stimulation with prostaglandin E2 [PubChem=5280360].

description_full:
  Many tumors, including Hodgkin's lymphoma, are associated with decreased cellular immunity and elevated levels of prostaglandin E(2) (PGE(2)), a known inhibitor of CD4+ T cell activation, suggested to be involved in immune deviation in cancer. To address the molecular mechanisms tumor-derived PGE(2) might have on primary human CD4+ T cells, we used a whole genome-based transcriptional approach and show that PGE(2) severely limited changes of gene expression induced by signaling through the T cell receptor and CD28. This data suggests an interference of PGE(2) at an early step of T cell receptor signaling: indeed, PGE(2) stimulation of T cells leads to inactivation of lck and reduced phosphorylation of ZAP70. Antiapoptotic genes escaped PGE(2)-induced inhibition resulting in partial protection from apoptosis in response to irradiation or Fas-mediated signaling. As a functional consequence, PGE(2)-treated CD4+ T cells are arrested in the cell cycle associated with up-regulation of the cyclin/cyclin-dependent kinase inhibitor p27(kip1). Most importantly, CD4+ T cells in Hodgkin's lymphoma show similar regulation of genes that were altered in vitro by PGE(2) in T cells from healthy individuals. These data strongly suggest that PGE(2) is an important factor leading to CD4+ T cell impairment observed in Hodgkin's lymphoma.


systematic_name: M8991
exact_source: Table 1S: FC > 0
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Selected genes up-regulated in DU145 and PC-3 cells (prostate cancer) after treatment with the NSAID (non-steroid anti-inflammatory drug) sulindac [PubChem=5352].

description_full:
  Numerous studies show that nonsteroidal anti-inflammatory drugs (NSAIDs) are effective in chemoprevention or treatment of cancer. Nevertheless, the mechanisms underlying these antineoplastic effects remain poorly understood. Here, we report that induction of the cancer-specific proapoptotic cytokine melanoma differentiation associated gene-7/interleukin-24 (MDA-7/IL-24) by several NSAIDs is an essential step for induction of apoptosis and G(2)-M growth arrest in cancer cells in vitro and inhibition of tumor growth in vivo. We also show that MDA-7/IL-24-dependent up-regulation of growth arrest and DNA damage inducible 45 alpha (GADD45alpha) and GADD45gamma gene expression is sufficient for cancer cell apoptosis via c-Jun NH(2)-terminal kinase (JNK) activation and growth arrest induction through inhibition of Cdc2-cyclin B checkpoint kinase. Knockdown of GADD45alpha and GADD45gamma transcription by small interfering RNA abrogates apoptosis and growth arrest induction by the NSAID treatment, blocks JNK activation, and restores Cdc2-cyclin B kinase activity. Our results establish MDA-7/IL-24 and GADD45alpha and GADD45gamma as critical mediators of apoptosis and growth arrest in response to NSAIDs in cancer cells.


systematic_name: M17956
exact_source: Table 1S: FC < 0
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Selected genes down-regulated in DU145 and PC-3 cells (prostate cancer) after treatment with the NSAID (non-steroid anti-inflammatory drug) sulindac [PubChem=5352].

description_full:
  Numerous studies show that nonsteroidal anti-inflammatory drugs (NSAIDs) are effective in chemoprevention or treatment of cancer. Nevertheless, the mechanisms underlying these antineoplastic effects remain poorly understood. Here, we report that induction of the cancer-specific proapoptotic cytokine melanoma differentiation associated gene-7/interleukin-24 (MDA-7/IL-24) by several NSAIDs is an essential step for induction of apoptosis and G(2)-M growth arrest in cancer cells in vitro and inhibition of tumor growth in vivo. We also show that MDA-7/IL-24-dependent up-regulation of growth arrest and DNA damage inducible 45 alpha (GADD45alpha) and GADD45gamma gene expression is sufficient for cancer cell apoptosis via c-Jun NH(2)-terminal kinase (JNK) activation and growth arrest induction through inhibition of Cdc2-cyclin B checkpoint kinase. Knockdown of GADD45alpha and GADD45gamma transcription by small interfering RNA abrogates apoptosis and growth arrest induction by the NSAID treatment, blocks JNK activation, and restores Cdc2-cyclin B kinase activity. Our results establish MDA-7/IL-24 and GADD45alpha and GADD45gamma as critical mediators of apoptosis and growth arrest in response to NSAIDs in cancer cells.


systematic_name: M18058
exact_source: Table 1S
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in primary cultures of ovarian surface epithlium cells exposed to progesterone [PubChem=5994] for 5 days.

description_full:
  BACKGROUND: Ovarian cancer (OvCa) most often derives from ovarian surface epithelial (OSE) cells. Several lines of evidence strongly suggest that increased exposure to progesterone (P4) protects women against developing OvCa. However, the underlying mechanisms of this protection are incompletely understood. METHODS: To determine downstream gene targets of P4, we established short term in vitro cultures of non-neoplastic OSE cells from six subjects, exposed the cells to P4 (10-6 M) for five days and performed transcriptional profiling with oligonucleotide microarrays containing over 22,000 transcripts. RESULTS: We identified concordant but modest gene expression changes in cholesterol/lipid homeostasis genes in three of six samples (responders), whereas the other three samples (non-responders) showed no expressional response to P4. The most up-regulated gene was TMEM97 which encodes a transmembrane protein of unknown function (MAC30). Analyses of outlier transcripts, whose expression levels changed most significantly upon P4 exposure, uncovered coordinate up-regulation of 14 cholesterol biosynthesis enzymes, insulin-induced gene 1, low density lipoprotein receptor, ABCG1, endothelial lipase, stearoyl- CoA and fatty acid desaturases, long-chain fatty-acyl elongase, and down-regulation of steroidogenic acute regulatory protein and ABCC6. Highly correlated tissue-specific expression patterns of TMEM97 and the cholesterol biosynthesis genes were confirmed by analysis of the GNF Atlas 2 universal gene expression database. Real-time quantitative RT-PCR analyses revealed 2.4-fold suppression of the TMEM97 gene expression in short-term cultures of OvCa relative to the normal OSE cells. CONCLUSION: These findings suggest that a co-regulated transcript network of cholesterol/lipid homeostasis genes and TMEM97 are downstream targets of P4 in normal OSE cells and that TMEM97 plays a role in cholesterol and lipid metabolism. The P4-induced alterations in cholesterol and lipid metabolism in OSE cells might play a role in conferring protection against OvCa.


systematic_name: M16774
exact_source: Table 1S
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in primary cultures of ovarian surface epithlium cells exposed to progesterone [PubChem=5994] for 5 days.

description_full:
  BACKGROUND: Ovarian cancer (OvCa) most often derives from ovarian surface epithelial (OSE) cells. Several lines of evidence strongly suggest that increased exposure to progesterone (P4) protects women against developing OvCa. However, the underlying mechanisms of this protection are incompletely understood. METHODS: To determine downstream gene targets of P4, we established short term in vitro cultures of non-neoplastic OSE cells from six subjects, exposed the cells to P4 (10-6 M) for five days and performed transcriptional profiling with oligonucleotide microarrays containing over 22,000 transcripts. RESULTS: We identified concordant but modest gene expression changes in cholesterol/lipid homeostasis genes in three of six samples (responders), whereas the other three samples (non-responders) showed no expressional response to P4. The most up-regulated gene was TMEM97 which encodes a transmembrane protein of unknown function (MAC30). Analyses of outlier transcripts, whose expression levels changed most significantly upon P4 exposure, uncovered coordinate up-regulation of 14 cholesterol biosynthesis enzymes, insulin-induced gene 1, low density lipoprotein receptor, ABCG1, endothelial lipase, stearoyl- CoA and fatty acid desaturases, long-chain fatty-acyl elongase, and down-regulation of steroidogenic acute regulatory protein and ABCC6. Highly correlated tissue-specific expression patterns of TMEM97 and the cholesterol biosynthesis genes were confirmed by analysis of the GNF Atlas 2 universal gene expression database. Real-time quantitative RT-PCR analyses revealed 2.4-fold suppression of the TMEM97 gene expression in short-term cultures of OvCa relative to the normal OSE cells. CONCLUSION: These findings suggest that a co-regulated transcript network of cholesterol/lipid homeostasis genes and TMEM97 are downstream targets of P4 in normal OSE cells and that TMEM97 plays a role in cholesterol and lipid metabolism. The P4-induced alterations in cholesterol and lipid metabolism in OSE cells might play a role in conferring protection against OvCa.


systematic_name: M14958
exact_source: Table 1, 2
source_species_code: HS
GEO_id: GSE4225
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in ACC3 cells (adenoid cystic carcinoma) after knockdown of SOX4 [GeneID=6659] by RNAi.

description_full:
  Microarray RNA gene expression profiling analysis has shown that Sox4 (Sry-related high mobility group (HMG) box 4) is one of the most upregulated genes in adenoid cystic carcinoma (ACC), relative to non-neoplastic tissue of origin. Here, we show that Sox4 protein is similarly upregulated in ACC by immunohistochemistry of 28 primary cancers and 20 normal tissues. To elucidate the functional significance of these findings, RNA interference (RNAi)-mediated RNA silencing was used to downregulate Sox4 expression in the ACC-derived cell line, ACC3. With confirmed knockdown of Sox4 protein, cell viability was reduced by 51%, with a corresponding increase of apoptosis to 85% as compared to 12% in controls. Apoptosis was confirmed by cell morphology, DNA fragmentation and flow cytometry. Cells could be rescued from the proapoptotic effects of Sox4 RNAi by co-transfection with a construct expressing functional Sox4. Microarray gene expression profiling of RNAi knockdown experiments shows that downregulation of Sox4-modulated expression of critical genes involved in apoptosis and cell cycle control. Overall, our findings suggest that Sox4 contributes to the malignant phenotype of ACC cells by promoting cell survival.


systematic_name: M2038
exact_source: Table 2S
source_species_code: HS
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in APL (acute promyeolocytic leukemia) blasts expressing PML-RARA fusion [GeneID=5371;5914] compared to normal promyeloblasts.

description_full:
  Acute promyelocytic leukemia (APL) is a clonal expansion of hematopoietic precursors blocked at the promyelocytic stage. Gene expression profiles of APL cells obtained from 16 patients were compared to eight samples of CD34+-derived normal promyelocytes. Malignant promyelocytes showed widespread changes in transcription in comparison to their normal counterpart and 1020 differentially expressed genes were identified. Discriminating genes include transcriptional regulators (FOS, JUN and HOX genes) and genes involved in cell cycle and DNA repair. The strong upregulation in APL of some transcripts (FLT3, CD33, CD44 and HGF) was also confirmed at protein level. Interestingly, a trend toward a transcriptional repression of genes involved in different DNA repair pathways was found in APL and confirmed by real-time polymerase chain reactor (PCR) in a new set of nine APLs. Our results suggest that both inefficient base excision repair and recombinational repair might play a role in APLs development. To investigate the expression pathways underlying the development of APL occurring as a second malignancy (sAPL), we included in our study eight cases of sAPL. Although both secondary and de novo APL were characterized by a strong homogeneity in expression profiling, we identified a small set of differentially expressed genes that discriminate sAPL from de novo cases.


systematic_name: M17427
exact_source: Table 1: Class A v B Fold Change > 1
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in ER(-) / PR(-) breast tumors (do not express ESR1 and PGR [GeneID=2099;5241]) with molecular similarity to ER(+) (class A) relative to the rest of the ER(-) / PR(-) samples (class B).

description_full:
[cell repeats an earlier one in this file: 1461 characters]


systematic_name: M7600
exact_source: Table 3S: Fold Change > 1
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in MDA-MB-453 cells (class A ER(-) [GeneID=2099] breast cancer) after exposure to the androgen R1881 [PubChem=13766].

description_full:
[cell repeats an earlier one in this file: 1461 characters]


systematic_name: M19439
exact_source: Table 2S: Up in ER P.txt
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in breast cancer samples positive for ESR1 [GeneID=2099] compared to the ESR1 negative tumors.

description_full:
[cell repeats an earlier one in this file: 1461 characters]


systematic_name: M16075
exact_source: Tables 1-3: Fold change in R1881 > 0
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in LNCaP cells (prostate cancer) treated with synthetic androgen R1881 [PubChem=13766].

description_full:
  Progression of prostate cancer to androgen independence is suspected to involve the androgen and protein kinase A (PKA) signaling pathways. Here for the first time, the transcriptomes associated with each pathway and common transcriptional targets in response to stimulation of both pathways were identified in human prostate cancer cells using Affymetrix GeneChip technology (Human Genome U133 plus2). Statistically significant changes in the levels of 858 genes in response to androgen and 303 genes in response to activation of the PKA pathway were determined using GeneSpring software. Expression of a subset of these genes (22) that were transcriptional targets for the androgen and/or PKA pathways were validated by reverse transcriptase-polymerase chain reaction and Western blot analyses. Application of small interfering RNAs to the androgen receptor (AR) revealed that in addition to KLK3, levels of expression of KLK2 and SESN1 were regulated by AR activated by both the androgen and PKA signaling pathways. SESN1 was identified as a gene repressed by activated AR. These results provide a broad view of the effects of the androgen and PKA signaling pathways on the transcriptional program of prostate cancer cells and indicate that only a limited number of genes are targeted by cross-talk between AR and PKA pathways.


systematic_name: M14942
exact_source: Tables 1-3: Fold change in FSK > 0
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in LNCaP cells (prostate cancer) treated with forskolin [PubChem=47936], an activator of PKA pathway.

description_full:
  Progression of prostate cancer to androgen independence is suspected to involve the androgen and protein kinase A (PKA) signaling pathways. Here for the first time, the transcriptomes associated with each pathway and common transcriptional targets in response to stimulation of both pathways were identified in human prostate cancer cells using Affymetrix GeneChip technology (Human Genome U133 plus2). Statistically significant changes in the levels of 858 genes in response to androgen and 303 genes in response to activation of the PKA pathway were determined using GeneSpring software. Expression of a subset of these genes (22) that were transcriptional targets for the androgen and/or PKA pathways were validated by reverse transcriptase-polymerase chain reaction and Western blot analyses. Application of small interfering RNAs to the androgen receptor (AR) revealed that in addition to KLK3, levels of expression of KLK2 and SESN1 were regulated by AR activated by both the androgen and PKA signaling pathways. SESN1 was identified as a gene repressed by activated AR. These results provide a broad view of the effects of the androgen and PKA signaling pathways on the transcriptional program of prostate cancer cells and indicate that only a limited number of genes are targeted by cross-talk between AR and PKA pathways.


systematic_name: M19162
exact_source: Tables 1-3: Fold changes in FSK < 0
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in LNCaP cells (prostate cancer) treated with forskolin [PubChem=47936], an activator of PKA pathway.

description_full:
  Progression of prostate cancer to androgen independence is suspected to involve the androgen and protein kinase A (PKA) signaling pathways. Here for the first time, the transcriptomes associated with each pathway and common transcriptional targets in response to stimulation of both pathways were identified in human prostate cancer cells using Affymetrix GeneChip technology (Human Genome U133 plus2). Statistically significant changes in the levels of 858 genes in response to androgen and 303 genes in response to activation of the PKA pathway were determined using GeneSpring software. Expression of a subset of these genes (22) that were transcriptional targets for the androgen and/or PKA pathways were validated by reverse transcriptase-polymerase chain reaction and Western blot analyses. Application of small interfering RNAs to the androgen receptor (AR) revealed that in addition to KLK3, levels of expression of KLK2 and SESN1 were regulated by AR activated by both the androgen and PKA signaling pathways. SESN1 was identified as a gene repressed by activated AR. These results provide a broad view of the effects of the androgen and PKA signaling pathways on the transcriptional program of prostate cancer cells and indicate that only a limited number of genes are targeted by cross-talk between AR and PKA pathways.


systematic_name: M5459
exact_source: Table 3S
source_species_code: HS
GEO_id: GSE3407
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in Cockayne syndrome fibroblasts rescued by expression of ERCC6 [GeneID=2074] off a plasmid vector.

description_full:
  Cockayne syndrome (CS) is an inherited neurodevelopmental disorder with progeroid features. Although the genes responsible for CS have been implicated in a variety of DNA repair- and transcription-related pathways, the nature of the molecular defect in CS remains mysterious. Using expression microarrays and a unique method for comparative expression analysis called L2L, we sought to define this defect in cells lacking a functional CS group B (CSB) protein, the SWI/SNF-like ATPase responsible for most cases of CS. Remarkably, many of the genes regulated by CSB are also affected by inhibitors of histone deacetylase and DNA methylation, as well as by defects in poly(ADP-ribose)-polymerase function and RNA polymerase II elongation. Moreover, consistent with these microarray expression data, CSB-null cells are sensitive to inhibitors of histone deacetylase or poly(ADP-ribose)-polymerase. Our data indicate a general role for CSB protein in maintenance and remodeling of chromatin structure and suggest that CS is a disease of transcriptional deregulation caused by misexpression of growth-suppressive, inflammatory, and proapoptotic pathways.


systematic_name: M6239
exact_source: Table 2S
source_species_code: HS
GEO_id: GSE3407
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in Cockayne syndrome fibroblasts rescued by expression of ERCC6 [GeneID=2074] off a plasmid vector.

description_full:
  Cockayne syndrome (CS) is an inherited neurodevelopmental disorder with progeroid features. Although the genes responsible for CS have been implicated in a variety of DNA repair- and transcription-related pathways, the nature of the molecular defect in CS remains mysterious. Using expression microarrays and a unique method for comparative expression analysis called L2L, we sought to define this defect in cells lacking a functional CS group B (CSB) protein, the SWI/SNF-like ATPase responsible for most cases of CS. Remarkably, many of the genes regulated by CSB are also affected by inhibitors of histone deacetylase and DNA methylation, as well as by defects in poly(ADP-ribose)-polymerase function and RNA polymerase II elongation. Moreover, consistent with these microarray expression data, CSB-null cells are sensitive to inhibitors of histone deacetylase or poly(ADP-ribose)-polymerase. Our data indicate a general role for CSB protein in maintenance and remodeling of chromatin structure and suggest that CS is a disease of transcriptional deregulation caused by misexpression of growth-suppressive, inflammatory, and proapoptotic pathways.


systematic_name: M10279
exact_source: Table 3S
source_species_code: HS
GEO_id: GSE2327
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in primary endothelial cells (HUVEC) after knockdown of WTAP [GeneID=9589] by RNAi.

description_full:
  Wilms' tumor 1-associating protein (WTAP) has been reported to be a ubiquitously expressed nuclear protein. Although a relation to splicing factors has been postulated, its actual physiological function still remains to be elucidated. To investigate the role of WTAP, we generated WTAP-knockout mice and performed small interfering RNA (siRNA)-mediated knockdown analyses in primary cultured cells. In DNA microarrays using human umbilical vein endothelial cells, WTAP-targeted siRNA treatment resulted in markedly reduced expression of cell-cycle-related genes. siRNA-mediated WTAP knockdown down-regulated the stability of cyclin A2 mRNA through a nine-nucleotide essential sequence in cyclin A2 mRNA 3' UTR. WTAP knockdown induced G2 accumulation, which is partially rescued by adenoviral overexpression of cyclin A2. Moreover, WTAP-null mice exhibited proliferative failure with death resulting at approximately embryonic day 6.5, an etiology almost identical to cyclin A2-null mice. Collectively, these findings establish WTAP as an essential factor for the stabilization of cyclin A2 mRNA, thereby regulating G2/M cell-cycle transition.


systematic_name: M14985
exact_source: Table 1S
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in SKOC-3 cells (ovarian cancer) after YB-1 (YBX1) [GeneID=4904] knockdown by RNAi.

description_full:
  Y-box-binding protein 1 (YB-1), which is a member of the DNA-binding protein family containing a cold-shock domain, has pleiotropic functions in response to various environmental stimuli. As we previously showed that YB-1 is a global marker of multidrug resistance in ovarian cancer and other tumor types. To identify YB-1-regulated genes in ovarian cancers, we investigated the expression profile of YB-1 small-interfering RNA (siRNA)-transfected ovarian cancer cells using a high-density oligonucleotide array. YB-1 knockdown by siRNA upregulated 344 genes, including MDR1, thymidylate synthetase, S100 calcium binding protein and cyclin B, and downregulated 534 genes, including CXCR4, N-myc downstream regulated gene 1, E-cadherin and phospholipase C. Exogenous serum addition stimulated YB-1 translocation from the cytoplasm to the nucleus, and treatment with Akt inhibitors as well as Akt siRNA and integrin-linked kinase (ILK) siRNA specifically blocked YB-1 nuclear localization. Inhibition of Akt activation downregulated CXCR4 and upregulated MDR1 (ABCB1) gene expression. Administration of Akt inhibitor resulted in decrease in nuclear YB-1-positive cancer cells in a xenograft animal model. Akt activation thus regulates the nuclear translocation of YB-1, affecting the expression of drug-resistance genes and other genes associated with the malignant characteristics in ovarian cancer cells. Therefore, the Akt pathway could be a novel target of disrupting the nuclear translocation of YB-1 that has important implications for further development of therapeutic strategy against ovarian cancers.


systematic_name: M2733
exact_source: Table 2
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Cellular proliferation, growth, apoptosis and Wnt signaling genes down-regulated in SNU638 cells (gastric cancer) by overexpression of SFRP2 [GeneID=6423] off a plasmid vector.

description_full:
  Activation of Wnt signaling has been implicated in gastric tumorigenesis, although mutations in APC (adenomatous polyposis coli), CTNNB1 (beta-catenin) and AXIN are seen much less frequently in gastric cancer (GC) than in colorectal cancer. In the present study, we investigated the relationship between activation of Wnt signaling and changes in the expression of secreted frizzled-related protein (SFRP) family genes in GC. We frequently observed nuclear beta-catenin accumulation (13/15; 87%) and detected the active form of beta-catenin in most (12/16; 75%) GC cell lines. CpG methylation-dependent silencing of SFRP1, SFRP2 and SFRP5 was frequently seen among GC cell lines (SFRP1, 16/16, 100%; SFRP2, 16/16, 100%; SFRP5, 13/16, 81%) and primary GC specimens (SFRP1, 42/46, 91%; SFRP2, 44/46, 96%; SFRP5, 30/46, 65%), and treatment with the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine rapidly restored SFRP expression. Ectopic expression of SFRPs downregulated T-cell factor/lymphocyte enhancer factor transcriptional activity, suppressed cell growth and induced apoptosis in GC cells. Analysis of global expression revealed that overexpression of SFRP2 repressed Wnt target genes and induced changes in the expression of numerous genes related to proliferation, growth and apoptosis in GC cells. It thus appears that aberrant SFRP methylation is one of the major mechanisms by which Wnt signaling is activated in GC.


systematic_name: M11857
exact_source: Table 3S: Direction=D
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in HCT8/S11 cells (colon cancer) engineered to stably express NTN1 [GeneID=1630] off a plasmid vector.

description_full:
[cell repeats an earlier one in this file: 1687 characters]


systematic_name: M14132
exact_source: Table 1S
source_species_code: HS
GEO_id: GSE3292
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in head and neck squamous cell carcinoma (HNSCC) samples positive for HPV compared to the HPV-negative tumors.

description_full:
  Human papillomavirus (HPV) is associated with a subset of head and neck squamous cell carcinoma (HNSCC). Between 15% and 35% of HNSCCs harbor HPV DNA. Demographic and exposure differences between HPV-positive (HPV+) and negative (HPV-) HNSCCs suggest that HPV+ tumors may constitute a subclass with different biology, whereas clinical differences have also been observed. Gene expression profiles of HPV+ and HPV- tumors were compared with further exploration of the biological effect of HPV in HNSCC. Thirty-six HNSCC tumors were analyzed using Affymetrix Human 133U Plus 2.0 GeneChip and for HPV by PCR and real-time PCR. Eight of 36 (22%) tumors were positive for HPV subtype 16. Statistical analysis using Significance Analysis of Microarrays based on HPV status as a supervising variable resulted in a list of 91 genes that were differentially expressed with statistical significance. Results for a subset of these genes were verified by real-time PCR. Genes highly expressed in HPV+ samples included cell cycle regulators (p16(INK4A), p18, and CDC7) and transcription factors (TAF7L, RFC4, RPA2, and TFDP2). The microarray data were also investigated by mapping genes by chromosomal location (DIGMAP). A large number of genes on chromosome 3q24-qter had high levels of expression in HPV+ tumors. Further investigation of differentially expressed genes may reveal the unique pathways in HPV+ tumors that may explain the different natural history and biological properties of these tumors. These properties may be exploited as a target of novel therapeutic agents in HNSCC treatment.


systematic_name: M12383
exact_source: supplementup.pdf
source_species_code: HS
GEO_id: GSE3003
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in hematopoietic stem cells (HSC, CD34+ [GeneID=947]) cultured in a three-dimentional collagen gel compared to the cells grown in suspension.

description_full:
  CD34+ hematopoietic stem/progenitor cells (HSCs) reside in the bone marrow in close proximity to the endosteal bone surface, surrounded by osteoblasts, stromal cells, and various extracellular matrix molecules. We used a bioartificial matrix of fibrillar collagen I, the major matrix component of bone, as a scaffold for ex vivo expansion of HSCs. CD34+ HSCs were isolated from umbilical cord blood and cultivated within reconstituted collagen I fibrils in the presence of fms-like tyrosine kinase-3 ligand, stem cell factor, and interleukin (IL)-3. After 7 days of culture, the cell number, number of colony-forming units (CFU-C), and gene-expression profile of the cultured cells were assessed. Although the total expansion factor of CD34+ cells was slightly lower when cells were cultivated in the collagen I gel, the frequency of CFU-C was greater than in control suspension cultures. Gene-expression analysis with microarray chip technology revealed the upregulation of more than 50 genes in the presence of collagen I. Among these, genes for several growth factors, cytokines, and chemokines (e.g., IL-8 and macrophage inhibitory protein 1alpha) could be confirmed using quantitative polymerase chain reaction. Furthermore, greater expression levels of the negative cell-cycle regulator BTG2/TIS21 and an inhibitor of the mitogen-activated protein kinase pathway, DUSP2, underline the regulatory role of the extracellular matrix. Together, these data show that the expansion of CD34+ cord blood cells in a culture system containing a three-dimensional collagen I matrix induces a qualitative change in the gene-expression profile of cultivated HSCs.


systematic_name: M15537
exact_source: Table 1S: module=turquoise & fold change >= 1.5
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes from the turquoise module which are up-regulated in HAEC cells (primary aortic endothelium) after exposure to the oxidized 1-palmitoyl-2-arachidonyl-sn-3-glycerophosphorylcholine (oxPAPC).

description_full:
[cell repeats an earlier one in this file: 1667 characters]


systematic_name: M19590
exact_source: Table 1S: module=turquoise & fold change < 0.667
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes from the turquoise module which are dn-regulated in HAEC cells (primary aortic endothelium) after exposure to the oxidized 1-palmitoyl-2-arachidonyl-sn-3-glycerophosphorylcholine (oxPAPC).

description_full:
[cell repeats an earlier one in this file: 1667 characters]


systematic_name: M4035
exact_source: Table 1S: module=red & fold change >= 1.5
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes from the red module which are up-regulated in HAEC cells (primary aortic endothelium) after exposure to the oxidized 1-palmitoyl-2-arachidonyl-sn-3-glycerophosphorylcholine (oxPAPC).

description_full:
[cell repeats an earlier one in this file: 1667 characters]


systematic_name: M2422
exact_source: Table 1S: module=magenta & fold change >= 1.5
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes from the magenta module which are up-regulated in HAEC cells (primary aortic endothelium) after exposure to the oxidized 1-palmitoyl-2-arachidonyl-sn-3-glycerophosphorylcholine (oxPAPC).

description_full:
[cell repeats an earlier one in this file: 1667 characters]


systematic_name: M2231
exact_source: Table 1S: module=black & fold change >= 1.5
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes from the black module which are up-regulated in HAEC cells (primary aortic endothelium) after exposure to the oxidized 1-palmitoyl-2-arachidonyl-sn-3-glycerophosphorylcholine (oxPAPC).

description_full:
[cell repeats an earlier one in this file: 1667 characters]


systematic_name: M8565
exact_source: Table 1S: module=grey & fold change < 0.667
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes from the grey module which are dn-regulated in HAEC cells (primary aortic endothelium) after exposure to the oxidized 1-palmitoyl-2-arachidonyl-sn-3-glycerophosphorylcholine (oxPAPC).

description_full:
[cell repeats an earlier one in this file: 1667 characters]


systematic_name: M18559
exact_source: Table 1S
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-rgulated in CD34+ [GeneID=947] hematopoetic cells by expression of NUP98-HOXA9 fusion [GeneID=4928;3205] off a retroviral vector at 6h.

description_full:
[cell repeats an earlier one in this file: 1913 characters]


systematic_name: M6670
exact_source: Table 2S
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in CD34+ [GeneID=947] hematopoetic cells by expression of NUP98-HOXA9 fusion [GeneID=4928;3205] off a retroviral vector at 3 days after transduction.

description_full:
[cell repeats an earlier one in this file: 1913 characters]


systematic_name: M17275
exact_source: Table 3S
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in CD34+ [GeneID=947] hematopoetic cells by expression of NUP98-HOXA9 fusion [GeneID=4928;3205] off a retroviral vector at 8 days after transduction.

description_full:
[cell repeats an earlier one in this file: 1913 characters]


systematic_name: M13479
exact_source: Table 4S
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in CD34+ [GeneID=947] hematopoetic cells by expression of NUP98-HOXA9 fusion [GeneID=4928;3205] off a retroviral vector at 10 days after transduction.

description_full:
[cell repeats an earlier one in this file: 1913 characters]


systematic_name: M15588
exact_source: Table 5S
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in CD34+ [GeneID=947] hematopoetic cells by expression of NUP98-HOXA9 fusion [GeneID=4928;3205] off a retroviral vector at 16 days after transduction.

description_full:
[cell repeats an earlier one in this file: 1913 characters]


systematic_name: M6451
exact_source: Table 7AS: fold change < -2
source_species_code: HS
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in P493-6 cells (B lymphocyte, Burkitt's lymphoma model) upon knockdown of TFRC [GeneID=7037] by RNAi.

description_full:
  Overexpression of transferrin receptor 1 (TFRC1), a major mediator of iron uptake in mammalian cells, is a common feature of human malignancies. Therapeutic strategies designed to interfere with tumor iron metabolism have targeted TFRC1. The c-Myc oncogenic transcription factor stimulates proliferation and growth by activating thousands of target genes. Here we demonstrate that TFRC1 is a critical downstream target of c-Myc. Using in vitro and in vivo models of B-cell lymphoma, we show that TFRC1 expression is activated by c-Myc. Chromatin immunoprecipitation experiments reveal that c-Myc directly binds a conserved region of TFRC1. In light of these findings, we sought to determine whether TFRC1 is required for c-Myc-mediated cellular proliferation and cell size control. TFRC1 inhibition decreases cellular proliferation and results in G1 arrest without affecting cell size. Consistent with these findings, expression profiling reveals that TFRC1 depletion alters expression of genes that regulate the cell cycle. Furthermore, enforced TFRC1 expression confers a growth advantage to cells and significantly enhances the rate of c-Myc-mediated tumor formation in vivo. These findings provide a molecular basis for increased TFRC1 expression in human tumors, illuminate the role of TFRC1 in the c-Myc target gene network, and support strategies that target TFRC1 for cancer therapy.


systematic_name: M6792
exact_source: Table 7BS
source_species_code: HS
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in P493-6 cells (B lymphocyte, Burkitt's lymphoma model) by MYC [GeneID=4609] and down-regulated by RNAi knockdown of TFRC [GeneID=7037].

description_full:
[cell repeats an earlier one in this file: 1391 characters]


systematic_name: M15196
exact_source: Table 1S: 2h coculture
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in Caco-2 cells (intestinal epithelium) after coculture with the probiotic bacteria L. casei for 2h.

description_full:
[cell repeats an earlier one in this file: 1732 characters]


systematic_name: M19251
exact_source: Table 1S
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in Caco-2 cells (intestinal epithelium) after coculture with the probiotic bacteria L. casei for 6h.

description_full:
[cell repeats an earlier one in this file: 1732 characters]


systematic_name: M19666
exact_source: Table 1S: 24h coculture
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in Caco-2 cells (intestinal epithelium) after coculture with the probiotic bacteria L. casei for 24h.

description_full:
[cell repeats an earlier one in this file: 1732 characters]


systematic_name: M6787
exact_source: Table S1
source_species_code: HS
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in HB2 cells (mammary epithelium) upon expression of KDM5B [GeneID=10765] off an adenoviral vector.

description_full:
  The PLU-1/JARID1B nuclear protein, which is upregulated in breast cancers, belongs to the ARID family of DNA binding proteins and has strong transcriptional repression activity. To identify the target genes regulated by PLU-1/JARID1B, we overexpressed or silenced the human PLU-1/JARID1B gene in human mammary epithelial cells by using adenovirus and RNA interference systems, respectively, and then applied microarray analysis to identify candidate genes. A total of 100 genes showed inversely correlated differential expression in the two systems. Most of the candidate genes were downregulated by the overexpression of PLU-1/JARID1B, including the MT genes, the tumor suppressor gene BRCA1, and genes involved in the regulation of the M phase of the mitotic cell cycle. Chromatin immunoprecipitation assays confirmed that the metallothionein 1H (MT1H), -1F, and -1X genes are direct transcriptional targets of PLU-1/JARID1B in vivo. Furthermore, the level of trimethyl H3K4 of the MT1H promoter was increased following silencing of PLU-1/JARID1B. Both the PLU-1/JARID1B protein and the ARID domain selectively bound CG-rich DNA. The GCACA/C motif, which is abundant in metallothionein promoters, was identified as a consensus binding sequence of the PLU-1/JARID1B ARID domain. As expected from the microarray data, cells overexpressing PLU-1/JARID1B have an impaired G(2)/M checkpoint. Our study provides insight into the molecular function of the breast cancer-associated transcriptional repressor PLU-1/JARID1B.


systematic_name: M9128
exact_source: Table 1S
source_species_code: HS
GEO_id: GSE5117
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in UB27 cells (osteosarcoma) at any time point after inducing the expression of a mutant form of WT1 [GeneID=7490].

description_full:
[cell repeats an earlier one in this file: 1371 characters]


systematic_name: M8857
exact_source: Table 1S
source_species_code: HS
GEO_id: GSE5117
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in UB27 cells (osteosarcoma) at 8 hr after inducing the expression of a mutant form of WT1 [GeneID=7490].

description_full:
[cell repeats an earlier one in this file: 1371 characters]


systematic_name: M15535
exact_source: Table 1S
source_species_code: HS
GEO_id: GSE5117
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in UB27 cells (osteosarcoma) at 12 hr after inducing the expression of a mutated form of WT1 [GeneID=7490].

description_full:
[cell repeats an earlier one in this file: 1371 characters]


systematic_name: M9197
exact_source: Tables 3S, 4S: DMOG fold change > 0 & q-val < 0.01
source_species_code: HS
GEO_id: GSE3188
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in MCF7 cells (breast cancer) treated with hypoxia mimetic DMOG [PubChem=3080614].

description_full:
[cell repeats an earlier one in this file: 1645 characters]


systematic_name: M6189
exact_source: Tables 3S, 4S: HIF12si fold change < 0 & q-value < 0.01
source_species_code: HS
GEO_id: GSE3188
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in MCF7 cells (breast cancer) after knockdown of both HIF1A and HIF2A [GeneID=3091;2034] by RNAi.

description_full:
[cell repeats an earlier one in this file: 1645 characters]


systematic_name: M19744
exact_source: Table 2S: Ratio CG/CD > 3
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in quiescent (G0) vs dividing (M) CD34+ [GeneID=8842] cells isolated from peripheral blood of CML (chronic myeloid leukemia) patients.

description_full:
[cell repeats an earlier one in this file: 1512 characters]


systematic_name: M18983
exact_source: Table 3S: Ratio CG/NG > 3
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in quiescent (G0) CD34+ [GeneID=8842] cells isolated from peripheral blood of CML (chronic myeloid leukemia) patients compared to the quiescent cells from normal donors.

description_full:
[cell repeats an earlier one in this file: 1512 characters]


systematic_name: M17730
exact_source: Table 4S: Ratio CG v ND > 3
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in quescent CD34+ [GeneID=8842] cells isolated from peripheral blood of CML (chronic myeloblastic leukemia) patients compared to the dividing cells from normal donors.

description_full:
[cell repeats an earlier one in this file: 1512 characters]


systematic_name: M3155
exact_source: Table 6S: Ratio CDvNG > 3
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in quiescent CD34+ [GeneID=8842] cells isolated from peripheral blood of normal donors compared to the dividing cells from CML (chronic myeloid leukemia) patients.

description_full:
[cell repeats an earlier one in this file: 1512 characters]


systematic_name: M5198
exact_source: Table 7S: Ratio ND/NG > 3
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in quiescent vs dividing CD34+ [GeneID=8842] cells isolated from peripheral blood of normal donors.

description_full:
[cell repeats an earlier one in this file: 1512 characters]


systematic_name: M15866
exact_source: Table 1S
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in endometroid endometrial tumors from patients with lymph node metastases compared to those without the metastases.

description_full:
  PURPOSE: To characterize the gene expression profiles of endometrioid endometrial cancers associated with lymph node metastasis in an effort to identify genes associated with metastatic spread. EXPERIMENTAL DESIGN: Tumors from 41 patients with endometrioid endometrial cancer grossly confined to the uterine cavity were evaluated. Positive lymph nodes were noted in 12 of 41 patients. RNA was analyzed for gene expression using the Affymetrix HG133A and HG133B GeneChip set, representing 45,000 array features covering >28,000 UniGene clusters. Data analysis was done using multidimensional scaling, binary comparison, and hierarchical clustering. Gene expression for several differentially expressed genes was examined using quantitative PCR. RESULTS: Gene expression data was obtained from 30,964 genes that were detected in at least 5% of the cases. Supervised analysis of node-positive versus node-negative cases indicated that 450 genes were significantly differentially expressed between the two classes at P < 0.005, 81 of which were differentially expressed by at least 2-fold at P < 0.005. Overexpressed genes included two cell cycle checkpoint genes, CDC2 and MAD2L1, which have previously been described in association with lymph node metastasis in other cancer types. The ZIC2 zinc finger gene was overexpressed in endometrial cancers with positive nodes versus those with negative nodes. CONCLUSION: Gene expression profiling of the primary tumors in patients with endometrioid endometrial cancers seems promising for identifying genes associated with lymph node metastasis. Future studies should address whether the status of nodal metastasis can be determined from the expression profiles of preoperative tissue specimens.


systematic_name: M19982
exact_source: Table 1S
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in mucinous ovarian carcinoma tumors of low malignant potential (LMP) compared to normal ovarian surface epithelium tissue.

description_full:
  PURPOSE: To elucidate the molecular mechanisms contributing to the unique clinicopathologic characteristics of mucinous ovarian carcinoma, global gene expression profiling of mucinous ovarian tumors was carried out. EXPERIMENTAL DESIGN: Gene expression profiling was completed for 25 microdissected mucinous tumors [6 cystadenomas, 10 low malignant potential (LMP) tumors, and 9 adenocarcinomas] using Affymetrix U133 Plus 2.0 oligonucleotide microarrays. Hierarchical clustering and binary tree prediction analysis were used to determine the relationships among mucinous specimens and a series of previously profiled microdissected serous tumors and normal ovarian surface epithelium. PathwayAssist software was used to identify putative signaling pathways involved in the development of mucinous LMP tumors and adenocarcinomas. RESULTS: Comparison of the gene profiles between mucinous tumors and normal ovarian epithelial cells identified 1,599, 2,916, and 1,765 differentially expressed in genes in the cystadenomas, LMP tumors, and adenocarcinomas, respectively. Hierarchical clustering showed that mucinous and serous LMP tumors are distinct. In addition, there was a close association of mucinous LMP tumors and adenocarcinomas with serous adenocarcinomas. Binary tree prediction revealed increased heterogeneity among mucinous tumors compared with their serous counterparts. Furthermore, the cystadenomas coexpressed a subset of genes that were differentially regulated in LMP and adenocarcinoma specimens compared with normal ovarian surface epithelium. PathwayAssist highlighted pathways with expression of genes involved in drug resistance in both LMP and adenocarcinoma samples. In addition, genes involved in cytoskeletal regulation were specifically up-regulated in the mucinous adenocarcinomas. CONCLUSIONS: These data provide a useful basis for understanding the molecular events leading to the development and progression of mucinous ovarian cancer.


systematic_name: M2435
exact_source: Table 1S
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in mucinous ovarian carcinoma tumors of grades 1 and 2 compared to the normal ovarian survace epithelium tissue.

description_full:
[cell repeats an earlier one in this file: 1966 characters]


systematic_name: M9775
exact_source: Table 5S: M >= 1
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in T helper cells (defines as CD4+) isolated from patients with mucosis fungoides compared to those from normal control donors.

description_full:
[cell repeats an earlier one in this file: 1743 characters]


systematic_name: M16637
exact_source: Table 1
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in HET1A cells (esophagus epithelium) engineered to stably express CDX2 [GeneID=1045].

description_full:
  Caudal-related homeobox 2 (Cdx2) has been suggested as an early marker of Barrett's esophagus (BE), which is the premalignant lesion of esophageal adenocarcinoma (EAC). However, the mechanism of ectopic Cdx2 expression in the esophageal epithelial cells and its role in the development of BE remained unclear. RT-PCR, pyrosequencing and methylation-specific PCR were used to determine expression and promoter methylation of Cdx2 in human esophageal epithelial cells (HET1A and SEG1) after treatment with 5-aza-2'-deoxycytidine (DAC), acid, bile acids and their combination. HET1A cells with stable transfection of Cdx2 were characterized for morphology and gene expression profiles with Affymetrix array. We found Cdx2 was expressed in most human EAC cell lines, but not in squamous epithelial cell lines. DAC-induced demethylation and expression of Cdx2 in HET1A and SEG1 cells, and treatment with a DNA methylating agent counteracted the effect of DAC. Treatment of HET1A and SEG1 cells with acid, bile acids or both also resulted in promoter demethylation and expression of Cdx2. HET1A cells with stable transfection of human Cdx2 formed crypt-like structures in vitro. Microarray analysis and quantitative real-time PCR showed that stable transfection of Cdx2 up-regulated differentiation markers of intestinal columnar epithelial cells and goblet cells in HET1A cells. This may be partially due to modulation of Notch signaling pathway, as western blotting confirmed down-regulation of Hes1 and up-regulation of Atoh1 and Muc2. Our data suggest that exposure to acid and/or bile acids may activate Cdx2 expression in human esophageal epithelial cells through promoter demethylation, and ectopic Cdx2 expression in esophageal squamous epithelial cells may contribute to intestinal metaplasia of the esophagus.


systematic_name: M6744
exact_source: Table 2S
source_species_code: HS
GEO_id: GSE4342
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in NSCLC (non-small cell lung carcinoma) cell lines resistant to gefitinib [PubChem=123631] compared to the sensitive ones.

description_full:
  Tyrosine kinase inhibitors (TKI) of the epidermal growth factor receptor (EGFR) produce objective responses in a minority of patients with advanced-stage non-small cell lung cancer (NSCLC), and about half of all treated patients progress within 6 weeks of instituting therapy. Because the target of these agents is known, it should be possible to develop biological predictors of response, but EGFR protein levels have not been proven useful as a predictor of TKI response in patients and the mechanism of primary resistance is unclear. We used microarray gene expression profiling to uncover a pattern of gene expression associated with sensitivity to EGFR-TKIs by comparing NSCLC cell lines that were either highly sensitive or highly resistant to gefitinib. This sensitivity-associated expression profile was used to predict gefitinib sensitivity in a panel of NSCLC cell lines with known gene expression profiles but unknown gefitinib sensitivity. Gefitinib sensitivity was then determined for members of this test panel, and the microarray-based sensitivity prediction was correct in eight of nine NSCLC cell lines. Gene and protein expression differences were confirmed with a combination of quantitative reverse transcription-PCR, flow cytometry, and immunohistochemistry. This gene expression pattern related to gefitinib sensitivity was independent from sensitivity associated with EGFR mutations. Several genes associated with sensitivity encode proteins involved in HER pathway signaling or pathways that interrelate to the HER signaling pathway. Some of these genes could be targets of pharmacologic interventions to overcome primary resistance.


description_brief: Genes up-regulated in MEWO cells (melanoma) after 48h of methionine [PubChem=876] deprivation.
systematic_name: M13537
exact_source: Table 1S
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_full:
  Methionine deprivation stress (MDS) eliminates mitotic activity in melanoma cells regardless of stage, grade, or TP53 status, whereas it has a negligible effect on normal skin fibroblasts. In most cases, apoptosis accounts for the elimination of up to 90% of tumor cells from the culture within 72 hours after MDS, leaving a scattered population of multinucleated resistant cells. Loss of mitosis in tumor cells is associated with marked reduction of cyclin-dependent kinase (CDK) 1 transcription and/or loss of its active form (CDK1-P-Thr(161)), which is coincident with up-regulation of CDKN1A, CDKN1B, and CDKN1C (p21, p27, and p57). Expression of the proapoptotic LITAF, IFNGR, EREG, TNFSF/TNFRSF10 and TNFRSF12, FAS, and RNASEL is primarily up-regulated/induced in cells destined to undergo apoptosis. Loss of Aurora kinase B and BIRC5, which are required for histone H3 phosphorylation, is associated with the accumulation of surviving multinucleated cells. Nevertheless, noncycling survivors of MDS are sensitized to temozolomide, carmustin, and cisplatin to a much greater extent than normal skin fibroblasts possibly because of the suppression of MGMT/TOP1/POLB, MGMT/RAD52/RAD54, and cMET/RADD52, respectively. Sensitivity to these and additional genotoxic agents and radiation may also be acquired due to loss of cMET/OGG1, reduced glutathione reductase levels, and a G(2)-phase block that is a crucial step in the damage response associated with enhancement of drug toxicity. Although the genes controlling mitotic arrest and/or apoptosis in response to low extracellular methionine levels are unknown, it is likely that such control is exerted via the induction/up-regulation of tumor suppressors/growth inhibitor genes, such as TGFB, PTEN, GAS1, EGR3, BTG3, MDA7, and the proteoglycans (LUM, BGN, and DCN), as well as the down-regulation/loss of function of prosurvival genes, such as NFkappaB, MYC, and ERBB2. Although MDS targets several common genes in tumors, mutational variability among melanomas may decide which metabolic and signal transduction pathways will be activated or shutdown.


systematic_name: M1411
exact_source: Table 1
source_species_code: HS
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated by UV-irradiation in cervical cancer cells after knockdown of CDKN2A [GeneID=1029].

description_full:
  p16(INK4A) (p16) has been suggested to be an early biomarker for the detection of cervical cancer. However, its functional role in cervical cancer is not well characterized. In this study, we reported the consistent and significant upregulation of p16 in cervical cancer tissues when compared to both matched non-tumourous tissues of the same patient and normal cervical tissues from non-cancer patients. We have employed p16 small interfering RNA (siRNA) to dissect the role of p16 in cervical carcinogenesis. Although the silencing of p16 was accompanied by the upregulation of p53, p21 and RB in the p16 siRNA-transfected cells, no significant effect on cell cycle progression was observed. When the p16 siRNA-silenced cells were subjected to DNA damage stress including ultraviolet-irradiation and cisplatin treatments, a significantly higher percentage of apoptotic cells could be observed in the p16-siRNA silenced cells compared to control siRNA-treated cells. Moreover, induction of apoptosis was associated with the activation of p53 through phosphorylation, and this process, when studied by gene profiling experiments, involved both the intrinsic and extrinsic apoptotic pathways. The observation that silencing of p16 expression augments DNA damage-induced apoptosis in cervical cancer cells offers alternative strategies for anti-cancer therapies for human cervical cancer.


systematic_name: M17788
exact_source: Table 2BS
source_species_code: HS
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Down-regulated genes whose expression profile is specific to Custer I of urothelial cell carcinoma (UCC) tumors.

description_full:
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systematic_name: M1096
exact_source: Table 1S
source_species_code: HS
GEO_id: GSE2138
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in colorectal carcinoma samples positive for MSI (microsatellite instability) compared to the MSI negative ones.

description_full:
  Mutation or epigenetic silencing of mismatch repair genes, such as MLH1 and MSH2, results in microsatellite instability (MSI) in the genome of a subset of colorectal carcinomas (CRCs). However, little is yet known of genes that directly contribute to tumor formation in such cancers. To characterize MSI-dependent changes in gene expression, we have now compared transcriptomes between fresh CRC specimens positive or negative for MSI (n=10 for each) with the use of high-density oligonucleotide microarrays harboring >44,000 probe sets. Correspondence analysis of the expression patterns of isolated MSI-associated genes revealed that the transcriptome of MSI+ CRCs is clearly distinct from that of MSI- CRCs. Such MSI-associated genes included that for AXIN2, an important component of the WNT signaling pathway. AXIN2 was silenced, apparently as a result of extensive methylation of its promoter region, specifically in MSI+ CRC specimens. Forced expression of AXIN2, either by treatment with 5'-azacytidine or by transfection with AXIN2 cDNA, resulted in rapid cell death in an MSI+ CRC cell line. These data indicate that epigenetic silencing of AXIN2 is specifically associated with carcinogenesis in MSI+ CRCs.


systematic_name: M15377
exact_source: Table 1: RAD001-sensitive
source_species_code: HS
GEO_id: GSE1379
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes in the AKT1 [GeneID=207] pathway which depend on MTOR [GeneID=2475], sensitive to RAD001 (everolimus) [PubChem=6442177].

description_full:
  The Akt pathway is commonly deregulated in many cancers. Clinical trials are currently underway to test the effectiveness of breast cancer treatment by inhibition of various Akt pathway intermediates. A set of genes induced by Akt in a transgenic mouse model, a subset of which were sensitive to mammalian target of rapamycin (mTOR) inhibitor RAD001, was examined in five public gene expression profile data sets of clinical breast tumor specimens (representing >1000 different samples in all). In each of the clinical data sets, the Akt mouse model genes as a group were significantly overexpressed in human tumors having high levels of AKT1 mRNA. The subset of genes both upregulated by Akt and dependent on mTOR activity were associated with estrogen receptor-negative status, higher grade, increasing tumor size and poor prognosis in multiple patient cohorts; these associations were either not present or not as strong for the Akt-induced, mTOR-independent genes or for AKT1 expression alone. The genes shown here to be relevant to Akt-mTOR both experimentally and pathologically have the potential for use in a molecular diagnostic to determine which patients should receive mTOR antagonist treatment.


systematic_name: M6862
exact_source: Table 1
source_species_code: HS
GEO_id: E-UCON-1
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Up-regulated genes in the breast cancer prognostic signature of 70 genes that significantly correlated with survival.

description_full:
  Prognostic signatures in breast cancer derived from microarray expression profiling have been reported by two independent groups. These signatures, however, have not been validated in external studies, making clinical application problematic. We performed microarray expression profiling of 135 early-stage tumors, from a cohort representative of the demographics of breast cancer. Using a recently proposed semisupervised method, we identified a prognostic signature of 70 genes that significantly correlated with survival (hazard ratio (HR): 5.97, 95% confidence interval: 3.0-11.9, P = 2.7e-07). In multivariate analysis, the signature performed independently of other standard prognostic classifiers such as the Nottingham Prognostic Index and the 'Adjuvant!' software. Using two different prognostic classification schemes and measures, nearest centroid (HR) and risk ordering (D-index), the 70-gene classifier was also found to be prognostic in two independent external data sets. Overall, the 70-gene set was prognostic in our study and the two external studies which collectively include 715 patients. In contrast, we found that the two previously described prognostic gene sets performed less optimally in external validation. Finally, a common prognostic module of 29 genes that associated with survival in both our cohort and the two external data sets was identified. In spite of these results, further studies that profile larger cohorts using a single microarray platform, will be needed before prospective clinical use of molecular classifiers can be contemplated.


systematic_name: M16108
exact_source: Table 2S
source_species_code: HS
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in SH-SY5Y cells (neuroblastoma) after treatment with epoxomicin [PubChem=3035402], a protease inhibitor causing apoptosis.

description_full:
  The proteasome has emerged as a novel target for antineoplastic treatment of hematological malignancies and solid tumors, including those of the central nervous system. To identify cell death pathways activated in response to inhibition of the proteasome system in cancer cells, we treated human SH-SY5Y neuroblastoma cells with the selective proteasome inhibitor (PI) epoxomicin (Epoxo). Prolonged exposure to Epoxo was associated with increased levels of poly-ubiquitinylated proteins and p53, release of cytochrome c from the mitochondria, and activation of caspases. Analysis of global gene expression using high-density oligonucleotide microarrays revealed that Epoxo triggered transcriptional activation of the two Bcl-2-homology domain-3-only (BH3-only) genes p53 upregulated modulator of apoptosis (PUMA) and Bim. Subsequent studies in PUMA- and Bim-deficient cells indicated that Epoxo-induced caspase activation and apoptosis was predominantly PUMA-dependent. Further characterization of the transcriptional response to Epoxo in HCT116 human colon cancer cells demonstrated that PUMA induction was p53-dependent; with deficiency in either p53 or PUMA significantly protected HCT116 cells against Epoxo-induced apoptosis. Our data suggest that p53 activation and the transcriptional induction of its target gene PUMA play an important role in the sensitivity of cancer cells to apoptosis induced by proteasome inhibition, and imply that antineoplastic therapies with PIs might be especially useful in cancers with functional p53.


systematic_name: M12016
exact_source: Table 4S: Pgc < 0
source_species_code: HS
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in epithelial ovarian cancer (EOC) biopsies: invasive (TOV) vs low malignant potential (LMP) tumors.

description_full:
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systematic_name: M16812
exact_source: Table 1: fold change > 0
source_species_code: HS
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes genes up-regulated in NT2/D1 cells (embryonal carcinoma) in response to treatment with cisplatin [PubChem=2767].

description_full:
  Testicular germ cell cancers remain one of the few solid tumors routinely cured in advanced stages with conventional cisplatin-based chemotherapy. The mechanisms remain largely unknown. Through use of gene-expression array profiling we define immediate transcriptional targets in response to cisplatin in testicular germ cell-derived human embryonal carcinoma cells. We report 46 genes upregulated and five genes repressed by cisplatin. Several of these gene products, including FAS, TRAILR3, PHLDA3, LRDD, and IER3 are previously implicated in the apoptotic death receptor pathway, while others including SESN1, FDXR, PLK3, and DDIT4 are known mediators of reactive oxygen species generation. Approximately 54% of the upregulated genes are established or suspected downstream targets of p53. Specific siRNA to p53 prevents cisplatin-mediated activation of p53 and p53 pathway genes and renders embryonal carcinoma cells relatively resistant to cisplatin cytotoxicity. Interestingly, in p53 knockdown cells nearly the entire set of identified cisplatin targets fail to respond or have a diminished response to cisplatin, suggesting that many are new direct or indirect targets of p53 including GPR87, STK17A, INPP5D, FLJ11259, and EPS8L2. The data indicate that robust transcriptional activation of p53 is linked to the known hypersensitivity of testicular germ cell tumors to chemotherapy. Many of the gene products may participate in the unique curability of this disease.


systematic_name: M6866
exact_source: Table 2S
source_species_code: HS
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in PaCa44 and CFPAC1 cells (pancreatic cancer) after treatment with decitabine [PubChem=451668], a DNA hypomethylating agent similar to azacitidine [PubChem=9444].

description_full:
  Alteration of methylation status has been recognized as a possible epigenetic mechanism of selection during tumorigenesis in pancreatic cancer. This type of cancer is characterized by poor prognosis partly due to resistance to conventional drug treatments. We have used microarray technology to investigate the changes in global gene expression observed after treatment of different pancreatic cancer cell lines with the methylase inhibitor 5-aza-2'-deoxycytidine (5-aza-CdR). We have observed that this agent is able to inhibit to various degrees the growth of three pancreatic cancer cell lines. In particular, this inhibition was associated with induction of interferon (IFN)-related genes, as observed in other tumour types. Thus, expression of STAT1 seems to play a key role in the cellular response to treatment with the cytosine analogue. Moreover, we found increased p21(WAF1) and gadd45A expression to be associated with the efficacy of the treatment; this induction may correlate with activation of the IFN signalling pathway. Expression of the p16(INK) protein was also linked to the ability of cells to respond to 5-aza-CdR. Finally, genome-wide demethylation induced sensitization that significantly increased response to further treatment with various chemotherapy agents.


systematic_name: M11850
exact_source: Table 1S
source_species_code: HS
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in WI-38 cells (senescent primary fibroblasts) after inactivation of TP53 [GeneID=7157] by GSE56 polypeptide.

description_full:
  The tumor suppressor p53 is a key modulator of the cellular stress response, inducing cell-cycle arrest, apoptosis, senescence and cell differentiation. To evaluate further the molecular mechanism underlying p53 function, the transcriptional profiles of proliferating and senescent WI-38 cells, both wild-type p53 expressers and counterparts with an inactivated p53, were compared by DNA microarray analysis. In particular, the amyloid-beta precursor-like protein 1 (APLP1) is induced in senescent cells in a p53-dependent manner. APLP1 was confirmed to be a novel transcriptional target of p53 by in vivo and in vitro characterization of a p53 responsive element found in the first intron of the APLP1 gene locus. APLP1 knockdown experiments demonstrate that APLP1 is required for the proliferation of fibroblastic and epithelial cells. Moreover, depletion of APLP1 expression diminishes stress-induced apoptosis of neural cells, whereas ectopic APLP1 expression augments apoptosis. Based on these data, a mechanism is proposed whereby p53-dependent induction of APLP1 is involved in neural cell death, and which may exacerbate neuronal cell loss in some acute or chronic neurodegenerative disorders.


systematic_name: M6171
exact_source: Table 2S
source_species_code: HS
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in WI-38 cells (senescent primary fibroblasts) after inactivation of TP53 [GeneID=7157] by GSE56 polypeptide.

description_full:
  The tumor suppressor p53 is a key modulator of the cellular stress response, inducing cell-cycle arrest, apoptosis, senescence and cell differentiation. To evaluate further the molecular mechanism underlying p53 function, the transcriptional profiles of proliferating and senescent WI-38 cells, both wild-type p53 expressers and counterparts with an inactivated p53, were compared by DNA microarray analysis. In particular, the amyloid-beta precursor-like protein 1 (APLP1) is induced in senescent cells in a p53-dependent manner. APLP1 was confirmed to be a novel transcriptional target of p53 by in vivo and in vitro characterization of a p53 responsive element found in the first intron of the APLP1 gene locus. APLP1 knockdown experiments demonstrate that APLP1 is required for the proliferation of fibroblastic and epithelial cells. Moreover, depletion of APLP1 expression diminishes stress-induced apoptosis of neural cells, whereas ectopic APLP1 expression augments apoptosis. Based on these data, a mechanism is proposed whereby p53-dependent induction of APLP1 is involved in neural cell death, and which may exacerbate neuronal cell loss in some acute or chronic neurodegenerative disorders.


systematic_name: M11619
exact_source: Table 1: log2 (fold induction) < 0
source_species_code: HS
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in MDA-MB-231 cells (breast cancer) after knockdown of PRKCA and ETS1 [GeneID=5578;2113] by RNAi.

description_full:
  PKCalpha and Ets1 are both associated with breast cancer progression. Our previous studies suggested that these proteins are likely to functionally interact with one another. Here, we show that attenuation of endogenous PKCalpha expression (siPalpha) by RNA interference leads to reduced Ets1 protein expression in a variety of cancer cells. Pulse-chase experiments and treatment with proteasome inhibitor MG-132 revealed that siPalpha interferes with both Ets1 protein synthesis and stability. The effect of siPalpha on Ets1 expression could be partially prevented by KN-93, suggesting that calcium/calmodulin-dependent kinase II (CaMKII), a modulator of Ets1 activity, may play a role in PKCalpha-dependent Ets1 regulation. In contrast, Ets1-regulating kinases ERK1/2 were not found to be involved in this process. To assess the importance of the PKCalpha/Ets1 interaction, we compared the biological responses of MDA-MB-231 cells to PKCalpha- and Ets1-specific siRNAs (siE1). While only siPalpha induced changes in cellular morphology and anchorage-independent growth, both siRNAs similarly affected cellular responses to the antitumor drug mithramycin A and to UV light. Microarray analyses further showed that the expression of a certain set of genes was equally affected by siPalpha and siE1. The data suggest that Ets1 serves as an effector for PKCalpha to fulfil certain functions in cancer cells.


systematic_name: M4902
exact_source: Figure 3: blue in PAX8-PPARg(-)
source_species_code: HS
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Top down-regulated genes distinguishing between follicular thyroid carcinoma (FTC) samples by the presence or absence of the PAX8-PPARG [GeneID=7849;5468] fusion protein.

description_full:
[cell repeats an earlier one in this file: 1254 characters]


systematic_name: M8292
exact_source: Table 1: Fold change in MS427 < 0
source_species_code: HS
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in MS427 cells (Wilms tumor with normal WT1 [GeneID=7490]) after treatment with 10 microM tretinoin (ATRA) [PubChem=444795] for 24 h.

description_full:
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systematic_name: M15510
exact_source: Fig 3, 4
source_species_code: HS
GEO_id: GSE2810
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in K562 cells (bone marrow) after treatment with dasatinib [PubChem=3062316] or imatinib [PubChem=5291].

description_full:
  Dasatinib is an ATP-competitive, multi-targeted SRC and ABL kinase inhibitor that can bind BCR-ABL in both the active and inactive conformations. From a clinical standpoint, dasatinib is particularly attractive because it has been shown to induce hematologic and cytogenetic responses in imatinib-resistant chronic myeloid leukemia patients. The fact because the combination of imatinib and dasatinib shows the additive/synergistic growth inhibition on wild-type p210 BCR-ABL-expressing cells, we reasoned that these ABL kinase inhibitors might induce the different molecular pathways. To address this question, we used DNA microarrays to identify genes whose transcription was altered by imatinib and dasatinib. K562 cells were cultured with imatinib or dasatinib for 16 h, and gene expression data were obtained from three independent microarray hybridizations. Almost all of the imatinib- and dasatinib-responsive genes appeared to be similarly increased or decreased in K562 cells; however, small subsets of genes were identified as selectively altered expression by either imatinib or dasatinib. The distinct genes that are selectively modulated by dasatinib are cyclin-dependent kinase 2 (CDK2) and CDK8, which had a maximal reduction of <5-fold in microarray screen. To assess the functional importance of dasatinib regulated genes, we used RNA interference to determine whether reduction of CDK2 and CDK8 affected the growth inhibition. K562 and TF-1BCR-ABL cells, pretreated with CDK2 or CDK8 small interfering RNA, showed additive growth inhibition with imatinib, but not with dasatinib. These findings demonstrate that the additive/synergistic growth inhibition by imatinib and dasatinib may be mediated in part by CDK2 and CDK8.


systematic_name: M14174
exact_source: Fig 3, 4
source_species_code: HS
GEO_id: GSE2810
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in K562 cells (bone marrow) after treatment with dasatinib [PubChem=3062316] or imatinib [PubChem=5291].

description_full:
  Dasatinib is an ATP-competitive, multi-targeted SRC and ABL kinase inhibitor that can bind BCR-ABL in both the active and inactive conformations. From a clinical standpoint, dasatinib is particularly attractive because it has been shown to induce hematologic and cytogenetic responses in imatinib-resistant chronic myeloid leukemia patients. The fact because the combination of imatinib and dasatinib shows the additive/synergistic growth inhibition on wild-type p210 BCR-ABL-expressing cells, we reasoned that these ABL kinase inhibitors might induce the different molecular pathways. To address this question, we used DNA microarrays to identify genes whose transcription was altered by imatinib and dasatinib. K562 cells were cultured with imatinib or dasatinib for 16 h, and gene expression data were obtained from three independent microarray hybridizations. Almost all of the imatinib- and dasatinib-responsive genes appeared to be similarly increased or decreased in K562 cells; however, small subsets of genes were identified as selectively altered expression by either imatinib or dasatinib. The distinct genes that are selectively modulated by dasatinib are cyclin-dependent kinase 2 (CDK2) and CDK8, which had a maximal reduction of <5-fold in microarray screen. To assess the functional importance of dasatinib regulated genes, we used RNA interference to determine whether reduction of CDK2 and CDK8 affected the growth inhibition. K562 and TF-1BCR-ABL cells, pretreated with CDK2 or CDK8 small interfering RNA, showed additive growth inhibition with imatinib, but not with dasatinib. These findings demonstrate that the additive/synergistic growth inhibition by imatinib and dasatinib may be mediated in part by CDK2 and CDK8.


description_brief: Cancer motility and invasion genes up-regulated by the AP-1 transcription factor.
systematic_name: M15822
exact_source: Table 1
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_full:
  Metastasis, the aggressive spread of a malignant tumor to distant organs, is a major cause of death in cancer patients. Despite this critical role in cancer outcomes, the molecular mechanisms that control this process are just beginning to be understood. Metastasis is largely dependent upon the ability of tumor cells to invade the barrier formed by the basement membrane and to migrate through neighboring tissues. This review will summarize the evidence that tumor cell invasion is the result of oncogene-mediated signal transduction pathways that control the expression of a specific set of genes that together mediate tumor cell invasion. We focus on the role of the transcription factor AP-1 to both induce the expression of genes that function as invasion effectors and repress other genes that function as invasion suppressors. This identifies AP-1 as a critical regulator of a complex program of gene expression that defines the invasive phenotype.


systematic_name: M6679
exact_source: Table 2S
source_species_code: HS
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in SaOS-2 cells (osteosarcoma) upon expression of PAX3-FOXO1 [GeneID=5077;2308] fusion protein off an adenoviral vector.

description_full:
  The oncogenic fusion protein, Pax3/FKHR, is a more potent transcription factor relative to its normal counterpart, Pax3. Since Pax3 induced a mesenchymal to epithelial transition (MET) in human SaOS-2 osteosarcomas, we hypothesized that Pax3/FKHR would also induce a morphological change in SaOS-2 cells. We demonstrate here that Pax3/FKHR more potently induces a MET in SaOS-2 cells than Pax3. This greater potency was further evident where Pax3/FKHR, but not Pax3, induced a morphological alteration in U2-OS osteosarcoma cells. By microarray analysis, we determined that Pax3/FKHR altered the expression of gene targets in a manner quantitatively and qualitatively distinct from Pax3. Three classes of genes were identified: (i) genes induced or repressed by Pax3 and Pax3/FKHR, (ii) genes induced or repressed by Pax3/FKHR but not Pax3 and (iii) genes induced by Pax3/FKHR but repressed by Pax3. Chromatin immunoprecipitations confirmed the direct binding of Pax3/FKHR to the promoter region of several factors including cannabinoid receptor-1, EPHA2 and EPHA4. Verification of the microarray data also revealed coordinate alteration in the expression of factors involved in BMP4 signalling. Regulation of gene expression by Pax3 and Pax3/FKHR is, however, cell-type specific. BMP4 expression, for example, was repressed by both Pax3 and Pax3/FKHR in SaOS-2 cells, while in the rhabdomyosarcoma, RD, Pax3/FKHR, but not Pax3, induced BMP4 expression. Thus, our data reveal that Pax3/FKHR regulates a distinct but overlapping set of genes relative to Pax3 and that the global set of Pax3 and Pax3/FKHR gene targets is cell-type specific.


systematic_name: M1148
exact_source: Table 2: OSE vs OSEb
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in ovarian epithelial cells in response to dihydrotestosterone (DHT) [PubChem=10635].

description_full:
  Epidemiological studies have implicated androgens in the etiology and progression of epithelial ovarian cancer. We previously reported that some androgen responses were dysregulated in malignant ovarian epithelial cells relative to control, non-malignant ovarian surface epithelial (OSE) cells. Moreover, dysregulated androgen responses were observed in OSE cells derived from patients with germline BRCA-1 or -2 mutations (OSEb), which account for the majority of familial ovarian cancer predisposition, and such altered responses may be involved in ovarian carcinogenesis or progression. In the present study, gene expression profiling using cDNA microarrays identified 17 genes differentially expressed in response to continuous androgen exposure in OSEb cells and ovarian cancer cells as compared to OSE cells derived from control patients. A subset of these differentially affected genes was selected and verified by quantitative real-time reverse transcription-polymerase chain reaction. Six of the gene products mapped to the OPHID protein-protein interaction database, and five were networked within two interacting partners. Basic leucine zipper transcription factor 2 (BACH2) and acetylcholinesterase (ACHE), which were upregulated by androgen in OSEb cells relative to OSE cells, were further investigated using an ovarian cancer tissue microarray from a separate set of 149 clinical samples. Both cytoplasmic ACHE and BACH2 immunostaining were significantly increased in ovarian cancer relative to benign cases. High levels of cytoplasmic ACHE staining correlated with decreased survival, whereas nuclear BACH2 staining correlated with decreased time to disease recurrence. The finding that products of genes differentially responsive to androgen in OSEb cells may predict survival and disease progression supports a role for altered androgen effects in ovarian cancer. In addition to BACH2 and ACHE, this study highlights a set of potentially functionally related genes for further investigation in ovarian cancer.


systematic_name: M952
exact_source: Table 1
source_species_code: HS
GEO_id: GSE6131
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in the 5637 cell line (bladder cancer) after knockdown of E2F3 [GeneID=1871] by RNAi.

description_full:
  Amplification and overexpression of the E2F3 gene at 6p22 in human bladder cancer is associated with increased tumour stage, grade and proliferation index, and in prostate cancer E2F3 overexpression is linked to tumour aggressiveness. We first used small interfering RNA technology to confirm the potential importance of E2F3 overexpression in bladder cancer development. Knockdown of E2F3 expression in bladder cells containing the 6p22 amplicon strongly reduced the extent of bromodeoxyuridine (BrdU) incorporation and the rate of cellular proliferation. In contrast, knockdown of CDKAL1/FLJ20342, another proposed oncogene, from this amplicon had no effect. Expression cDNA microarray analysis on bladder cancer cells following E2F3 knockdown was then used to identify genes regulated by E2F3, leading to the identification of known E2F3 targets such as Cyclin A and CDC2 and novel targets including pituitary tumour transforming gene 1, Polo-like kinase 1 (PLK1) and Caveolin-2. For both bladder and prostate cancer, we have proposed that E2F3 protein overexpression may cooperate with removal of the E2F inhibitor retinoblastoma tumor suppressor protein (pRB) to drive cellular proliferation. In support of this model, we found that ectopic expression of E2F3a enhanced the BrdU incorporation, a marker of cellular proliferation rate, of prostate cancer DU145 cells, which lack pRB, but had no effect on the proliferation rate of PC3 prostate cancer cells that express wild-type pRB. BrdU incorporation in PC3 cells could, however, be increased by overexpressing E2F3a in cells depleted of pRB. When taken together, these observations indicate that E2F3 levels have a critical role in modifying cellular proliferation rate in human bladder and prostate cancer.


systematic_name: M4455
exact_source: Table 1
source_species_code: HS
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  RB1 [GeneID=5925] target genes involved in cell cycle regulation: genes down-regulated by doxorubicin [PubChem=31703] only in cells expressing RB1.

description_full:
  As alterations in retinoblastoma (RB)/E2F pathway are commonly found in human cancers, the molecular mechanism underlying cell cycle deregulation caused by the mutations in the RB/E2F pathway needs to be investigated extensively. Compared with good understanding of RB/E2F functions in G1-S cell cycle progression, it is not fully understood how an abrogated RB pathway affects the G2-M phase of the cell cycle. Here, we report that disruption of RB accelerated G2-M progression in the presence of DNA damage by elevating the expression of a set of mitotic regulatory genes. We generated RB(+)- and (-)-matched cells using short hairpin RNA. In the RB(-) cells, the G2/M checkpoint mediated by a DNA-damaging agent was over-ridden. With microarray analysis, we found that the expression of key G2-M regulatory genes was upregulated in RB(-) cells. In particular, we demonstrated that the proto-oncogene ECT2 was directly regulated by E2Fs. Furthermore, suppression of ECT2 expression by small interfering RNA in RB(-) cells resulted in cytokinesis arrest, suggesting that RB(-) cells lack the regulation of E2F-mediated cytokinesis. These results indicate that aberrant ECT2 expression, observed in various human tumors, could be the direct result of RB/E2F pathway deficiency, thereby contributing to cell division in cancers.


systematic_name: M1158
exact_source: Table 1
source_species_code: HS
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Putative E2F4 [GeneID=1874] target genes identified as mitotic genes down-regulated in the LNCaP C4-2 cells (prostate cancer) at both 6 and 24 h following irradiation.

description_full:
  The retinoblastoma (pRB) family proteins regulate the E2F transcription factors; their complexes regulate critical transitions through the cell cycle. The function of these pRB family/E2F complexes, which includes p130/E2F4, in response to genotoxic agents, is not well understood. We investigated the role of E2F4 in the genotoxic stress response. Following radiation treatment, E2F4 colocalized with p130 in the nucleus during a radiation-induced stable G(2)-phase arrest. Arrested cells had significantly decreased expression of Cyclins A2 and B1 and decreased phosphorylation of mitotic protein monoclonal-2 (MPM-2) mitotic proteins. Small interference RNA (siRNA)-mediated knockdown of E2F4 sensitized cells to subsequent irradiation, resulting in enhanced cellular DNA damage and cell death, as determined by caspase activation and decreased clonogenic cell survival. Downstream E2F4 targets potentially involved in the progression from G(2) into M phase were identified by oligonucleotide microarray expression profiling. Chromatin immunoprecipitation localized E2F4 at promoter regions of the Bub3 and Pttg1 mitotic genes following irradiation, which were among the downregulated genes identified by the microarray. These data suggest that in response to radiation, E2F4 becomes active in the nucleus, enforces a stable G(2) arrest by target gene repression, and thus provides increased cell survival ability by minimizing propagation of cells that have irreparable DNA damage.


description_brief: List of the transcription factors up-regulated 1 hr after wounding HDF cells (dermal fibroblasts).
systematic_name: M13038
exact_source: Table 1
source_species_code: HS
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_full:
  P27kip is a key inhibitory protein of the cell-cycle progression, which is rapidly downregulated in early G1 phase by a post-translational mechanism involving the proteosomal degradation. In this study, using a wounding model that induces cell-cycle entry of human dermal fibroblasts, we demonstrate that p27mRNA is downregulated when cells progress into the G1 phase, and then it returns to its basal level when cells approach the S phase. By using a quantitative polymerase chain reaction screening we identified inhibitors of differentiation (Id3), a bHLH transcriptional repressor, as a candidate mediator accounting for p27 mRNA decrease. Id3 silencing, using an small interfering RNA approach, reversed the injury mediated p27 downregulation demonstrating that Id3 is involved in the transcriptional repression of p27. Reporter gene experiments and a chromatin immunoprecipitation assay showed that Id3 likely exerts its repressive action through ELK1 inhibition. By inhibiting early p27 downregulation, Id3 depletion blocked (i) the G1-phase progression as assessed by the inhibition of pRb phosphorylation and p130 degradation and (ii) the G1/S transition as observed by the inhibition of cyclin A induction, demonstrating that p27 mRNA decrease is required for cell proliferation. Apart from its effect on the early p27 diminution, Id3 appears also involved in the control of the steady-state level of p27 at the G1/S boundary. In conclusion, this study identifies a novel mechanism of p27 regulation which besides p27 protein degradation also implicates a transcriptional mechanism mediated by Id3.


systematic_name: M78
exact_source: Table 2S
source_species_code: HS
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in Rh4 cells (alveolar rhabdomyosarcoma, ARMS) after knockdown of the PAX3-FOXO1 [GeneiD=5077;2308] fusion protein by RNAi for 72 hr.

description_full:
  The chromosomal translocation t(2;13), characteristic for the aggressive childhood cancer alveolar rhabdomyosarcoma (aRMS), generates the chimeric transcription factor PAX3/FKHR with a well known oncogenic role. However, the molecular mechanisms mediating essential pathophysiological functions remain poorly defined. Here, we used comparative expression profiling of PAX3/FKHR silencing in vitro and PAX3/FKHR-specific gene signatures in vivo to identify physiologically important target genes. Hereby, 51 activated genes, both novel and known, were identified. We also found repression of skeletal muscle-specific genes suggesting that PAX3/FKHR blocks further differentiation of aRMS cells. Importantly, TFAP2B was validated as direct target gene mediating the anti-apoptotic function of PAX3/FKHR. Hence, we developed a pathophysiologically relevant transcriptional profile of PAX3/FKHR and identified a critical target gene for aRMS development.


description_brief: DNA repair genes whose promoters contain putative ZNF143 [GeneID=7702] binding sites.
systematic_name: M9575
exact_source: Table 1S
source_species_code: HS
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_full:
  Zinc-finger protein 143 (ZNF143) is a human homolog of Xenopus transcriptional activator staf that is involved in selenocystyl tRNA transcription. We previously showed that ZNF143 expression is induced by treatment with DNA-damaging agents and that it preferentially binds to cisplatin-modified DNA. In this study, the potential function of ZNF143 was investigated. ZNF143 was overexpressed in cisplatin-resistant cells. ZNF143 knockdown in prostate cancer caused increased sensitivity for cisplatin, but not for oxaliplatin, etoposide and vincristine. We also showed that ZNF143 is associated with tumor suppressor gene product p73 but not with p53. p73 could stimulate the binding of ZNF143 to both ZNF143 binding site and cisplatin-modified DNA, and modulate the function of ZNF143. We provide a direct evidence that both Rad51 and flap endonuclease-1 are target genes of ZNF143 and overexpressed in cisplatin-resistant cells. Taken together, these experiments demonstrate that an interplay of ZNF143, p73 and ZNF143 target genes is involved in DNA repair gene expression and cisplatin resistance.


systematic_name: M18122
exact_source: Table 5, 2S: SLR 4h >= 1 or SLR 8h >= 1
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes exclusively up-regulated in fibroblasts expressing the XP/CS mutant form of ERCC3 [GeneID=2071] after high dose UVC irradiation.

description_full:
[cell repeats an earlier one in this file: 1438 characters]


systematic_name: M10575
exact_source: Table 5, 2S: SLR 4h >= 1 or SLR 8h >= 1
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes exclusively down-regulated in fibroblasts expressing the XP/CS mutant form of ERCC3 [GeneID=2071] after high dose UVC irradiation.

description_full:
[cell repeats an earlier one in this file: 1438 characters]


systematic_name: M15844
exact_source: Table 4, 2S (XP/CS signature): SLR 4h >= 1 or SLR 8h >= 1
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes exclusively up-regulated in fibroblasts expressing the TTD mutant form of ERCC3 [GeneID=2071], after UVC irradiation.

description_full:
[cell repeats an earlier one in this file: 1438 characters]


systematic_name: M13008
exact_source: Table 4, 2S (XP/CS signature): SLR 4h =< -1 or SLR 8h =< -1
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes exclusively down-regulated in fibroblasts expressing the TTD mutant form of ERCC3 [GeneID=2071], after UVC irradiation.

description_full:
[cell repeats an earlier one in this file: 1438 characters]


systematic_name: M15804
exact_source: Table 1: ERK 1,2
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Examples of transcription factors whose activities are regulated by MAPK1 and MAPK3 [GeneID=5594;5595] phosphorylation.

description_full:
  The mitogen-activated protein kinases (MAPKs) are a family of serine/threonine kinases that play an essential role in signal transduction by modulating gene transcription in the nucleus in response to changes in the cellular environment. They include the extracellular signal-regulated protein kinases (ERK1 and ERK2); c-Jun N-terminal kinases (JNK1, JNK2, JNK3); p38s (p38alpha, p38beta, p38gamma, p38delta) and ERK5. The molecular events in which MAPKs function can be separated in discrete and yet interrelated steps: activation of the MAPK by their upstream kinases, changes in the subcellular localization of MAPKs, and recognition, binding and phosphorylation of MAPK downstream targets. The resulting pattern of gene expression will ultimately depend on the integration of the combinatorial signals provided by the temporal activation of each group of MAPKs. This review will focus on how the specificity of signal transmission by MAPKs is achieved by scaffolding molecules and by the presence of structural motifs in MAPKs that are dynamically regulated by phosphorylation and protein-protein interactions. We discuss also how MAPKs recognize and phosphorylate their target nuclear proteins, including transcription factors, co-activators and repressors and chromatin-remodeling molecules, thereby affecting an intricate balance of nuclear regulatory molecules that ultimately control gene expression in response to environmental cues.


systematic_name: M9841
exact_source: Table 1: JNK 1,2
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Examples of transcription factors whose activities are regulated by MAPK8 and MAPK9 [GeneID=5599;5601].

description_full:
  The mitogen-activated protein kinases (MAPKs) are a family of serine/threonine kinases that play an essential role in signal transduction by modulating gene transcription in the nucleus in response to changes in the cellular environment. They include the extracellular signal-regulated protein kinases (ERK1 and ERK2); c-Jun N-terminal kinases (JNK1, JNK2, JNK3); p38s (p38alpha, p38beta, p38gamma, p38delta) and ERK5. The molecular events in which MAPKs function can be separated in discrete and yet interrelated steps: activation of the MAPK by their upstream kinases, changes in the subcellular localization of MAPKs, and recognition, binding and phosphorylation of MAPK downstream targets. The resulting pattern of gene expression will ultimately depend on the integration of the combinatorial signals provided by the temporal activation of each group of MAPKs. This review will focus on how the specificity of signal transmission by MAPKs is achieved by scaffolding molecules and by the presence of structural motifs in MAPKs that are dynamically regulated by phosphorylation and protein-protein interactions. We discuss also how MAPKs recognize and phosphorylate their target nuclear proteins, including transcription factors, co-activators and repressors and chromatin-remodeling molecules, thereby affecting an intricate balance of nuclear regulatory molecules that ultimately control gene expression in response to environmental cues.


systematic_name: M11218
exact_source: Table 1: ERK5
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Examples of transcription factors whose activities are regulated by MAPK7 [GeneID=5598] phosphorylation.

description_full:
  The mitogen-activated protein kinases (MAPKs) are a family of serine/threonine kinases that play an essential role in signal transduction by modulating gene transcription in the nucleus in response to changes in the cellular environment. They include the extracellular signal-regulated protein kinases (ERK1 and ERK2); c-Jun N-terminal kinases (JNK1, JNK2, JNK3); p38s (p38alpha, p38beta, p38gamma, p38delta) and ERK5. The molecular events in which MAPKs function can be separated in discrete and yet interrelated steps: activation of the MAPK by their upstream kinases, changes in the subcellular localization of MAPKs, and recognition, binding and phosphorylation of MAPK downstream targets. The resulting pattern of gene expression will ultimately depend on the integration of the combinatorial signals provided by the temporal activation of each group of MAPKs. This review will focus on how the specificity of signal transmission by MAPKs is achieved by scaffolding molecules and by the presence of structural motifs in MAPKs that are dynamically regulated by phosphorylation and protein-protein interactions. We discuss also how MAPKs recognize and phosphorylate their target nuclear proteins, including transcription factors, co-activators and repressors and chromatin-remodeling molecules, thereby affecting an intricate balance of nuclear regulatory molecules that ultimately control gene expression in response to environmental cues.


systematic_name: M2492
exact_source: Table 1: p38alpha
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Examples of transcription factors whose activities are regulated by MAPK11 [GeneID=5600] phosphorylation.

description_full:
[cell repeats an earlier one in this file: 1443 characters]


systematic_name: M14718
exact_source: Table 1: p38alpha
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Examples of transcription factors whose activities are regulated by MAPK14 [GeneID=1432] phosphorylation.

description_full:
[cell repeats an earlier one in this file: 1443 characters]


systematic_name: M6900
exact_source: Table 2
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in the GIST (gastrointestinal stromal tumor) cell line resistant to imatinib [PubChem=5291] that may correlate with the morphological switch in these cells.

description_full:
  KIT or alpha-platelet-derived growth factor receptor (alpha-PDGFR) activating mutations are the pathogenic mechanisms that characterize gastrointestinal stromal tumors (GIST). Despite excellent responses to imatinib mesylate (IM), patients are relapsing. We developed an IM-resistant GIST cell line (GIST-R) from the IM-sensitive GIST882 cell line (GIST-S) by growing these cells in IM. Gene expression profiling (GEP) of GIST-S, GIST-R cells and two IM resistant GIST patients demonstrated that KIT is downregulated implying a major role in IM resistance. Instead, GIST-R cells have acquired IM resistance by overexpressing the oncogenic receptor tyrosine kinase - AXL - in a 'kinase switch'. Further, the two IM resistant GIST patients express AXL and not c-Kit, seen by immunohistochemistry (IHC). Real time reverse transcriptase-polymerase chain reaction and Western blotting of the GIST-S and GIST-R cells confirmed the switch from Kit to AXL. In GIST-R, AXL is tyrosine phosphorylated and its ligand growth-arrest-specific gene 6 is overexpressed implying autocrine activation. The kinase switch is associated with a morphological change from spindle to epithelioid. Molecular modeling of the kinase domain of mutant c-Kit (V654A) and AXL showed no binding to IM but efficient binding to MP470, a novel c-Kit/AXL kinase inhibitor. MP470 synergizes with docetaxel (taxotere) and is cytotoxic to GIST cells.


systematic_name: M3206
exact_source: Table 1
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in BJ cells (forskin fibroblasts) upon overexpression of the most abundant alternative splicing forms of MDM2 [GeneID=4193], HDM2-A and HDM2-B, off a retroviral vector.

description_full:
  The HDM2 oncoprotein is a cellular inhibitor of p53 and is frequently deregulated in human cancer. However, the HDM2 gene encodes alternatively spliced variants whose functional significance is poorly understood. We had previously reported the detection of alternative HDM2 forms in Hodgkin's lymphoma (HL)-derived cell lines. Here, we have cloned several of these transcripts, including the previously described HDM2-A, -B and -C (which encode the COOH terminus of HDM2), and two novel variants (HDM2-HL1 and -HL2) containing a complete p53 interaction domain. Real-time PCR assays demonstrated that HDM2-A and -B were selectively expressed by HL cell lines and primary tumors, compared with their non-neoplastic counterparts. In transient transfection experiments, alternatively spliced HDM2 isoforms were partially or totally localized within the cytoplasm. HDM2-HL2 was able to inhibit transactivation of a p53-inducible reporter construct and induced a partial relocalization of p53 to the cytoplasm. Expression of HDM2-A and -B caused the activation of p53/p21 and induced growth arrest in primary cells, but also increased the expression levels of cyclins D1 and E. Other possible genes regulated by HDM2-A and -B were identified using cDNA microarray technology. These results imply that HDM2 isoforms may have multiple effects on cell cycle control, and provide insight into the mechanisms through which these molecules contribute to tumorigenesis.


description_brief: Growth factor signaling components up-regulated in hepatocellular carcinoma (HCC).
systematic_name: M18219
exact_source: Table 1
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_full:
  Dysregulation of pleiotropic growth factors, receptors and their downstream signaling pathway components represent a central protumorigenic principle in human hepatocarcinogenesis. Especially the Insulin-like Growth Factor/IGF-1 receptor (IGF/IGF-1R), Hepatocyte Growth Factor (HGF/MET), Wingless (Wnt/beta-catenin/FZD), Transforming Growth Factor alpha/Epidermal Growth Factor receptor (TGFalpha/EGFR) and Transforming Growth Factor beta (TGFbeta/TbetaR) pathways contribute to proliferation, antiapoptosis and invasive behavior of tumor cells. This review focuses on the relevant alterations in these pathways identified in human human hepatocellular carcinomas (HCCs). Resultant functional effects are modulated by multiple cross-talks between the different signaling pathways and additional tumor-relevant factors, such as cyclooxygenase-2 and p53. Several specific strategies are currently under development such as receptor kinase inhibitors, neutralizing antibodies and antagonistic proteins, which may improve the systemic treatment of human HCCs.


description_brief: Proteins that permeabilize mitochondria.
systematic_name: M9642
exact_source: Table 1
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_full:
  Mitochondria are vital for cellular bioenergetics and play a central role in determining the point-of-no-return of the apoptotic process. As a consequence, mitochondria exert a dual function in carcinogenesis. Cancer-associated changes in cellular metabolism (the Warburg effect) influence mitochondrial function, and the invalidation of apoptosis is linked to an inhibition of mitochondrial outer membrane permeabilization (MOMP). On theoretical grounds, it is tempting to develop specific therapeutic interventions that target the mitochondrial Achilles' heel, rendering cancer cells metabolically unviable or subverting endogenous MOMP inhibitors. A variety of experimental therapeutic agents can directly target mitochondria, causing apoptosis induction. This applies to a heterogeneous collection of chemically unrelated compounds including positively charged alpha-helical peptides, agents designed to mimic the Bcl-2 homology domain 3 of Bcl-2-like proteins, ampholytic cations, metals and steroid-like compounds. Such MOMP inducers or facilitators can induce apoptosis by themselves (monotherapy) or facilitate apoptosis induction in combination therapies, bypassing chemoresistance against DNA-damaging agents. In addition, it is possible to design molecules that neutralize inhibitor of apoptosis proteins (IAPs) or heat shock protein 70 (HSP70). Such IAP or HSP70 inhibitors can mimic the action of mitochondrion-derived mediators (Smac/DIABLO, that is, second mitochondria-derived activator of caspases/direct inhibitor of apoptosis-binding protein with a low isoelectric point, in the case of IAPs; AIF, that is apoptosis-inducing factor, in the case of HSP70) and exert potent chemosensitizing effects.


description_brief: Genes identified with the Fanconi anemia (FA) and the FA pathway.
systematic_name: M12972
exact_source: Table 1
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_full:
  Fanconi anaemia (FA) is a rare recessive disorder associated with chromosomal fragility, aplastic anaemia, congenital abnormalities and a high risk of cancer, including acute myeloid leukaemia and squamous cell carcinomas. The identification of 11 different FA genes has revealed a complex web of interacting proteins that are involved in the recognition or repair of DNA interstrand crosslinks and perhaps other forms of DNA damage. Bi-allelic mutations in BRCA2 are associated with a rare and highly cancer-prone form of FA, and the DNA helicase BRIP1 (formerly BACH1) is mutated in FA group J. There is little convincing evidence that FA heterozygotes are at increased risk of cancer, but larger studies are needed to address the possibility of modest risk effects. Somatic inactivation of the FA pathway by mutation or epigenetic silencing has been observed in several different types of sporadic cancer, and this may have important implications for targeted chemotherapy. Inhibition of this pathway represents a possible route to sensitization of tumours to DNA crosslinking drugs such as cisplatin.


description_brief: Genes encoding the NF-kB core signaling proteins.
systematic_name: M8804
exact_source: Table 1: Human
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_full:
  This article serves as an introduction to the collection of reviews on nuclear factor-kappaB (NF-kappaB). It provides an overview of the discovery and current status of NF-kappaB as a research topic. Described are the structures, activities and regulation of the proteins in the NF-kappaB family of transcription factors. NF-kappaB signaling is primarily regulated by inhibitor kappaB (IkappaB) proteins and the IkappaB kinase complex through two major pathways: the canonical and non-canonical NF-kappaB pathways. The organization and focus of articles included in the following reviews are described, as well as likely future areas of research interest on NF-kappaB.


description_brief: Genes encoding substrates of IkappaB kinase (IKK) complex.
systematic_name: M17115
exact_source: Table 1
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_full:
  Transcription factors of the NF-kappaB family regulate hundreds of genes in the context of multiple important physiological and pathological processes. NF-kappaB activation depends on phosphorylation-induced proteolysis of inhibitory IkappaB molecules and NF-kappaB precursors by the ubiquitin-proteasome system. Most of the diverse signaling pathways that activate NF-kappaB converge on IkappaB kinases (IKK), which are essential for signal transmission. Many important details of the composition, regulation and biological function of IKK have been revealed in the last years. This review summarizes current aspects of structure and function of the regular stoichiometric components, the regulatory transient protein interactions of IKK and the mechanisms that contribute to its activation, deactivation and homeostasis. Both phosphorylation and ubiquitinatin (destructive as well as non-destructive) are crucial post-translational events in these processes. In addition to controlling induced IkappaB degradation in the cytoplasm and processing of the NF-kappaB precursor p100, nuclear IKK components have been found to act directly at the chromatin level of induced genes and to mediate responses to DNA damage. Finally, IKK is engaged in cross talk with other pathways and confers functions independently of NF-kappaB.


description_brief: NF-kB target genes involved in the regulation of programmed cell death.
systematic_name: M9440
exact_source: Table 1
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_full:
  The nuclear factor-kappaB (NF-kappaB) transcription factors have emerged as major regulators of programmed cell death (PCD) whether via apoptosis or necrosis. In this context, NF-kappaB's activity has important ramifications for normal tissue development, homoeostasis and the physiological functions of various cell systems including the immune, hepatic, epidermal and nervous systems. However, improper regulation of PCD by NF-kappaB can have severe pathologic consequences, ranging from neurodegeneration to cancer, where its activity often precludes effective therapy. Although NF-kappaB generally protects cells by inducing the expression genes encoding antiapoptotic and antioxidizing proteins, its role in apoptosis and necrosis can vary markedly in different cell contexts, and NF-kappaB can sensitize cells to death-inducing stimuli in some instances. This article describes our current knowledge of the role of NF-kappaB in apoptosis and necrosis, and focuses on the many advances since we last reviewed this rapidly evolving topic in Oncogene 3 years ago. There has been substantial progress in understanding NF-kappaB's mode of action in apoptosis and necrosis and the mechanisms that regulate its anti- vs proapoptotic activities. These recent developments shed new light on the role of NF-kappaB in many disease conditions including tumor development, tumor progression and anticancer treatment.


description_brief: NF-kB-driven pro-inflammatory genes that are negatively regulated by glucocorticoids.
systematic_name: M17340
exact_source: Table 1
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_full:
  A variety of studies have shown that some activated nuclear receptors (NRs), especially the glucorticoid receptor, the estrogen receptor and peroxisome proliferator-activated receptor, can inhibit the activity of the transcription factor nuclear factor kappaB (NF-kappaB), which plays a key role in the control of genes involved in inflammation, cell proliferation and apoptosis. This review describes the molecular mechanisms of cross-talk between NRs and NF-kappaB and the biological relevance of this cross-talk. The importance and mechanistic aspects of selective NR modulation are discussed. Also included are future research prospects, which will lead to a new era in the field of NR research with the aim of specifically inhibiting NF-kappaB-driven gene expression for anti-inflammatory, anti-tumor and immune-modulatory purposes.


systematic_name: M14590
exact_source: Table 1
source_species_code: HS
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in MDA-MB-231 cells (breast cancer) after knockdown of ZEB1 [GeneID=6935] by RNAi.

description_full:
  Epithelial to mesenchymal transition (EMT) is implicated in the progression of primary tumours towards metastasis and is likely caused by a pathological activation of transcription factors regulating EMT in embryonic development. To analyse EMT-causing pathways in tumourigenesis, we identified transcriptional targets of the E-cadherin repressor ZEB1 in invasive human cancer cells. We show that ZEB1 repressed multiple key determinants of epithelial differentiation and cell-cell adhesion, including the cell polarity genes Crumbs3, HUGL2 and Pals1-associated tight junction protein. ZEB1 associated with their endogenous promoters in vivo, and strongly repressed promotor activities in reporter assays. ZEB1 downregulation in undifferentiated cancer cells by RNA interference was sufficient to upregulate expression of these cell polarity genes on the RNA and protein level, to re-establish epithelial features and to impair cell motility in vitro. In human colorectal cancer, ZEB1 expression was limited to the tumour-host interface and was accompanied by loss of intercellular adhesion and tumour cell invasion. In invasive ductal and lobular breast cancer, upregulation of ZEB1 was stringently coupled to cancer cell dedifferentiation. Our data show that ZEB1 represents a key player in pathologic EMTs associated with tumour progression.


systematic_name: M1175
exact_source: Table 3
source_species_code: RN
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in REF52 cells (embryonic fibroblast) by expression of E2F1 [GeneID=1869] that were not induced at all at 16 hr after serum stimulation.

description_full:
  The transcription factor E2F mediates cell cycle-dependent expression of genes important for cell proliferation in response to growth stimulation. To further understand the role of E2F, we utilized a sensitive subtraction method to explore new E2F1 targets, which are expressed at low levels and might have been unrecognized in previous studies. We identified 33 new E2F1-inducible genes, including checkpoint genes Claspin and Rad51ap1, and four genes with unknown function required for cell cycle progression. Moreover, we found three groups of E2F1-inducible genes that were not induced by growth stimulation. At least, two groups of genes were directly induced by E2F1, indicating that E2F1 can regulate expression of genes not induced during the cell cycle. One included Neogenin, WASF1 and SGEF genes, which may have a role in differentiation or development. The other was the cyclin-dependent kinase inhibitor p27(Kip1), which was involved in suppression of inappropriate cell cycle progression induced by deregulated E2F. E2F1-responsive regions of these genes were located more upstream than those of typical E2F targets and did not have typical E2F sites. These results indicate that there are groups of E2F1 targets, which are regulated in a distinct manner from that of typical E2F targets.


systematic_name: M5792
exact_source: Table 1
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes with increased copy number that correlates with increased expression across six different lung adenocarcinoma cell lines.

description_full:
  Amplification and overexpression of putative oncogenes confer growth advantages for tumor development. We used a functional genomic approach that integrated simultaneous genomic and transcript microarray, proteomics, and tissue microarray analyses to directly identify putative oncogenes in lung adenocarcinoma. We first identified 183 genes with increases in both genomic copy number and transcript in six lung adenocarcinoma cell lines. Next, we used two-dimensional polyacrylamide gel electrophoresis and mass spectrometry to identify 42 proteins that were overexpressed in the cancer cells relative to normal cells. Comparing the 183 genes with the 42 proteins, we identified four genes - PRDX1, EEF1A2, CALR, and KCIP-1 - in which elevated protein expression correlated with both increased DNA copy number and increased transcript levels (all r > 0.84, two-sided P < 0.05). These findings were validated by Southern, Northern, and Western blotting. Specific inhibition of EEF1A2 and KCIP-1 expression with siRNA in the four cell lines tested suppressed proliferation and induced apoptosis. Parallel fluorescence in situ hybridization and immunohistochemical analyses of EEF1A2 and KCIP-1 in tissue microarrays from patients with lung adenocarcinoma showed that gene amplification was associated with high protein expression for both genes and that protein overexpression was related to tumor grade, disease stage, Ki-67 expression, and a shorter survival of patients. The amplification of EEF1A2 and KCIP-1 and the presence of overexpressed protein in tumor samples strongly suggest that these genes could be oncogenes and hence potential targets for diagnosis and therapy in lung adenocarcinoma.


systematic_name: M16123
exact_source: Table 2
source_species_code: HS
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Muscle development genes up-regulated in Rh4 cells (alveolar rhabdomyosarcoma, ARMS) but not in the RD cells (embryonal rhabdomyosarcoma, ERMS) after knockdown of PAX3-FOXO1 [GeneID=5077;2308] fusion by RNAi for 72 hr.

description_full:
  The chromosomal translocation t(2;13), characteristic for the aggressive childhood cancer alveolar rhabdomyosarcoma (aRMS), generates the chimeric transcription factor PAX3/FKHR with a well known oncogenic role. However, the molecular mechanisms mediating essential pathophysiological functions remain poorly defined. Here, we used comparative expression profiling of PAX3/FKHR silencing in vitro and PAX3/FKHR-specific gene signatures in vivo to identify physiologically important target genes. Hereby, 51 activated genes, both novel and known, were identified. We also found repression of skeletal muscle-specific genes suggesting that PAX3/FKHR blocks further differentiation of aRMS cells. Importantly, TFAP2B was validated as direct target gene mediating the anti-apoptotic function of PAX3/FKHR. Hence, we developed a pathophysiologically relevant transcriptional profile of PAX3/FKHR and identified a critical target gene for aRMS development.


systematic_name: M154
exact_source: Figure 5A
source_species_code: HS
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated by TP53 [GeneID=7157]  and down-regulated by an isoform of TP63 [GeneID=8626] in primary HEK cells (epidermal keratinocytes).

description_full:
  The mechanism by which the p53 family of proteins coordinately regulates select target genes after various types of cell stress is not well understood. To further define factors that dictate regulation of target genes, we examined the binding of p53, DeltaNp63alpha and RNA polymerase II (pol II) to the regulatory regions of select target genes in primary human epidermal keratinocytes (HEKs) using chromatin immunoprecipitation. In rapidly proliferating cells, we observed constitutive binding of DeltaNp63alpha and varying levels of p53 binding, to consensus sites in target genes involved in cell cycle arrest, DNA repair and apoptosis. Following genotoxic stress, p53 occupancy increased whereas DeltaNp63alpha occupancy decreased at the majority of binding sites examined. Microarray analysis of transcripts isolated from HEKs ectopically expressing p53 and DeltaNp63alpha revealed an inverse regulation of select target genes by the two family members. Collectively, our results suggest that DeltaNp63alpha can function as a repressor of select p53 target genes involved in growth arrest, DNA repair and apoptosis, and that the location of the p53 consensus binding site(s) in a target gene may dictate whether pol II is constitutively bound in proliferating cells.


systematic_name: M16845
exact_source: Table 1: 17q11.1-q21; 17q25
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Amplification hot spot 12: colocolized fragile sites and cancer genes in the 17q11.1-q21; 17q25 region.

description_full:
[cell repeats an earlier one in this file: 1561 characters]


systematic_name: M10973
exact_source: Table 1S: figure 2a
source_species_code: HS
GEO_id: GSE2113
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes changed in MGUS (monoclonal gammopathy of undetermined significance) compared to PCL (plasma cell leukemia) samples.

description_full:
  Multiple myeloma (MM) is the most common form of plasma cell dyscrasia, characterized by a marked heterogeneity of genetic lesions and clinical course. It may develop from a premalignant condition (monoclonal gammopathy of undetermined significance, MGUS) or progress from intramedullary to extramedullary forms (plasma cell leukemia, PCL). To provide insights into the molecular characterization of plasma cell dyscrasias and to investigate the contribution of specific genetic lesions to the biological and clinical heterogeneity of MM, we analysed the gene expression profiles of plasma cells isolated from seven MGUS, 39 MM and six PCL patients by means of DNA microarrays. MMs resulted highly heterogeneous at transcriptional level, whereas the differential expression of genes mainly involved in DNA metabolism and proliferation distinguished MGUS from PCLs and the majority of MM cases. The clustering of MM patients was mainly driven by the presence of the most recurrent translocations involving the immunoglobulin heavy-chain locus. Distinct gene expression patterns have been found to be associated with different lesions: the overexpression of CCND2 and genes involved in cell adhesion pathways was observed in cases with deregulated MAF and MAFB, whereas genes upregulated in cases with the t(4;14) showed apoptosis-related functions. The peculiar finding in patients with the t(11;14) was the downregulation of the alpha-subunit of the IL-6 receptor. In addition, we identified a set of cancer germline antigens specifically expressed in a subgroup of MM patients characterized by an aggressive clinical evolution, a finding that could have implications for patient classification and immunotherapy.


systematic_name: M2555
exact_source: Table 1S: figure 2c
source_species_code: HS
GEO_id: GSE2113
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes distinguishing between MGUS (monoclonal gammopathy of undetermined significance) and multiple myeloma (MM) samples.

description_full:
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systematic_name: M4008
exact_source: Table 2S: AL rank
source_species_code: HS
GEO_id: GSE1561
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes which best discriminate between two groups of breast cancer according to the status of ESR1 and AR [GeneID=2099;367]: apocrine (ESR1- AR+) and luminal (ESR1+ AR+).

description_full:
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systematic_name: M2631
exact_source: Table 2S: AB rank
source_species_code: HS
GEO_id: GSE1561
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes which best discriminate between two groups of breast cancer according the status of ESR1 and AR [GeneID=2099;367]: apocrine (ESR1- AR+) vs basal (ESR1- AR-).

description_full:
[cell repeats an earlier one in this file: 1670 characters]


systematic_name: M5652
exact_source: Table 2S: BL rank
source_species_code: HS
GEO_id: GSE1561
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes which best discriminated between two groups of breast cancer according to the status of ESR1 and AR [GeneID=2099;367]: basal (ESR1- AR-) and luminal (ESR1+ AR+).

description_full:
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systematic_name: M4290
exact_source: Table 1S: Cluster 3
source_species_code: HS
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Cluster 3: genes with similar expression profiles across follicular thyrorid carcinoma (FTC) samples; genes in this cluster correlated well with the presence of PAX8-PPARG [GeneID=7849;5468] fusion protein.

description_full:
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systematic_name: M4333
exact_source: Table 1S: Cluster 4
source_species_code: HS
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Cluster 4: genes with similar expression profiles across follicular thyroid carcinoma (FTC) samples.

description_full:
[cell repeats an earlier one in this file: 1254 characters]


systematic_name: M13462
exact_source: Table 1S: Cluster 5
source_species_code: HS
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Cluster 5: genes with similar expression profiles across follicular thyroid carcinoma (FTC) samples.

description_full:
[cell repeats an earlier one in this file: 1254 characters]


systematic_name: M13314
exact_source: Figure 1a
source_species_code: HS
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in follicular thyroid carcinoma (FTC) samples that bear PAX8-PPARG [GeneID=7849;5468] fusion protein.

description_full:
[cell repeats an earlier one in this file: 1254 characters]


systematic_name: M5075
exact_source: Table 7S
source_species_code: HS
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Cluster 7: genes up-regulated in B493-6 cells (B lymphocytes) by MYC [GeneID=4609] and down-regulated by the combination of MYC and serum.

description_full:
[cell repeats an earlier one in this file: 1496 characters]


systematic_name: M2138
exact_source: Table 6S
source_species_code: HS
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Cluster 6: genes down-regulated in B493-6 cells (B lymphocytes) by MYC [GeneID=4609] in combination with serum but not affected by serum alone; they are also up-regulated by MYC alone.

description_full:
[cell repeats an earlier one in this file: 1496 characters]


systematic_name: M7081
exact_source: Figure 5S: cluster 8
source_species_code: HS
GEO_id: GSE1561
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Cluster 8: selected ERBB2 [GeneID=2064] amplicon genes clustered together across breast cancer samples.

description_full:
[cell repeats an earlier one in this file: 1670 characters]


systematic_name: M17333
exact_source: Figure 5S: cluster 2
source_species_code: HS
GEO_id: GSE1561
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Cluster 2: selected proliferation and 8q amplicon genes clustered together across breast cancer samples.

description_full:
[cell repeats an earlier one in this file: 1670 characters]


systematic_name: M15664
exact_source: Table 3S
source_species_code: HS
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  The 'Cervical Cancer Proliferation Cluster' (CCPC): genes whose expression in cervical carcinoma positively correlates with that of the HPV E6 and E7 oncogenes; they are also differentially expressed according to disease outcome.

description_full:
  Specific HPV DNA sequences are associated with more than 90% of invasive carcinomas of the uterine cervix. Viral E6 and E7 oncogenes are key mediators in cell transformation by disrupting TP53 and RB pathways. To investigate molecular mechanisms involved in the progression of invasive cervical carcinoma, we performed a gene expression study on cases selected according to viral and clinical parameters. Using Coupled Two-Way Clustering and Sorting Points Into Neighbourhoods methods, we identified a 'cervical cancer proliferation cluster' composed of 163 highly correlated transcripts. Most of these transcripts corresponded to E2F pathway genes controlling cell division or proliferation, whereas none was known as TP53 primary target. The average expression level of the genes of this cluster was higher in tumours with an early relapse than in tumours with a favourable course (P = 0.026). Moreover, we found that E6/E7 mRNA expression level was positively correlated with the expression level of the cluster genes and with viral DNA load. These findings suggest that HPV E6/E7 expression level plays a key role in the progression of invasive carcinoma of the uterine cervix via the deregulation of cellular genes controlling tumour cell proliferation. HPV expression level may thus provide a biological marker useful for prognosis assessment and specific therapy of the disease.


systematic_name: M6364
exact_source: Table 2: soft tissue tumors
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes from selected recurrently amplified regions in soft tissue tumors with supernumerary  ring chromosomes.

description_full:
  Ring chromosomes and/or giant marker chromosomes have been observed in a variety of human tumor types, but they are particularly common in a subgroup of mesenchymal tumors of low-grade or borderline malignancy. These rings and markers have been shown to contain amplified material predominantly from 12q13-15, but also sequences from other chromosomes. Such amplified sequences were mapped in detail by genome-wide array comparative genomic hybridization in ring-containing tumor samples from soft tissue (n = 15) and bone (n = 6), using tiling resolution microarrays, encompassing 32 433 bacterial artificial chromosome clones. The DNA copy number profiles revealed multiple amplification targets, in many cases highly discontinuous, leading to delineation of large numbers of very small amplicons. A total number of 356 (median size: 0.64 Mb) amplicons were seen in the soft tissue tumors and 90 (median size: 1.19 Mb) in the bone tumors. Notably, more than 40% of all amplicons in both soft tissue and bone tumors were mapped to chromosome 12, and at least one of the previously reported recurrent amplifications in 12q13.3-14.1 and 12q15.1, including SAS and CDK4, and MDM2, respectively, were present in 85% of the soft tissue tumors and in all of the bone tumors. Although chromosome 12 was the only chromosome displaying recurrent amplification in the bone tumors, the soft tissue tumors frequently showed recurrent amplicons mapping to other chromosomes, that is, 1p32, 1q23-24, 3p11-12, 6q24-25 and 20q11-12. Of particular interest, amplicons containing genes involved in the c-jun NH2-terminal kinase/mitogen-activated protein kinase pathway, that is, JUN in 1p32 and MAP3K7IP2 (TAB2) in 6q24-25, were found to be independently amplified in eight of 11 cases with 12q amplification, providing strong support for the notion that aberrant expression of this pathway is an important step in the dedifferentiation of liposarcomas.


systematic_name: M7870
exact_source: Table 2: bone tumors
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes from selected recurrently amplified regions in bone tissue tumors with supernumerary  ring chromosomes.

description_full:
  Ring chromosomes and/or giant marker chromosomes have been observed in a variety of human tumor types, but they are particularly common in a subgroup of mesenchymal tumors of low-grade or borderline malignancy. These rings and markers have been shown to contain amplified material predominantly from 12q13-15, but also sequences from other chromosomes. Such amplified sequences were mapped in detail by genome-wide array comparative genomic hybridization in ring-containing tumor samples from soft tissue (n = 15) and bone (n = 6), using tiling resolution microarrays, encompassing 32 433 bacterial artificial chromosome clones. The DNA copy number profiles revealed multiple amplification targets, in many cases highly discontinuous, leading to delineation of large numbers of very small amplicons. A total number of 356 (median size: 0.64 Mb) amplicons were seen in the soft tissue tumors and 90 (median size: 1.19 Mb) in the bone tumors. Notably, more than 40% of all amplicons in both soft tissue and bone tumors were mapped to chromosome 12, and at least one of the previously reported recurrent amplifications in 12q13.3-14.1 and 12q15.1, including SAS and CDK4, and MDM2, respectively, were present in 85% of the soft tissue tumors and in all of the bone tumors. Although chromosome 12 was the only chromosome displaying recurrent amplification in the bone tumors, the soft tissue tumors frequently showed recurrent amplicons mapping to other chromosomes, that is, 1p32, 1q23-24, 3p11-12, 6q24-25 and 20q11-12. Of particular interest, amplicons containing genes involved in the c-jun NH2-terminal kinase/mitogen-activated protein kinase pathway, that is, JUN in 1p32 and MAP3K7IP2 (TAB2) in 6q24-25, were found to be independently amplified in eight of 11 cases with 12q amplification, providing strong support for the notion that aberrant expression of this pathway is an important step in the dedifferentiation of liposarcomas.


description_brief: Candidate substrate proteins of AURKA [GeneID=6790].
systematic_name: M1180
exact_source: Fig 6A
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_full:
  Mammalian Aurora-A is related to a serine/threonine protein kinase that was originally identified by its close homology with Saccharomyces cerevisiae Ipl1p and Drosophila melanogaster aurora that are key regulators in the orchestration of mitotic events. The protein level of Aurora-A, its peak kinase activity during mitosis, and its activation have been attributed to phosphorylation. Here we show that this enzyme is an arginine-directed kinase and define its substrate specificity. We also found that Thr288 within the activation loop is a critical residue for activating phosphorylation events in vitro and that it is spatiotemporally restricted to a brief window at mitosis on duplicated centrosomes and on spindle microtubules proximal to the poles in vivo. Immunodepletion assays indicated that an upstream kinase(s) of Aurora-A might exist in mammalian cells in addition to autophosphorylation. Furthermore, human activated Aurora-A forms complexes with the negative regulator protein serine/threonine phosphatase type 1 (PP1) that was negatively phosphorylated on Thr320. Interestingly, phospho-specific Aurora-A monoclonal antibodies restrain Aurora-A kinase activity in vitro, providing further therapeutic avenues to explore.


systematic_name: M9630
exact_source: Table 1
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes changed in H1299 cells (non-small cell lung cancer, NSCLC) transiently transfected to express the TP63 [GeneID=8626] gamma splice variant.

description_full:
  p63, a p53 homolog has been shown to play a role in development and cancer. p63 is essential for both commitment of ectoderm to stratified epithelia and for the proliferative potential of epithelial stem cells. p63 knockout mice are born with severe development defects and lack organs of epithelial origin. In addition, p63 has also been shown to play a role in cancer development through the differential regulation of genes with tumor suppressor function and genes involved in metastasis. In order to understand the role of p63 in cancer and development, genes that are specifically regulated by p63 but not p53 were identified. In this study, we provide evidence that p63gamma specifically upregulates vitamin D Receptor (VDR). In contrast, p53 does not appear to be involved in upregulation of VDR expression. Additionally, we demonstrate that a naturally occurring p63 missense mutant, p63gamma (R279H) and p14(ARF), both act in a dominant negative manner to inhibit p63gamma-mediated upregulation of VDR. Furthermore, using chromatin immunoprecipitation assays, we demonstrated that p63 directly binds to the VDR promoter in vivo. Our findings clearly demonstrate that VDR is a direct target of p63 and suggests that p63 may play a role in cancer and differentiation through modulation of the VDR pathway.


systematic_name: M9940
exact_source: Fig 1
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes distinguishing between breast cancer tumors bearing mutations in BRCA1 [GeneID=672] and those with mutated BRCA2 [GeneID=675].

description_full:
  Tumors arising in BRCA1 and BRCA2 mutation carriers appear to have specific pathological and gene expression profiles, which show a high level of concordance. BRCA1 tumors are high-grade, negative for hormone receptors, have a high proliferation rate, and are positive for some cell cycle promoter genes. BRCA2 tumors present a phenotype opposite to BRCA1 tumors but very similar to sporadic tumors, except that BRCA2 overexpress some DNA repair markers such as CHEK2, show high cytoplasmic expression of RAD51, and are negative for HER-2 amplification and expression. Some of these characteristics have also been found in cDNA expression studies, although more analysis are necessary in order to obtain new markers that can be associated with a germ line mutation in BRCA1 or BRCA2. In this way, some studies in normal tissues of BRCA1/2 carriers suggest that differences exist in the level of expression of some genes when compared with noncarriers. Finally, IHC studies in tumors carrying a mutation in CHEK2 are rare and show contradictory results, probably due to the low number of these cases. However, they represent an example showing how different mutations of the same gene may be associated with specific histological subtypes of cancer.


systematic_name: M6162
exact_source: Table 1: ECM HMEC-E6
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated by growing HMEC-E6 cells (mammary epithelial cells damaged by expression of HPV-16 E6 [GeneID=1489078]) in extracellular matrix (ECM).

description_full:
  Interactions between extracellular matrix (ECM) and mammary epithelial cells are critical for mammary gland homeostasis and apoptotic signaling. Interferon regulatory factor-1 (IRF-1) is a transcriptional regulator that promotes apoptosis during mammary gland involution and p53-independent apoptosis. We have recently shown that rapid cell surface tamoxifen (Tam) signaling promotes apoptosis in normal human mammary epithelial cells that were acutely damaged by expression of human papillomavirus type-16 E6 protein (*HMEC-E6). Apoptosis was mediated by recruitment of CREB-binding protein (CBP) to the gamma-activating sequence (GAS) element of the IRF-1 promoter, induction of IRF-1 and caspase-1/-3 activation. Here, we show that growth factor-depleted, reconstituted ECM (rECM), similar to Tam, promotes apoptosis in *HMEC-E6 cells through induction of IRF-1. Apoptosis was temporally associated with recruitment of CBP to the GAS element of the IRF-1 promoter, induction of IRF-1 expression and caspase-1/-3 activation. Small interfering RNA-mediated suppression of IRF-1 protein expression in *HMEC-E6 cells blocked (1) induction of IRF-1, (2) caspase-1/-3 activation and (3) apoptosis. These observations demonstrate that IRF-1 promotes rECM-mediated apoptosis and provide evidence that both rECM and rapid Tam signaling transcriptionally activate IRF-1 through recruitment of CBP to the IRF-1 GAS promoter complex.


systematic_name: M3283
exact_source: Table 1: Tam HMEC-E6
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated  by tamoxifen [PubChem=5376] in HMEC-E6 cells (mammary epithelial cells damaged by expression of HPV-16 E6 [GeneID=1489078]).

description_full:
  Interactions between extracellular matrix (ECM) and mammary epithelial cells are critical for mammary gland homeostasis and apoptotic signaling. Interferon regulatory factor-1 (IRF-1) is a transcriptional regulator that promotes apoptosis during mammary gland involution and p53-independent apoptosis. We have recently shown that rapid cell surface tamoxifen (Tam) signaling promotes apoptosis in normal human mammary epithelial cells that were acutely damaged by expression of human papillomavirus type-16 E6 protein (*HMEC-E6). Apoptosis was mediated by recruitment of CREB-binding protein (CBP) to the gamma-activating sequence (GAS) element of the IRF-1 promoter, induction of IRF-1 and caspase-1/-3 activation. Here, we show that growth factor-depleted, reconstituted ECM (rECM), similar to Tam, promotes apoptosis in *HMEC-E6 cells through induction of IRF-1. Apoptosis was temporally associated with recruitment of CBP to the GAS element of the IRF-1 promoter, induction of IRF-1 expression and caspase-1/-3 activation. Small interfering RNA-mediated suppression of IRF-1 protein expression in *HMEC-E6 cells blocked (1) induction of IRF-1, (2) caspase-1/-3 activation and (3) apoptosis. These observations demonstrate that IRF-1 promotes rECM-mediated apoptosis and provide evidence that both rECM and rapid Tam signaling transcriptionally activate IRF-1 through recruitment of CBP to the IRF-1 GAS promoter complex.


systematic_name: M1187
exact_source: Table 2S: Fold < 0
source_species_code: HS
GEO_id: GSE5149
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in MCF7 cells (breast cancer, normal TP53 [GeneID=7157]) undergoing mitotic arrest and apoptosis after treatment with 100 nM docetaxel [PubChem=148124].

description_full:
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systematic_name: M18356
exact_source: Table 2S
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes changed in DU-145 cells (prostate cancer) in the absence but not presence of a dominant negative form of AKT1 [GeneID=207] upon exposure to HGF [GeneID=3082] for 6 h.

description_full:
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systematic_name: M11536
exact_source: Table 3S
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in DU-145 cells (prostate cancer) in the absence and presence of a dominant negative form of AKT1 [GeneID=207] upon exposure to HGF [GeneID=3082] for 48 h.

description_full:
[cell repeats an earlier one in this file: 1689 characters]


systematic_name: M18912
exact_source: Table 4S
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in DU-145 cells (prostate cancer) in the absence but not in the presence of a dominant negative form of AKT1 [GeneID=207] upon exposure to HGF [GeneID=3082] for 48 h.

description_full:
[cell repeats an earlier one in this file: 1689 characters]


systematic_name: M18724
exact_source: Table 6S
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in DU-145 cells (prostate cancer) expressing a dominant negative form of AKT1 [GeneID=207] upon sham-treatment for 6 h (as a control for the HGF [GeneID=3082] experiments).

description_full:
[cell repeats an earlier one in this file: 1689 characters]


description_brief: Subunits of the anaphase promoting complex (APC).
systematic_name: M7890
exact_source: Table 2: Human
source_species_code: HS
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_full:
  Genomic instability can be found in most cancer cells. Cell proliferation is under tight control to ensure accurate DNA replication and chromosome segregation. Cyclin-dependent kinases (Cdks) and their activating subunits, the cyclins, are the driving forces of the cell division cycle. Regulation of cyclin oscillation by ubiquitin-dependent proteolysis thereby has a central role in cell cycle regulation. The anaphase-promoting complex (APC) is a specific ubiquitin ligase and is essential for chromosome segregation, exit from mitosis and a stable subsequent G1 phase allowing cell differentiation or accurate DNA replication in the following S phase. The APC is activated by the regulatory subunits Cdc20 (APC(Cdc20)) and Cdh1 (APC(Cdh1)) to target securin, mitotic cyclins and other cell cycle regulatory proteins for proteasomal degradation. This review is focused on the role of APC-dependent proteolysis in cell cycle regulation and how its deregulation may lead to genomic instability of cancer cells.


systematic_name: M13941
exact_source: Table 1: clusters 1 and 2
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Clusters 1 and 2: genes up-regulated in B2264-19/3 cells (primary B lymphocytes) within 30-60 min after activation of LMP1 (an oncogene encoded by Epstein-Barr virus, EBV).

description_full:
  Latent membrane protein 1 (LMP1), an oncoprotein encoded by Epstein-Barr virus (EBV), is an integral membrane protein, which acts like a constitutively active receptor. LMP1 is critical for some facet of EBV's induction and maintenance of proliferation of infected B cells. It, in part, mimics signaling by the CD40 receptor and has been implicated in regulating proliferation, survival, or both properties of EBV-infected cells. We established a conditional LMP1 allele in the context of the intact EBV genome to define the immediate-early cellular target genes regulated by LMP1 in order to assess its contributions to infected human B cells. The functional analysis of this conditional system indicated that LMP1 specifically induces mitogenic B-cell activation through c-myc and Jun/AP1 family members and confirms its direct role in upregulating expression of multiple genes with opposing activities involved in cell survival. LMP1's signals were found to be essential for the G1/S transition in human B cells; cells lacking LMP1's signals are cell cycle arrested and survive quiescently. LMP1's activities are therefore not required to maintain survival in nonproliferating cells. LMP1 does induce both pro- and antiapoptotic genes whose balance seems to permit survival during LMP1's induction and maintenance of proliferation.


systematic_name: M5091
exact_source: Table 1: TNoM2 p-value
source_species_code: HS
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  A gene expression signature found in a subset of cancer patients suggestive of a deregulated immune or inflammatory response.

description_full:
  On the basis of epidemiological studies, infection was suggested to play a role in the etiology of human cancer. While for some cancers such a role was indeed demonstrated, there is no direct biological support for the role of viral pathogens in the pathogenesis of childhood leukemia. Using a novel bioinformatic tool that alternates between clustering and standard statistical methods of analysis, we performed a 'double-blind' search of published gene expression data of subjects with different childhood acute lymphoblastic leukemia (ALL) subtypes, looking for unanticipated partitions of patients, induced by unexpected groups of genes with correlated expression. We discovered a group of about 30 genes, related to the interferon response pathway, whose expression levels divide the ALL samples into two subgroups; high in 50, low in 285 patients. Leukemic subclasses prevalent in early childhood (the age most susceptible to infection) are over-represented in the high-expression subgroup. Similar partitions, induced by the same genes, were found also in breast and ovarian cancer but not in lung cancer, prostate cancer and lymphoma. About 40% of breast cancer samples expressed the 'interferon-related' signature. It is of interest that several studies demonstrated mouse mammary tumor virus-like sequences in about 40% of breast cancer samples. Our discovery of an unanticipated strong signature of an interferon-induced pathway provides molecular support for a role for either inflammation or viral infection in the pathogenesis of childhood leukemia as well as breast and ovarian cancer.


systematic_name: M12391
exact_source: Table 1
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Top 50 genes up-regulated in A549 cells (lung cancer) expressing STAT3 [GeneID=6774] off an adenovirus vector.

description_full:
  Wound healing and cancer are both characterized by cell proliferation, remodeling of extracellular matrix, cell invasion and migration, new blood vessel formation, and modulation of blood coagulation. The mechanisms that link wound healing and cancer are poorly understood. We report here that Stat3, a common signaling mechanism involved in oncogenesis and tissue injury, regulates a common set of genes involved in wound healing and cancer. Using oligonucleotide gene arrays and quantitative real-time PCR, we evaluated changes in global gene expression resulting from expression of Stat3 in lung epithelial cells. We report here previously uncharacterized genes induced by Stat3 implicated in signaling pathways common to both wound healing and cancer including cell invasion and migration, angiogenesis, modulation of coagulation, and repression of interferon-inducible genes. Consistent with these results, we found increased Stat3 activity associated with wound healing in chronically inflamed mouse lungs and increased Stat3 activity was identified at the leading edge of lung tumors invading adjacent nontumor stroma. These findings provide a molecular basis for understanding cancer as a deregulation of normal wound healing processes.


systematic_name: M13696
exact_source: Table 2
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Top 50 genes down-regulated in A549 cells (lung cancer) expressing STAT3 [GeneID=6774] off an adenovirus vector.

description_full:
  Wound healing and cancer are both characterized by cell proliferation, remodeling of extracellular matrix, cell invasion and migration, new blood vessel formation, and modulation of blood coagulation. The mechanisms that link wound healing and cancer are poorly understood. We report here that Stat3, a common signaling mechanism involved in oncogenesis and tissue injury, regulates a common set of genes involved in wound healing and cancer. Using oligonucleotide gene arrays and quantitative real-time PCR, we evaluated changes in global gene expression resulting from expression of Stat3 in lung epithelial cells. We report here previously uncharacterized genes induced by Stat3 implicated in signaling pathways common to both wound healing and cancer including cell invasion and migration, angiogenesis, modulation of coagulation, and repression of interferon-inducible genes. Consistent with these results, we found increased Stat3 activity associated with wound healing in chronically inflamed mouse lungs and increased Stat3 activity was identified at the leading edge of lung tumors invading adjacent nontumor stroma. These findings provide a molecular basis for understanding cancer as a deregulation of normal wound healing processes.


systematic_name: M9951
exact_source: Table 1
source_species_code: HS
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in MDA468 cells (breast cancer) vs DU99 cells (normal breast) after treatment with azacytidine [PubChem=9444].

description_full:
  Treatment of the breast cancer cell line, MDAMB468 with the DNA methylation inhibitor, 5-azacytidine (5-AzaC) results in growth arrest, whereas the growth of the normal breast epithelial line DU99 (telomerase immortalized) is relatively unaffected. Comparing gene expression profiles of these two lines after 5-AzaC treatment, we identified 36 genes that had relatively low basal levels in MDAMB468 cells compared to the DU99 line and were induced in the cancer cell line but not in the normal breast epithelial line. Of these genes, 33 have associated CpG islands greater than 300 bp in length but only three have been previously described as targets for aberrant methylation in human cancer. Northern blotting for five of these genes (alpha-Catenin, DTR, FYN, GADD45a, and Zyxin) verified the array results. Further analysis of one of these genes, GADD45a, showed that 5-AzaC induced expression in five additional breast cancer cell lines with little or no induction in three additional lines derived from normal breast epithelial cells. The CpG island associated with GADD45a was analysed by bisulfite sequencing, sampling over 100 CpG dinucleotides. We found that four CpG's, located approximately 700 bp upstream of the transcriptional start site are methylated in the majority of breast cancer cell lines and primary tumors but not in DNA from normal breast epithelia or matched lymphocytes from cancer patients. Therefore, this simple method of dynamic transcriptional profiling yielded a series of novel methylation-sensitive genes in breast cancer including the BRCA1 and p53 responsive gene, GADD45a.


systematic_name: M7284
exact_source: Table 1S: Log Ratio CT60/4 vs. MDA-MB-231 > 0
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in CT60/4 cells (breast cancer reverted to normal by transfer of chromosome 8p region) vs parental MDA-MB-231 cells (deleted chromosome 8p).

description_full:
  Several investigations have supposed that tumor suppressor genes might be located on human chromosome 8. We used microcell-mediated transfer of chromosome 8 into MDA-MB-231 breast cancer cells and generated independent hybrids with strongly reduced tumorigenic potential. Loss of the transferred chromosome results in reappearance of the malignant phenotype. Expression analysis identified a set of 109 genes (CT8-ps) differentially expressed in microcell hybrids as compared to the tumorigenic MDA-MB-231 and rerevertant cells. Of these, 44.9% are differentially expressed in human breast tumors. The expression pattern of CT8-ps was associated with prognostic factors such as tumor size and grading as well as loss of heterozygosity at the short arm of chromosome 8. We identified CT8-ps networks suggesting that these genes act cooperatively to cause reversion of tumorigenicity in MDA-MB-231 cells. Our findings provide a conceptual basis and experimental system to identify and evaluate genes and gene networks involved in the development and/or progression of breast cancer.


systematic_name: M740
exact_source: Table 1S: Log Ratio CT60/4 vs. MDA-MB-231 < 0
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in CT60/4 cells (breast cancer reverted to normal by transfer of chromosome 8p region) vs parental MDA-MB-231 cells (deleted chromosome 8p).

description_full:
  Several investigations have supposed that tumor suppressor genes might be located on human chromosome 8. We used microcell-mediated transfer of chromosome 8 into MDA-MB-231 breast cancer cells and generated independent hybrids with strongly reduced tumorigenic potential. Loss of the transferred chromosome results in reappearance of the malignant phenotype. Expression analysis identified a set of 109 genes (CT8-ps) differentially expressed in microcell hybrids as compared to the tumorigenic MDA-MB-231 and rerevertant cells. Of these, 44.9% are differentially expressed in human breast tumors. The expression pattern of CT8-ps was associated with prognostic factors such as tumor size and grading as well as loss of heterozygosity at the short arm of chromosome 8. We identified CT8-ps networks suggesting that these genes act cooperatively to cause reversion of tumorigenicity in MDA-MB-231 cells. Our findings provide a conceptual basis and experimental system to identify and evaluate genes and gene networks involved in the development and/or progression of breast cancer.


systematic_name: M3003
exact_source: Table 2: Higher relative expression in LMP-G1
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in low grade (LMP and G1) serous ovarian carcinomas vs the higher grade invasive tumors (G2 and G3).

description_full:
  Profiles of gene transcription have begun to delineate the molecular basis of ovarian cancer, including distinctions between carcinomas of differing histology, tumor progression and patient outcome. However, the similarities and differences among the most commonly diagnosed noninvasive borderline (low malignant potential, LMP) lesions and invasive serous carcinomas of varying grade (G1, G2 and G3) have not yet been explored. Here, we used oligonucleotide arrays to profile the expression of 12,500 genes in a series of 57 predominantly stage III serous ovarian adenocarcinomas from 52 patients, eight with borderline tumors and 44 with adenocarcinomas of varying grade. Unsupervised and supervised analyses showed that LMP lesions were distinct from high-grade serous adenocarcinomas, as might be expected; however, well-differentiated (G1) invasive adenocarcinomas showed a strikingly similar profile to LMP tumors as compared to cancers with moderate (G2) or poor (G3) cellular differentiation, which were also highly similar. Comparative genomic hybridization of an independent cohort of five LMP and 63 invasive carcinomas of varying grade demonstrated LMP and G1 were again similar, exhibiting significantly less chromosomal aberration than G2/G3 carcinomas. A majority of LMP and G1 tumors were characterized by high levels of p21/WAF1, with concomitant expression of cell growth suppressors, gadd34 and BTG-2. In contrast, G2/G3 cancers were characterized by the expression of genes associated with the cell cycle and by STAT-1-, STAT-3/JAK-1/2-induced gene expression. The distinction between the LMP-G1 and G2-G3 groups of tumors was highly correlated to patient outcome (chi(2) for equivalence of death rates=7.681189; P=0.0056, log-rank test). Our results are consistent with the recent demonstration of a poor differentiation molecular 'meta-signature' in human cancer, and underscore a number of cell-cycle- and STAT-associated targets that may prove useful as points of therapeutic intervention for those patients with aggressive disease.


systematic_name: M867
exact_source: Table 2: Higher relative expression in G2-G3
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in low grade (LMP and G1) serous ovarian carcinomas vs the higher grade invasive tumors (G2 and G3).

description_full:
  Profiles of gene transcription have begun to delineate the molecular basis of ovarian cancer, including distinctions between carcinomas of differing histology, tumor progression and patient outcome. However, the similarities and differences among the most commonly diagnosed noninvasive borderline (low malignant potential, LMP) lesions and invasive serous carcinomas of varying grade (G1, G2 and G3) have not yet been explored. Here, we used oligonucleotide arrays to profile the expression of 12,500 genes in a series of 57 predominantly stage III serous ovarian adenocarcinomas from 52 patients, eight with borderline tumors and 44 with adenocarcinomas of varying grade. Unsupervised and supervised analyses showed that LMP lesions were distinct from high-grade serous adenocarcinomas, as might be expected; however, well-differentiated (G1) invasive adenocarcinomas showed a strikingly similar profile to LMP tumors as compared to cancers with moderate (G2) or poor (G3) cellular differentiation, which were also highly similar. Comparative genomic hybridization of an independent cohort of five LMP and 63 invasive carcinomas of varying grade demonstrated LMP and G1 were again similar, exhibiting significantly less chromosomal aberration than G2/G3 carcinomas. A majority of LMP and G1 tumors were characterized by high levels of p21/WAF1, with concomitant expression of cell growth suppressors, gadd34 and BTG-2. In contrast, G2/G3 cancers were characterized by the expression of genes associated with the cell cycle and by STAT-1-, STAT-3/JAK-1/2-induced gene expression. The distinction between the LMP-G1 and G2-G3 groups of tumors was highly correlated to patient outcome (chi(2) for equivalence of death rates=7.681189; P=0.0056, log-rank test). Our results are consistent with the recent demonstration of a poor differentiation molecular 'meta-signature' in human cancer, and underscore a number of cell-cycle- and STAT-associated targets that may prove useful as points of therapeutic intervention for those patients with aggressive disease.


systematic_name: M11171
exact_source: Table 1S: CC = I & SLR >= 1 in at least one condition
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in fibroblasts expressing mutant forms of ERCC3 [GeneID=2071] after UV irradiation.

description_full:
[cell repeats an earlier one in this file: 1438 characters]


systematic_name: M4976
exact_source: Table 1S: cluster 3
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Cluster 3: genes up-regulated in B2264-19/3 cells (primary B lymphocytes) within 60-180 min after activation of LMP1 (an oncogene encoded by Epstein-Barr virus, EBV).

description_full:
  Latent membrane protein 1 (LMP1), an oncoprotein encoded by Epstein-Barr virus (EBV), is an integral membrane protein, which acts like a constitutively active receptor. LMP1 is critical for some facet of EBV's induction and maintenance of proliferation of infected B cells. It, in part, mimics signaling by the CD40 receptor and has been implicated in regulating proliferation, survival, or both properties of EBV-infected cells. We established a conditional LMP1 allele in the context of the intact EBV genome to define the immediate-early cellular target genes regulated by LMP1 in order to assess its contributions to infected human B cells. The functional analysis of this conditional system indicated that LMP1 specifically induces mitogenic B-cell activation through c-myc and Jun/AP1 family members and confirms its direct role in upregulating expression of multiple genes with opposing activities involved in cell survival. LMP1's signals were found to be essential for the G1/S transition in human B cells; cells lacking LMP1's signals are cell cycle arrested and survive quiescently. LMP1's activities are therefore not required to maintain survival in nonproliferating cells. LMP1 does induce both pro- and antiapoptotic genes whose balance seems to permit survival during LMP1's induction and maintenance of proliferation.


description_brief: Genes most up-regulated in hypoxia tolerant NCI H460 cells (lung cancer).
systematic_name: M11948
exact_source: Table 2a, 2d
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_full:
  Tumor hypoxia is an adverse prognostic factor. In a recent study, we could demonstrate that cyclic hypoxia selects for hypoxia-tolerant tumor cells, which are cross-resistant to other stimuli of mitochondrial death pathways. In contrast, sensitivity of the cells to death-receptor ligands was mainly not affected. The aim of the present study was to further elucidate cellular changes induced by cyclic hypoxia and to identify alterations in gene expression pattern upon hypoxic selection by means of DNA-microarray analysis. Our data reveal that cyclic hypoxia resulted in the selection of cells with resistance to doxorubicine and radiation. Furthermore, hypoxic selection was accompanied by constitutive changes of the gene expression pattern with downregulation of 156 and upregulation of 82 genes. Most of the differentially regulated genes were involved in cellular responses to hypoxia and reoxygenation. While many of the genes that were downregulated upon hypoxic selection represent genes that are usually upregulated by acute hypoxia, the genes that were upregulated represent genes that are involved in stress resistance and anti-apoptotic signalling. Most importantly, hypoxic selection was not associated with changes of single apoptosis relevant genes, but with alterations in gene expression levels of a wide variety of genes indicating a more complex adaptation process.


systematic_name: M1215
exact_source: Table 2: change > 0
source_species_code: HS
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Selected up-regulated genes distinguishing between Wilms tumors of different histological types: anaplastic vs favorable histology.

description_full:
  Anaplasia (unfavorable histology) is associated with therapy resistance and poor prognosis of Wilms tumor, but the molecular basis for this phenotype is unclear. Here, we used a cDNA array with 9240 clones relevant to cancer biology and/or kidney development to examine the expression profiles of 54 Wilms tumors, five normal kidneys and fetal kidney. By linking genes differentially expressed between fetal kidney and Wilms tumors to kidney morphogenesis, we found that genes expressed at a higher level in Wilms tumors tend to be expressed more in uninduced metanephrogenic mesenchyme or blastema than in their differentiated structures. Conversely, genes expressed at a lower level in Wilms tumors tend to be expressed less in uninduced metanephrogenic mesenchyme or blastema. We also identified 97 clones representing 76 Unigenes or unclustered ESTs that clearly separate anaplastic Wilms tumors from tumors with favorable histology. Genes in this set provide insight into the nature of the abnormal nuclear morphology of anaplastic tumors and may facilitate identification of molecular targets to improve their responsiveness to treatment.


systematic_name: M18954
exact_source: Table 1, 2
source_species_code: HS
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in HCT116 cells (colon cancer) after treatment with amifostine [PubChem=2141] depending on the presence of TP53 [GeneID=7157]: TP53-positive vs TP53-null cells.

description_full:
  The aminothiol WR1065 exerts selective cytoprotective effects in normal cells compared to cancer cells and has clinical applications for the protection of normal cells in cancer patients undergoing radio- or chemotherapy. There is evidence that p53 is activated in response to WR1065. To examine the effects of WR1065 on the signalling pathways controlled by p53, isogeneic human colon carcinoma cell lines (HCT116) differing only in the presence or absence of wild-type p53 were used. Treatment with WR1065 resulted in G1 cell cycle arrest in the p53-positive cell line but not in the p53-negative cell line. Long-term exposure resulted in minimal apoptosis of either cell line. Changes in gene expression in p53-positive or -negative cells treated with WR1065 were examined using commercial human stress and cancer gene arrays (Clontech Atlas arrays). Genes found to be specifically upregulated in a p53-dependent manner included coproporphyrinogen oxidase, ICErel-II cysteine protease, macrophage inhibitory cytokine-1 (also known as placental transforming growth factor beta), S100A4, and Waf1/p21. However, most proapoptotic genes typically upregulated by p53 in response to DNA damage were not activated. These studies show that WR1065 specifically modulates a subset of p53 target genes in a colon carcinoma cell line, consistent with the observation that this agent elicits essentially p53-dependent, cell cycle arrest responses.


systematic_name: M16463
exact_source: Table 1, 2
source_species_code: HS
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in HCT116 cells (colon cancer) after treatment with amifostine [PubChem=2141] depending on the presence of TP53 [GeneID=7157]: TP53-positive vs TP53-null cells.

description_full:
  The aminothiol WR1065 exerts selective cytoprotective effects in normal cells compared to cancer cells and has clinical applications for the protection of normal cells in cancer patients undergoing radio- or chemotherapy. There is evidence that p53 is activated in response to WR1065. To examine the effects of WR1065 on the signalling pathways controlled by p53, isogeneic human colon carcinoma cell lines (HCT116) differing only in the presence or absence of wild-type p53 were used. Treatment with WR1065 resulted in G1 cell cycle arrest in the p53-positive cell line but not in the p53-negative cell line. Long-term exposure resulted in minimal apoptosis of either cell line. Changes in gene expression in p53-positive or -negative cells treated with WR1065 were examined using commercial human stress and cancer gene arrays (Clontech Atlas arrays). Genes found to be specifically upregulated in a p53-dependent manner included coproporphyrinogen oxidase, ICErel-II cysteine protease, macrophage inhibitory cytokine-1 (also known as placental transforming growth factor beta), S100A4, and Waf1/p21. However, most proapoptotic genes typically upregulated by p53 in response to DNA damage were not activated. These studies show that WR1065 specifically modulates a subset of p53 target genes in a colon carcinoma cell line, consistent with the observation that this agent elicits essentially p53-dependent, cell cycle arrest responses.


systematic_name: M1221
exact_source: Table 1S
source_species_code: RN
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in IEC-18 cells (intestinal epithelial cells) which avoided anoikis (a form of apoptosis) after detachment.

description_full:
  We reported earlier that IL-1beta, an NF-kappaB-regulated cytokine, was made by intestinal epithelial cells during detachment-induced apoptosis (anoikis) and that IL-1 was antiapoptotic for detached cells. Since surviving anoikis is a prerequisite for cancer progression and metastases, we are further exploring the link between anoikis and cytokines. Here we determined that multiple genes are expressed following detachment including a number of NF-kappaB-regulated products and therefore aimed to determine whether NF-kappaB signalling plays any role in regulating apoptosis. Using Western blotting, we detected that IkappaBalpha becomes phosphorylated immediately following detachment and that levels of phospho-IkappaBalpha peaked within 20 min. Phosphorylation of IkappaBalpha was followed by Rel A (p65) nuclear translocation. Increased NF-kappaB activity following detachment was confirmed using the detection of NF-kappaB-promoted luciferase gene expression delivered by adenovirus infection. Infection of cells with adenovirus expressing a super-repressor IkappaBalpha protein and pharmacological inhibitors of NF-kappaB resulted in the failure to phosphorylate IkappaBalpha, a more rapid activation of caspases and earlier apoptosis. We also detected that IkappaB kinase alpha (IKKalpha) and not IKKbeta became phosphorylated following detachment. Since IKKalpha is activated by NF-kappaB-inducing kinase (NIK), we overexpressed native NIK using an adenovirus vector that resulted in enhanced phospho-IkappaBalpha and nuclear p65 in detached cells compared to control detached cells but did not result in a significantly greater number of cells surviving to 24 h. We conclude that detachment directly activates NF-kappaB, which, in addition to launching an inflammatory cytokine wave, contributes to a delay in apoptosis in intestinal epithelial cells.


systematic_name: M18608
exact_source: Table 1
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Selected genes up-regulated in WT-A10 cells (gastric epithelium) expressing the H. pilori virulence gene CagA.

description_full:
  Infection with Helicobacter pylori cagA-positive strains is associated with gastric adenocarcinoma. Intestinal metaplasia is a precancerous lesion of the stomach characterized by transdifferentiation of the gastric mucosa to an intestinal phenotype. The H. pylori cagA gene product, CagA, is delivered into gastric epithelial cells, where it undergoes tyrosine phosphorylation by Src family kinases. Tyrosine-phosphorylated CagA specifically binds to and activates SHP-2 phosphatase, thereby inducing cell-morphological transformation. We report here that CagA physically interacts with E-cadherin independently of CagA tyrosine phosphorylation. The CagA/E-cadherin interaction impairs the complex formation between E-cadherin and beta-catenin, causing cytoplasmic and nuclear accumulation of beta-catenin. CagA-deregulated beta-catenin then transactivates beta-catenin-dependent genes such as cdx1, which encodes intestinal specific CDX1 transcription factor. In addition to beta-catenin signal, CagA also transactivates p21(WAF1/Cip1), again, in a phosphorylation-independent manner. Consequently, CagA induces aberrant expression of an intestinal-differentiation marker, goblet-cell mucin MUC2, in gastric epithelial cells that have been arrested in G1 by p21(WAF1/Cip1). These results indicate that perturbation of the E-cadherin/beta-catenin complex by H. pylori CagA plays an important role in the development of intestinal metaplasia, a premalignant transdifferentiation of gastric epithelial cells from which intestinal-type gastric adenocarcinoma arises.


systematic_name: M17552
exact_source: Table 2: Microarray fold change < 0 or -
source_species_code: HS
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in RCC4 cells (renal cell carcinoma) engineered to stably express VHL [GeneID=7428] off a plasmid vector.

description_full:
  Upregulation of hypoxia-inducible factors HIF-1 and HIF-2 is frequent in human cancers and may result from tissue hypoxia or genetic mechanisms, in particular the inactivation of the von Hippel-Lindau (VHL) tumour suppressor gene (TSG). Tumours with VHL inactivation are highly vascular, but it is unclear to what extent HIF-dependent and HIF-independent mechanisms account for pVHL tumour suppressor activity. As the identification of novel pVHL targets might provide insights into pVHL tumour suppressor activity, we performed gene expression microarray analysis in VHL-wild-type and VHL-null renal cell carcinoma (RCC) cell lines. We identified 30 differentially regulated pVHL targets (26 of which were 'novel') and the results of microarray analysis were confirmed in all 11 novel targets further analysed by real-time RT-PCR or Western blotting. Furthermore, nine of 11 targets were dysregulated in the majority of a series of primary clear cell RCC with VHL inactivation. Three of the nine targets had been identified previously as candidate TSGs (DOC-2/DAB2, CDKN1C and SPARC) and all were upregulated by wild-type pVHL. The significance for pVHL function of two further genes upregulated by wild-type pVHL was initially unclear, but re-expression of GNG4 (G protein gamma-4 subunit/guanine nucleotide-binding protein-4) and MLC2 (myosin light chain) in a RCC cell line suppressed tumour cell growth. pVHL regulation of CDKN1C, SPARC and GNG4 was not mimicked by hypoxia, whereas for six of 11 novel targets analysed (including DOC-2/DAB2 and MLC2) the effects of pVHL inactivation and hypoxia were similar. For GPR56 there was evidence of a tissue-specific hypoxia response. Such a phenomenon might, in part, explain organ-specific tumorigenesis in VHL disease. These provide insights into mechanisms of pVHL tumour suppressor function and identify novel hypoxia-responsive targets that might be implicated in tumorigenesis in both VHL disease and in other cancers with HIF upregulation.


systematic_name: M1252
exact_source: Table 1, 2
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in K562 cells (chronic myelogenous leukemia, CML) expressing TP53 and MYC [GeneID=7157;4609].

description_full:
  We have previously demonstrated that c-Myc impairs p53-mediated apoptosis in K562 human leukemia cells, which lack ARF. To investigate the mechanisms by which c-Myc protects from p53-mediated apoptosis, we used K562 cells that conditionally express c-Myc and harbor a temperature-sensitive allele of p53. Gene expression profiles of cells expressing wild-type conformation p53 in the presence of either uninduced or induced c-Myc were analysed by cDNA microarrays. The results show that multiple p53 target genes are downregulated when c-Myc is present, including p21WAF1, MDM2, PERP, NOXA, GADD45, DDB2, PIR121 and p53R2. Also, a number of genes that are upregulated by c-Myc in cells expressing wild-type conformation p53 encode chaperones related to cell death protection as HSP105, HSP90 and HSP27. Both downregulation of p53 target genes and upregulation of chaperones could explain the inhibition of apoptosis observed in K562 cells with ectopic c-Myc. Myc-mediated impairment of p53 transactivation was not restricted to K562 cells, but it was reproduced in a panel of human cancer cell lines derived from different tissues. Our data suggest that elevated levels of Myc counteract p53 activity in human tumor cells that lack ARF. This mechanism could contribute to explain the c-Myc deregulation frequently found in cancer.


systematic_name: M8512
exact_source: Table 1S
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in TK6, WTK1, and NH32 cell lines (lymphoblast) in response to ionizing radiation.

description_full:
  The p53 protein has been implicated in multiple cellular responses related to DNA damage. Alterations in any of these cellular responses could be related to increased genomic instability. Our previous study has shown that mutations in p53 lead to hypermutability to ionizing radiation. To investigate further how p53 is involved in regulating mutational processes, we used 8K cDNA microarrays to compare the patterns of gene expression among three closely related human cell lines with different p53 status including TK6 (wild-type p53), NH32 (p53-null), and WTK1 (mutant p53). Total RNA samples were collected at 1, 3, 6, 9, and 24 h after 10 Gy gamma-irradiation. Template-based clustering analysis of the gene expression over the time course showed that 464 genes are either up or downregulated by at least twofold following radiation treatment. In addition, cluster analyses of gene expression profiles among these three cell lines revealed distinct patterns. In TK6, 165 genes were upregulated, while 36 genes were downregulated. In contrast, in WTK1 75 genes were upregulated and 12 genes were downregulated. In NH32, only 54 genes were upregulated. Furthermore, we found several genes associated with DNA repair namely p53R2, DDB2, XPC, PCNA, BTG2, and MSH2 that were highly induced in TK6 compared to WTK1 and NH32. p53R2, which is regulated by the tumor suppressor p53, is a small subunit of ribonucleotide reductase. To determine whether it is involved in radiation-induced mutagenesis, p53R2 protein was inhibited by siRNA in TK6 cells and followed by 2 Gy radiation. The background mutation frequencies at the TK locus of siRNA-transfected TK6 cells were about three times higher than those seen in TK6 cells. The mutation frequencies of siRNA-transfected TK6 cells after 2 Gy radiation were significantly higher than the irradiated TK6 cells without p53R2 knock down. These results indicate that p53R2 was induced by p53 protein and is involved in protecting against radiation-induced mutagenesis.


systematic_name: M18299
exact_source: Table 1S: Relative expression +
source_species_code: HS
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in early primary breast tumors expressing ESR1 [GeneID=2099] vs the ESR1 negative ones.

description_full:
[cell repeats an earlier one in this file: 1632 characters]


systematic_name: M9823
exact_source: Table 1
source_species_code: HS
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in SK-N-DZ cells (neuroblastoma) after knockdown of MIF [GeneID=4282] by antisense RNA.

description_full:
  Macrophage migration inhibitory factor (MIF) has been defined as a novel oncogene. Our previous results have shown that MIF may contribute to the progression of neuroblastoma by (a) inducing N-Myc expression and (b) upregulating the expression of angiogenic factors. The aim of this study was to test whether tumor growth could be inhibited by reduction of endogenous MIF expression in neuroblastoma and clarify the molecular mechanisms underlying MIF reduction on the control of neuroblastoma growth. We established human neuroblastoma cell lines stably expressing antisense MIF (AS-MIF) cDNA. These stable transfectants were characterized by cell proliferation, gene expression profile, tumorigenicity and metastasis in vitro and in vivo. Decreased MIF expression was observed after transfection with AS-MIF in neuroblastoma cells and downregulation of MIF expression significantly correlated with decreased expression of N-Myc, Ras, c-Met and TrkB at protein level. Affymetrix microarray analysis revealed that expression of IL-8 and c-met was inhibited and neuroblastoma-favorable genes such as EPHB6 and BLU were upregulated in MIF reduced cells. Neuroblastoma cell growth exhibited a nearly 80% reduction in AS-MIF transfectants in vitro. Furthermore, mice in which tumors formed after subcutaneous injection of AS-MIF transfectants showed a 90% reduction in tumor growth compared to control. Metastasis in mice was also suppressed dramatically. Our data demonstrate that targeting MIF expression is a promising therapeutic strategy in human neuroblastoma therapy, and also identifies the MIF target genes for further study.


systematic_name: M14812
exact_source: Table 1: Fold change > 1
source_species_code: HS
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in H1299 cells (non-small cell lung cancer, NSCLC) expressing the Y144F mutant form of FHIT [GeneID=2272].

description_full:
  The Fhit tumor suppressor binds and hydrolyses diadenosine polyphosphates and the Fhit-substrate complex has been proposed as a proapoptotic effector, as determined by infection of susceptible cancer cells with adenoviruses carrying wild-type fragile histidine triad (FHIT) or catalytic site mutants. The highly conserved Fhit tyrosine 114 (Y114), within the unstructured loop C-terminal of the catalytic site, can be phosphorylated by Src family tyrosine kinases, although endogenous phospho-Fhit is rarely detected. To explore the importance of Y114 and identify Fhit-mediated signaling events, wild-type and Y114 mutant FHIT-expressing adenoviruses were introduced into two human lung cancer cell lines. Caspase-dependent apoptosis was effectively induced only by wild-type but not Y114 mutant Fhit proteins. By expression profiling of FHIT versus mutant FHIT-infected cells, we found that survivin, an Inhibitor of Apoptosis Protein (IAP) family member, was significantly decreased by wild-type Fhit. In addition, Fhit inhibited activity of Akt, a key effector in the phosphatidylinositol 3-OH kinase (PI3K) pathway; loss of endogenous Fhit expression caused increased Akt activity in vitro and in vivo, and overexpression of constitutively active Akt inhibited Fhit-induced apoptosis. The results indicate that the Fhit Y114 residue plays a critical role in Fhit-induced apoptosis, occurring through inactivation of the PI3K-Akt-survivin signal pathway.


systematic_name: M10504
exact_source: Table 1: Fold change < 1
source_species_code: HS
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in H1299 cells (non-small cell lung cancer, NSCLC) expressing the Y144F mutant form of FHIT [GeneID=2272].

description_full:
  The Fhit tumor suppressor binds and hydrolyses diadenosine polyphosphates and the Fhit-substrate complex has been proposed as a proapoptotic effector, as determined by infection of susceptible cancer cells with adenoviruses carrying wild-type fragile histidine triad (FHIT) or catalytic site mutants. The highly conserved Fhit tyrosine 114 (Y114), within the unstructured loop C-terminal of the catalytic site, can be phosphorylated by Src family tyrosine kinases, although endogenous phospho-Fhit is rarely detected. To explore the importance of Y114 and identify Fhit-mediated signaling events, wild-type and Y114 mutant FHIT-expressing adenoviruses were introduced into two human lung cancer cell lines. Caspase-dependent apoptosis was effectively induced only by wild-type but not Y114 mutant Fhit proteins. By expression profiling of FHIT versus mutant FHIT-infected cells, we found that survivin, an Inhibitor of Apoptosis Protein (IAP) family member, was significantly decreased by wild-type Fhit. In addition, Fhit inhibited activity of Akt, a key effector in the phosphatidylinositol 3-OH kinase (PI3K) pathway; loss of endogenous Fhit expression caused increased Akt activity in vitro and in vivo, and overexpression of constitutively active Akt inhibited Fhit-induced apoptosis. The results indicate that the Fhit Y114 residue plays a critical role in Fhit-induced apoptosis, occurring through inactivation of the PI3K-Akt-survivin signal pathway.


systematic_name: M7339
exact_source: Table 2AS
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in PCI-35 cells (pancreatic cancer, lack endogenous DUSP6 [GeneID=1848]) upon expression of DUSP6 off an adenoviral vector.

description_full:
  DUSP6/MKP-3, a specific inhibitor of MAPK1/ERK2, frequently loses its expression in primary pancreatic cancer tissues. This evidence suggests that constitutive activation of MAPK1 synergistically induced by frequent mutation of KRAS2 and the loss of function of DUSP6 plays key roles in pancreatic carcinogenesis and progression. By profiling of gene expressions associated with downregulation of MAPK1 induced by exogenous overexpression of DUSP6 in pancreatic cancer cells, we found that AURKA/STK15, the gene encoding Aurora-A kinase, which plays key roles in cellular mitosis, was among the downregulated genes along with its related genes, which included AURKB, TPX2 and CENPA. An association of expression and promoter activity of AURKA with MAPK activity was verified. Knockdown of ETS2 resulted in a reduction of AURKA expression. These results indicate that AURKA is a direct target of the MAPK pathway and that its overexpression in pancreatic cancer is induced by hyperactivation of the pathway, at least via ETS2.


systematic_name: M11654
exact_source: Table 1
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in metaplastic carcinoma of the breast (MCB) subclass 2 compared to the MCB subclass 1.

description_full:
  Metaplastic carcinoma of the breast (MCB) is a poorly understood subtype of breast cancer. It is generally characterized by the coexistence of ductal carcinomatous and transdifferentiated sarcomatous components, but the underlying molecular alterations, possibly related to epithelial-mesenchymal transition (EMT), remain elusive. We performed transcriptional profiling using half-a-genome oligonucleotide microarrays to elucidate genetic profiles of MCBs and their differences to those of ductal carcinoma of breasts (DCBs) using discarded specimens of four MCBs and 34 DCBs. Unsupervised clustering disclosed distinctive expression profiles between MCBs and DCBs. Supervised analysis identified gene signatures discriminating MCBs from DCBs and between MCB subclasses. Notably, many of the discriminator genes were associated with downregulation of epithelial phenotypes and with synthesis, remodeling and adhesion of extracellular matrix, with some of them have known or inferred roles related to EMT. Importantly, several of the discriminator genes were upregulated in a mutant Snail-transfected MCF7 cell known to exhibit features of EMT, thereby indicating a crucial role for EMT in the pathogenesis of MCBs. Finally, the identification of SPARC and vimentin as poor prognostic factors reinforced the role of EMT in cancer progression. These data advance our understanding of MCB and offer clues to the molecular alterations underlying EMT.


systematic_name: M11504
exact_source: Fig 1aS
source_species_code: HS
GEO_id: GSE6099
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in prostate cancer vs benign prostate tissue, based on a meta-analysis of five gene expression profiling studies.

description_full:
[cell repeats an earlier one in this file: 1173 characters]


systematic_name: M1290
exact_source: Table 1S
source_species_code: HS
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes involved in serotonin [PubChem=5202] function, orthologs computed from D. melanogaster genes using InsParanoid resource.

description_full:
  Both serotonin (5-HT) and neuropeptide Y have been shown to affect a variety of mammalian behaviors, including aggression. Here we show in Drosophila melanogaster that both 5-HT and neuropeptide F, the invertebrate homolog of neuropeptide Y, modulate aggression. We show that drug-induced increases of 5-HT in the fly brain increase aggression. Elevating 5-HT genetically in the serotonergic circuits recapitulates these pharmacological effects, whereas genetic silencing of these circuits makes the flies behaviorally unresponsive to the drug-induced increase of 5-HT but leaves them capable of aggression. Genetic silencing of the neuropeptide F (npf) circuit also increases fly aggression, demonstrating an opposite modulation to 5-HT. Moreover, this neuropeptide F effect seems to be independent of 5-HT. The implication of these two modulatory systems in fly and mouse aggression suggest a marked degree of conservation and a deep molecular root for this behavior.


systematic_name: M15356
exact_source: Table 1S
source_species_code: HS
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes constituting the LIT-Int network of proteins interacting with breast cancer reference proteins BRCA1, BRCA2, ATM, and CHEK2 [GeneID=672;675;472;11200]; the interactions were manually curated from the literature.

description_full:
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systematic_name: M18811
exact_source: Table 2S: XPRSS-Int
source_species_code: HS
GEO_id: GSE6534
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes constituting the XPRSS-Int network: intersection of genes whose expression correlates with BRCA1, BRCA2, ATM, and CHEK2 [GeneID=672;675;472;11200] in a compendium of normal tissues.

description_full:
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systematic_name: M9516
exact_source: Table 2S: BRCA2-PCCs
source_species_code: HS
GEO_id: GSE6534
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes constituting the BRCA2-PCC network of transcripts whose expression positively correlated (Pearson correlation coefficient, PCC >= 0.4) with that of BRCA2 [GeneID=675] across a compendium of normal tissues.

description_full:
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systematic_name: M2431
exact_source: Table 1: M+ > M-
source_species_code: HS
GEO_id: E-TABM-2,E-TABM-1
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  DNA repair and replication genes up-regulated in melanoma patients who will relapse vs patients who will not.

description_full:
  We have identified a gene-profile signature for human primary malignant melanoma associated with metastasis to distant sites and poor prognosis. We analyse the differential gene expression by looking at whole biological pathways rather than individual genes. Among the most significant pathways associated with progression to metastasis, we found the DNA replication (P=10(-14)) and the DNA repair pathways (P=10(-16)). We concentrated our analysis on DNA repair and found that 48 genes of this category, among a list of 234 genes, are associated with metastatic progression. These genes belong essentially to the pathways allowing recovery of stalled replication forks due to spontaneous blockage or induced DNA lesions. Because almost all these differentially expressed repair genes were overexpressed in primary tumors with bad prognosis, we speculate that primary melanoma cells that will metastasize try to replicate in a fast and error-free mode. In contrast to the progression from melanocytes to primary melanoma, genetic stability appears to be necessary for a melanoma cell to give rise to distant metastasis. This overexpression of repair genes explains nicely the extraordinary resistance of metastatic melanoma to chemo- and radio-therapy. Our results may open a new avenue for the discovery of drugs active on human metastatic melanoma.


systematic_name: M2970
exact_source: Table 1
source_species_code: HS
GEO_id: E-MEXP-969
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  The 'ER-alpha profile': genes up-regulated in T47D cells (breast cancer, ESR2 [GeneID=2100] Tet-Off) upon activation of ESR1 [GeneID=2099] by estradiol (E2) [PubChem=5757].

description_full:
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systematic_name: M1307
exact_source: Table 3S: 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 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: M1308
exact_source: Table 4S: 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 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: M9402
exact_source: Table 1: selected by p53
source_species_code: HS
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Cell cycle genes down-regulated in H1299 cells (lung cancer) after overexpression of either P53 or P73 [GeneID=7157;7161].

description_full:
  When normal cells come under stress, the wild-type (WT) p53 level increases resulting in the regulation of gene expression responsible for growth arrest or apoptosis. Here we show that elevated levels of WT p53 or its homologue, p73, inhibit expression of a number of cell cycle regulatory and growth promoting genes. Our analysis also identified a group of genes whose expression is differentially regulated by WT p53 and p73. We have infected p53-null H1299 human lung carcinoma cells with recombinant adenoviruses expressing WT p53, p73 or beta-galactosidase, and have undertaken microarray hybridization analyses to identify genes whose expression profile is altered by p53 or p73. Quantitative real-time PCR verified the repression of E2F-5, centromere protein A and E, minichromosome maintenance proteins (MCM)-2, -3, -5, -6 and -7 and human CDC25B after p53 expression. 5-Fluorouracil treatment of colon carcinoma HCT116 cells expressing WT p53 results in a reduction of the cyclin B2 protein level suggesting that DNA damage may indeed cause repression of these genes. Transient transcriptional assays verified that WT p53 repressed promoters of a number of these genes. Interestingly, a gain-of-function p53 mutant instead upregulated a number of these promoters in transient transfection. Using promoter deletion mutants of MCM-7 we have found that WT p53-mediated repression needs a minimal promoter that contains a single E2F site and surrounding sequences. However, a single E2F site cannot be significantly repressed by WT p53. Many of the genes identified are also repressed by p21. Thus, our work shows that WT p53 and p73 repress a number of growth-related genes and that in many instances this repression may be through the induction of p21.


systematic_name: M8511
exact_source: Table S2a: down by p53 and up by p73b
source_species_code: HS
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes that were inversely correlated in H1299 cells (lung cancer): down-regulated by P53 [GeneID=7157] and up-regulated by P73 [GeneID=7161].

description_full:
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systematic_name: M9811
exact_source: Table 2S: WT to ATG
source_species_code: HS
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in 293 cells (embryonic kidney) expressing  polymorphic variants S427G (SNP ID=rs2070235) or I624M (SNP ID=rs11556379) of BMYB [GeneID=4605].

description_full:
  The B-MYB proto-oncogene is a transcription factor belonging to the MYB family that is frequently overexpressed or amplified in different types of human malignancies. While it is suspected that B-MYB plays a role in human cancer, there is still no direct evidence of its causative role. Looking for mutations of the B-MYB gene in human cell lines and primary cancer samples, we frequently isolated two nonsynonymous B-MYB polymorphic variants (rs2070235 and rs11556379). Compared to the wild-type protein, the B-MYB isoforms display altered conformation, impaired regulation of target genes and decreased antiapoptotic activity, suggesting that they are hypomorphic variants of the major allele. Importantly, the B-MYB polymorphisms are common; rs2070235 and rs11556379 are found, depending on the ethnic background, in 10-50% of human subjects. We postulated that, if B-MYB activity is important for transformation, the presence of common, hypomorphic variants might modify cancer risk. Indeed, the B-MYB polymorphisms are underrepresented in 419 cancer patients compared to 230 controls (odds ratio 0.53; (95%) confidence interval 0.385-0.755; P=0.001). This data imply that a large fraction of the human population is carrier of B-MYB alleles that might be associated with a reduced risk of developing neoplastic disease.


systematic_name: M589
exact_source: Table 2
source_species_code: HS
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in constitutively invasive HT-29 5M21 cells (colon cancer) vs those expressing functionally inactive TATI [GeneID=6690].

description_full:
  From the conditioned medium of the human colon carcinoma cells, HT-29 5M21 (CM-5M21), expressing a spontaneous invasive phenotype, tumor-associated trypsin inhibitor (TATI) was identified and characterized by proteomics, cDNA microarray approaches and functional analyses. Both CM-5M21 and recombinant TATI, but not the K18Y-TATI mutant at the protease inhibitor site, trigger collagen type I invasion by several human adenoma and carcinoma cells of the colon and breast, through phosphoinositide-3-kinase, protein kinase C and Rho-GTPases/Rho kinase-dependent pathways. Conversely, the proinvasive action of TATI in parental HT29 cells was alleviated by the TATI antibody PSKAN2 and the K18Y-TATI mutant. Stable expression of K18Y-TATI in HT-29 5M21 cells downregulated tumor growth, angiogenesis and the expression of several metastasis-related genes, including CSPG4 (13.8-fold), BMP-7 (9.7-fold), the BMP antagonist CHORDIN (5.2-fold), IGFBP-2 and IGF2 (9.6- and 4.6-fold). Accordingly, ectopic expression of KY-TATI inhibited the development of lung metastases from HT-29 5M21 tumor xenografts in immunodeficient mice. These findings identify TATI as an autocrine transforming factor potentially involved in early and late events of colon cancer progression, including local invasion of the primary tumor and its metastatic spread. Targeting TATI, its molecular partners and effectors may bring novel therapeutic applications for high-grade human solid tumors in the digestive and urogenital systems.


systematic_name: M7465
exact_source: Table 6S
source_species_code: HS
GEO_id: GSE8502
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in EVSA-T cells (breast cancer) after treatment with 3 micromolar THC (delta-9-tetrahydrocannabinol) [PubChem=6610319] for 24 h.

description_full:
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systematic_name: M16424
exact_source: Table 3: Status=UP DUC
source_species_code: HS
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in the invasive ductal carcinoma (IDC) compared to the invasive lobular carcinoma (ILC), the two major pathological types of breast cancer.

description_full:
  Invasive ductal carcinomas (IDCs) and invasive lobular carcinomas (ILCs) are the two major pathological types of breast cancer. Epidemiological and histoclinical data suggest biological differences, but little is known about the molecular alterations involved in ILCs. We undertook a comparative large-scale study by both array-compared genomic hybridization and cDNA microarray of a set of 50 breast tumors (21 classic ILCs and 29 IDCs) selected on homogeneous histoclinical criteria. Results were validated on independent tumor sets, as well as by quantitative RT-PCR. ILCs and IDCs presented differences at both the genomic and expression levels with ILCs being less rearranged and heterogeneous than IDCs. Supervised analysis defined a 75-BACs signature discriminating accurately ILCs from IDCs. Expression profiles identified two subgroups of ILCs: typical ILCs ( approximately 50%), which were homogeneous and displayed a normal-like molecular pattern, and atypical ILCs, more heterogeneous with features intermediate between ILCs and IDCs. Supervised analysis identified a 75-gene expression signature that discriminated ILCs from IDCs, with many genes involved in cell adhesion, motility, apoptosis, protein folding, extracellular matrix and protein phosphorylation. Although ILCs and IDCs share common alterations, our data show that ILCs and IDCs could be distinguished on the basis of their genomic and expression profiles suggesting that they evolve along distinct genetic pathways.


systematic_name: M14142
exact_source: Table 3: Status=UP LOB
source_species_code: HS
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in the invasive ductal carcinoma (IDC) compared to the invasive lobular carcinoma (ILC), the two major pathological types of breast cancer.

description_full:
  Invasive ductal carcinomas (IDCs) and invasive lobular carcinomas (ILCs) are the two major pathological types of breast cancer. Epidemiological and histoclinical data suggest biological differences, but little is known about the molecular alterations involved in ILCs. We undertook a comparative large-scale study by both array-compared genomic hybridization and cDNA microarray of a set of 50 breast tumors (21 classic ILCs and 29 IDCs) selected on homogeneous histoclinical criteria. Results were validated on independent tumor sets, as well as by quantitative RT-PCR. ILCs and IDCs presented differences at both the genomic and expression levels with ILCs being less rearranged and heterogeneous than IDCs. Supervised analysis defined a 75-BACs signature discriminating accurately ILCs from IDCs. Expression profiles identified two subgroups of ILCs: typical ILCs ( approximately 50%), which were homogeneous and displayed a normal-like molecular pattern, and atypical ILCs, more heterogeneous with features intermediate between ILCs and IDCs. Supervised analysis identified a 75-gene expression signature that discriminated ILCs from IDCs, with many genes involved in cell adhesion, motility, apoptosis, protein folding, extracellular matrix and protein phosphorylation. Although ILCs and IDCs share common alterations, our data show that ILCs and IDCs could be distinguished on the basis of their genomic and expression profiles suggesting that they evolve along distinct genetic pathways.


systematic_name: M13844
exact_source: Table 1S
source_species_code: HS
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in the A673 cells (Ewing sarcoma) after double knockdown of both FLI1 and DAX1 [GeneID=2313;190] by RNAi.

description_full:
  The molecular hallmark of the Ewing's family of tumors is the presence of balanced chromosomal translocations, leading to the formation of chimerical transcription factors (that is, EWS/FLI1) that play a pivotal role in the pathogenesis of Ewing's tumors by deregulating gene expression. We have recently demonstrated that DAX1 (NR0B1), an orphan nuclear receptor that was not previously implicated in cancer, is induced by the EWS/FLI1 oncoprotein and is highly expressed in Ewing's tumors, suggesting that DAX1 is a biologically relevant target of EWS/FLI1-mediated oncogenesis. In this study we demonstrate that DAX1 is a direct transcriptional target of the EWS/FLI1 oncoprotein through its binding to a GGAA-rich region in the DAX1 promoter and show that DAX1 is a key player of EWS/FLI1-mediated oncogenesis. DAX1 silencing using an inducible model of RNA interference induces growth arrest in the A673 Ewing's cell line and severely impairs its capability to grow in semisolid medium and form tumors in immunodeficient mice. Gene expression profile analysis demonstrated that about 10% of the genes regulated by EWS/FLI1 in Ewing's cells are DAX1 targets, confirming the importance of DAX1 in Ewing's oncogenesis. Functional genomic analysis, validated by quantitative RT-PCR, showed that genes implicated in cell-cycle progression, such as CDK2, CDC6, MCM10 or SKP2 were similarly regulated by EWS/FLI1 and DAX1. These findings indicate that DAX1 is important in the pathogenesis of the Ewing's family of tumors, identify new functions for DAX1 as a cell-cycle progression regulator and open the possibility to new therapeutic approaches based on DAX1 function interference.


systematic_name: M17006
exact_source: Table 4S: FC3/2 < 1
source_species_code: HS
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Down-regulated genes that vary between HNSCC (head and neck squamous cell carcinoma) groups formed on the basis of their level of pathological differentiation: moderately vs poorly differentiated tumors.

description_full:
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description_brief: Genes associated with migration rate of 40 human bladder cancer cells.
systematic_name: M2001
exact_source: Table 1S
source_species_code: HS
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_full:
  Cell migration is essential to cancer invasion and metastasis and is spatially and temporally integrated through transcriptionally dependent and independent mechanisms. As cell migration is studied in vitro, it is important to identify genes that both drive cell migration and are biologically relevant in promoting invasion and metastasis in patients with cancer. Here, gene expression profiling and a high-throughput cell migration system answers this question in human bladder cancer. In vitro migration rates of 40 microarray-profiled human bladder cancer cell lines were measured by radial migration assay. Genes whose expression was either directly or inversely associated with cell migration rate were identified and subsequently evaluated for their association with cancer stage in 61 patients. This analysis identified genes known to be associated with cell invasion such as versican, and novel ones, including metallothionein 1E (MT1E) and nicotinamide N-methyltransferase (NNMT), whose expression correlated positively with cancer cell migration and tumor stage. Using loss of function analysis, we show that MT1E and NNMT are necessary for cancer cell migration. These studies provide a general approach to identify the clinically relevant genes in cancer cell migration and mechanistically implicate two novel genes in this process in human bladder cancer.


description_brief: Proteins shown to interact with LCA5 [GeneID=167691] in vivo.
systematic_name: M1380
exact_source: Table 1
source_species_code: HS
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_full:
  Leber congenital amaurosis (LCA) causes blindness or severe visual impairment at or within a few months of birth. Here we show, using homozygosity mapping, that the LCA5 gene on chromosome 6q14, which encodes the previously unknown ciliary protein lebercilin, is associated with this disease. We detected homozygous nonsense and frameshift mutations in LCA5 in five families affected with LCA. In a sixth family, the LCA5 transcript was completely absent. LCA5 is expressed widely throughout development, although the phenotype in affected individuals is limited to the eye. Lebercilin localizes to the connecting cilia of photoreceptors and to the microtubules, centrioles and primary cilia of cultured mammalian cells. Using tandem affinity purification, we identified 24 proteins that link lebercilin to centrosomal and ciliary functions. Members of this interactome represent candidate genes for LCA and other ciliopathies. Our findings emphasize the emerging role of disrupted ciliary processes in the molecular pathogenesis of LCA.


systematic_name: M4740
exact_source: Table 5S: Core 9
source_species_code: HS
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Set 'Core 9': 'embryonic stem cell' transcription regulators that are preferentially and coordinately overexpressed in the high-grade, ER-negative breast cancer tumors.

description_full:
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systematic_name: M14079
exact_source: Table 5S
source_species_code: HS
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Breast cancer compendium: 100 transcription regulators showing most correlated expression with the 9 'embryonic stem cell' transcription factors that are preferentially and coordinately overexpressed in the high-grade, ER-negative breast cancer tumors.

description_full:
[cell repeats an earlier one in this file: 1354 characters]


systematic_name: M11038
exact_source: Table CS
source_species_code: HS
GEO_id: GSE13105
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Experimentally validated direct targets of MIR192 [GeneID=406967] microRNA; MIR192 caused cell cycle arrest in HCT116 cells (colon cancer).

description_full:
  Cell cycle arrest in response to DNA damage is an important antitumorigenic mechanism. MicroRNAs (miRNAs) were recently shown to play key regulatory roles in cell cycle progression. For example, miR-34a is induced in response to p53 activation and mediates G(1) arrest by down-regulating multiple cell cycle-related transcripts. Here we show that genotoxic stress promotes the p53-dependent up-regulation of the homologous miRNAs miR-192 and miR-215. Like miR-34a, activation of miR-192/215 induces cell cycle arrest, suggesting that multiple miRNA families operate in the p53 network. Furthermore, we define a downstream gene expression signature for miR-192/215 expression, which includes a number of transcripts that regulate G(1) and G(2) checkpoints. Of these transcripts, 18 transcripts are direct targets of miR-192/215, and the observed cell cycle arrest likely results from a cooperative effect among the modulations of these genes by the miRNAs. Our results showing a role for miR-192/215 in cell proliferation combined with recent observations that these miRNAs are underexpressed in primary cancers support the idea that miR-192 and miR-215 function as tumor suppressors.


systematic_name: M8180
exact_source: Table 1
source_species_code: HS
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Selected genes down-regulated in inflammatory monocytes infiltrating hepatocellular carcinoma (HCC).

description_full:
  Hepatocellular carcinoma (HCC) is frequently associated with infiltrating mononuclear inflammatory cells. We performed laser capture microdissection of HCC-infiltrating and noncancerous liver-infiltrating mononuclear inflammatory cells in patients with chronic hepatitis C (CH-C) and examined gene expression profiles. HCC-infiltrating mononuclear inflammatory cells had an expression profile distinct from noncancerous liver-infiltrating mononuclear inflammatory cells; they differed with regard to genes involved in biological processes, such as antigen presentation, ubiquitin-proteasomal proteolysis, and responses to hypoxia and oxidative stress. Immunohistochemical analysis and gene expression databases suggested that the up-regulated genes involved macrophages and Th1 and Th2 CD4 cells. We next examined the gene expression profile of peripheral blood mononuclear cells (PBMC) obtained from CH-C patients with or without HCC. The expression profiles of PBMCs from patients with HCC differed significantly from those of patients without HCC (P < 0.0005). Many of the up-regulated genes in HCC-infiltrating mononuclear inflammatory cells were also differentially expressed by PBMCs of HCC patients. Analysis of the commonly up-regulated or down-regulated genes in HCC-infiltrating mononuclear inflammatory cells and PBMCs of HCC patients showed networks of nucleophosmin, SMAD3, and proliferating cell nuclear antigen that are involved with redox status, the cell cycle, and the proteasome system, along with immunologic genes, suggesting regulation of anticancer immunity. Thus, exploring the gene expression profile of PBMCs may be a surrogate approach for the assessment of local HCC-infiltrating mononuclear inflammatory cells.


systematic_name: M9483
exact_source: Table 1S
source_species_code: HS
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in metastatic vs non-metastatic stromal cells originated from either bone or prostate tissues.

description_full:
  Human bone stromal cells, after three-dimensional coculture with human prostate cancer (PCa) cells in vitro, underwent permanent cytogenetic and gene expression changes with reactive oxygen species serving as mediators. The evolved stromal cells are highly inductive of human PCa growth in mice, and expressed increased levels of extracellular matrix (versican and tenascin) and chemokine (BDFN, CCL5, CXCL5, and CXCL16) genes. These genes were validated in clinical tissue and/or serum specimens and could be the predictors for invasive and bone metastatic PCa. These results, combined with our previous observations, support the concept of permanent genetic and behavioral changes of PCa epithelial cells after being either cocultured with prostate or bone stromal cells as three-dimensional prostate organoids or grown as tumor xenografts in mice. These observations collectively suggest coevolution of cancer and stromal cells occurred under three-dimensional growth condition, which ultimately accelerates cancer growth and metastasis.


systematic_name: M19826
exact_source: Table 1S
source_species_code: HS
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in BxPC3 cells (pancreatic cancer) after treatment with TNF [GeneID=7124] or IKI-1, an inhibitor of IkappaB kinase (IKK).

description_full:
  Tumor necrosis factor alpha (TNFalpha) has been used to treat patients with certain tumor types. However, its antitumor activity has been undermined by the activation of IkappaBalpha kinase (IKK), which in turn activates nuclear factor-kappaB (NF-kappaB) to help cancer cells survive. Therefore, inhibition of TNFalpha-induced IKK activity with specific IKK inhibitor represents an attractive strategy to treat cancer patients. This study reveals IKI-1 as a potent small molecule inhibitor of IKKalpha and IKKbeta, which effectively blocked TNFalpha-mediated IKK activation and subsequent NF-kappaB activity. Using gene profiling analysis, we show that IKI-1 blocked most of the TNFalpha-mediated mRNA expression, including many genes that play important roles in cell survival. We further show that in vitro and in vivo combination of TNFalpha with IKI-1 had superior potency than either agent alone. This increased potency was due primarily to the increased apoptosis in the presence of both TNFalpha and IKI-1. Additionally, IKKbeta small interfering RNA transfected cells were more sensitive to the treatment of TNFalpha. The study suggests that the limited efficacy of TNFalpha in cancer treatment was due in part to the activation of NF-kappaB, allowing tumor cells to escape apoptosis. Therefore, the combination of IKI-1 with TNFalpha may improve the efficacy of TNFalpha for certain tumor types.


systematic_name: M14137
exact_source: Suppl. Excel File 1S: 19p13
source_species_code: HS
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes within amplicon 19p13 identified in a copy number alterations study of 191 breast tumor samples.

description_full:
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systematic_name: M10597
exact_source: Table 1
source_species_code: HS
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes that reduced viability of NCI-H1155 cells (non-small-cell lung cancer, NSCLC) in the presence of otherwise sublethal concentrations of paclitaxel [PubChem=4666], based on RNAi synthetic lethal screen.

description_full:
  Abundant evidence suggests that a unifying principle governing the molecular pathology of cancer is the co-dependent aberrant regulation of core machinery driving proliferation and suppressing apoptosis. Anomalous proteins engaged in support of this tumorigenic regulatory environment most probably represent optimal intervention targets in a heterogeneous population of cancer cells. The advent of RNA-mediated interference (RNAi)-based functional genomics provides the opportunity to derive unbiased comprehensive collections of validated gene targets supporting critical biological systems outside the framework of preconceived notions of mechanistic relationships. We have combined a high-throughput cell-based one-well/one-gene screening platform with a genome-wide synthetic library of chemically synthesized small interfering RNAs for systematic interrogation of the molecular underpinnings of cancer cell chemoresponsiveness. NCI-H1155, a human non-small-cell lung cancer line, was employed in a paclitaxel-dependent synthetic lethal screen designed to identify gene targets that specifically reduce cell viability in the presence of otherwise sublethal concentrations of paclitaxel. Using a stringent objective statistical algorithm to reduce false discovery rates below 5%, we isolated a panel of 87 genes that represent major focal points of the autonomous response of cancer cells to the abrogation of microtubule dynamics. Here we show that several of these targets sensitize lung cancer cells to paclitaxel concentrations 1,000-fold lower than otherwise required for a significant response, and we identify mechanistic relationships between cancer-associated aberrant gene expression programmes and the basic cellular machinery required for robust mitotic progression.


systematic_name: M19304
exact_source: Table 1S: hES d5
source_species_code: HS
GEO_id: GSE7902
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in hES cells (human embryonic stem cells) after treatment with the ALK [GeneID=238] inhibitor SB-431542 [PubChem=4521392].

description_full:
  The application of human embryonic stem (ES) cells in medicine and biology has an inherent reliance on understanding the starting cell population. Human ES cells differ from mouse ES cells and the specific embryonic origin of both cell types is unclear. Previous work suggested that mouse ES cells could only be obtained from the embryo before implantation in the uterus. Here we show that cell lines can be derived from the epiblast, a tissue of the post-implantation embryo that generates the embryo proper. These cells, which we refer to as EpiSCs (post-implantation epiblast-derived stem cells), express transcription factors known to regulate pluripotency, maintain their genomic integrity, and robustly differentiate into the major somatic cell types as well as primordial germ cells. The EpiSC lines are distinct from mouse ES cells in their epigenetic state and the signals controlling their differentiation. Furthermore, EpiSC and human ES cells share patterns of gene expression and signalling responses that normally function in the epiblast. These results show that epiblast cells can be maintained as stable cell lines and interrogated to understand how pluripotent cells generate distinct fates during early development.


systematic_name: M4306
exact_source: Table 1S
source_species_code: HS
GEO_id: GSE9691
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in HMLE cells (immortalized nontransformed mammary epithelium) after E-cadhedrin (CDH1) [GeneID=999] knockdown by RNAi.

description_full:
[cell repeats an earlier one in this file: 1076 characters]


systematic_name: M9167
exact_source: Table 1
source_species_code: HS
GEO_id: GSE11668
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes linked to the ECM maintenance and angiogenesis that were changed in HT1080 cells (fibrosarcoma) over-expressing MMP14 [GeneID=4323] compared to those with knockdown of the gene by RNAi.

description_full:
  Invasion-promoting MT1-MMP is directly linked to tumorigenesis and metastasis. Our studies led us to identify those genes, the expression of which is universally linked to MT1-MMP in multiple tumor types. Genome-wide expression profiling of MT1-MMP-overexpressing versus MT1-MMP-silenced cancer cells and a further data mining analysis of the preexisting expression database of 190 human tumors of 14 cancer types led us to identify 11 genes, the expression of which correlated firmly and universally with that of MT1-MMP (P < 0.00001). These genes included regulators of energy metabolism (NNT), trafficking and membrane fusion (SLCO2A1 and ANXA7), signaling and transcription (NR3C1, JAG1, PI3K delta, and CK2 alpha), chromatin rearrangement (SMARCA1), cell division (STK38/NDR1), apoptosis (DAPK1), and mRNA splicing (SNRPB2). Our subsequent extensive analysis of cultured cells, tumor xenografts, and cancer patient biopsies supported our data mining. Our results suggest that transcriptional reprogramming of the specific downstream genes, which themselves are associated with tumorigenesis, represents a distinctive molecular signature of the proteolytically active MT1-MMP. We suggest that the transactivation activity of MT1-MMP contributes to the promigratory cell phenotype, which is induced by this tumorigenic proteinase. The activated downstream gene network then begins functioning in unison with MT1-MMP to rework the signaling, transport, cell division, energy metabolism, and other critical cell functions and to commit the cell to migration, invasion, and, consequently, tumorigenesis.


systematic_name: M2987
exact_source: Table 2
source_species_code: HS
GEO_id: GSE11668
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes whose expression most uniformly correlated with that of MMP14 [GeneID=4323] both in HT1080 cells (fibrosarcoma) and in 190 human tumors.

description_full:
  Invasion-promoting MT1-MMP is directly linked to tumorigenesis and metastasis. Our studies led us to identify those genes, the expression of which is universally linked to MT1-MMP in multiple tumor types. Genome-wide expression profiling of MT1-MMP-overexpressing versus MT1-MMP-silenced cancer cells and a further data mining analysis of the preexisting expression database of 190 human tumors of 14 cancer types led us to identify 11 genes, the expression of which correlated firmly and universally with that of MT1-MMP (P < 0.00001). These genes included regulators of energy metabolism (NNT), trafficking and membrane fusion (SLCO2A1 and ANXA7), signaling and transcription (NR3C1, JAG1, PI3K delta, and CK2 alpha), chromatin rearrangement (SMARCA1), cell division (STK38/NDR1), apoptosis (DAPK1), and mRNA splicing (SNRPB2). Our subsequent extensive analysis of cultured cells, tumor xenografts, and cancer patient biopsies supported our data mining. Our results suggest that transcriptional reprogramming of the specific downstream genes, which themselves are associated with tumorigenesis, represents a distinctive molecular signature of the proteolytically active MT1-MMP. We suggest that the transactivation activity of MT1-MMP contributes to the promigratory cell phenotype, which is induced by this tumorigenic proteinase. The activated downstream gene network then begins functioning in unison with MT1-MMP to rework the signaling, transport, cell division, energy metabolism, and other critical cell functions and to commit the cell to migration, invasion, and, consequently, tumorigenesis.


systematic_name: M12890
exact_source: Table 3S: Ratio HTMT/HTsiRNA > 1
source_species_code: HS
GEO_id: GSE11668
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in HT1080 cells (fibrosarcoma) over-expressing MMP14 [GeneID=4323] compared to those with knockdown of the gene by RNAi.

description_full:
  Invasion-promoting MT1-MMP is directly linked to tumorigenesis and metastasis. Our studies led us to identify those genes, the expression of which is universally linked to MT1-MMP in multiple tumor types. Genome-wide expression profiling of MT1-MMP-overexpressing versus MT1-MMP-silenced cancer cells and a further data mining analysis of the preexisting expression database of 190 human tumors of 14 cancer types led us to identify 11 genes, the expression of which correlated firmly and universally with that of MT1-MMP (P < 0.00001). These genes included regulators of energy metabolism (NNT), trafficking and membrane fusion (SLCO2A1 and ANXA7), signaling and transcription (NR3C1, JAG1, PI3K delta, and CK2 alpha), chromatin rearrangement (SMARCA1), cell division (STK38/NDR1), apoptosis (DAPK1), and mRNA splicing (SNRPB2). Our subsequent extensive analysis of cultured cells, tumor xenografts, and cancer patient biopsies supported our data mining. Our results suggest that transcriptional reprogramming of the specific downstream genes, which themselves are associated with tumorigenesis, represents a distinctive molecular signature of the proteolytically active MT1-MMP. We suggest that the transactivation activity of MT1-MMP contributes to the promigratory cell phenotype, which is induced by this tumorigenic proteinase. The activated downstream gene network then begins functioning in unison with MT1-MMP to rework the signaling, transport, cell division, energy metabolism, and other critical cell functions and to commit the cell to migration, invasion, and, consequently, tumorigenesis.


systematic_name: M5522
exact_source: Table 3S: Ratio HTMT/HTsiRNA < 1
source_species_code: HS
GEO_id: GSE11668
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in HT1080 cells (fibrosarcoma) over-expressing MMP14 [GeneID=4323] compared to those with knockdown of the gene by RNAi.

description_full:
[cell repeats an earlier one in this file: 1603 characters]


systematic_name: M10828
exact_source: unknown
source_species_code: DR
contributor: Jennifer Shepard
contrib_organization: Broad Institute
description_brief:
  Human orthologs of genes up-regulated in the crb ('crash and burn') zebrafish mutant that represents a loss-of-function mutation in BMYB [GeneID=4605].

description_full:
  A major goal of cancer research has been to identify genes that contribute to cancer formation. The similar pathology between zebrafish and human tumors, as well as the past success of large-scale genetic screens in uncovering human disease genes, makes zebrafish an ideal system in which to find such new genes. Here, we show that a zebrafish forward genetic screen uncovered multiple cell proliferation mutants including one mutant, crash&burn (crb), that represents a loss-of-function mutation in bmyb, a transcriptional regulator and member of a putative proto-oncogene family. crb mutant embryos have defects in mitotic progression and spindle formation, and exhibit genome instability. Regulation of cyclin B levels by bmyb appears to be the mechanism of mitotic accumulation in crb. Carcinogenesis studies reveal increased cancer susceptibility in adult crb heterozygotes. Gene-expression signatures associated with loss of bmyb in zebrafish are also correlated with conserved signatures in human tumor samples, and down-regulation of the B-myb signature genes is associated with retention of p53 function. Our findings show that zebrafish screens can uncover cancer pathways, and demonstrate that loss of function of bmyb is associated with cancer.


description_brief: Genes up-regulated by induction of E2F1 expression in Saos2 (osteosarcoma) cells.
systematic_name: M16061
exact_source: Table 1
source_species_code: HS
contributor: Yujin Hoshida
contrib_organization: Broad Institute
description_full:
  The p16/RB/E2F regulatory pathway, which controls transit through the G1 restriction point of the cell cycle, is one of the most frequent targets of genetic alterations in human cancer. Any of these alterations results in the deregulated expression of the transcription factor E2F, one of the key mediators of cell cycle progression. Under these conditions, E2F1 also participates in the induction of apoptosis by a p53-dependent pathway, and independently of p53. Recently, we identified the p53-homolog p73 as a first direct target of p53-independent apoptosis. Here, we used a cDNA microarray to screen an inducible E2F1-expressing Saos-2 cell line for E2F1 target genes. Expression analysis by cDNA microarray and RT-PCR revealed novel E2F1 target genes involved in E2F1-regulated cellular functions such as cell cycle control, DNA replication and apoptosis. In addition, the identification of novel E2F1 target genes participating in the processes of angiogenesis, invasion and metastasis supports the view that E2F1 plays a central role in many aspects of cancer development. These results provide new insight into the role of E2F1 in tumorigenesis as a basis for the development of novel anti-cancer therapeutics.


systematic_name: M6318
exact_source: Table 3
source_species_code: HS
contributor: Yujin Hoshida
contrib_organization: Broad Institute
description_brief:
  Genes up-regulated in Jurkat cells (T lymphocyte) by IFN1@, and IFNB1 [GeneID=3438;3456] but not by overexpression of a constitutively active form of IRF3 [GeneID=3661].

description_full:
  Ubiquitously expressed interferon regulatory factor 3 (IRF-3) is directly activated after virus infection and functions as a key activator of the immediate-early alpha/beta interferon (IFN) genes, as well as the RANTES chemokine gene. In the present study, a tetracycline-inducible expression system expressing a constitutively active form of IRF-3 (IRF-3 5D) was combined with DNA microarray analysis to identify target genes regulated by IRF-3. Changes in mRNA expression profiles of 8,556 genes were monitored after Tet-inducible expression of IRF-3 5D. Among the genes upregulated by IRF-3 were transcripts for several known IFN-stimulated genes (ISGs). Subsequent analysis revealed that IRF-3 directly induced the expression of ISG56 in an IFN-independent manner through the IFN-stimulated responsive elements (ISREs) of the ISG56 promoter. These results demonstrate that, in addition to its role in the formation of a functional immediate-early IFN-beta enhanceosome, IRF-3 is able to discriminate among ISRE-containing genes involved in the establishment of the antiviral state as a direct response to virus infection.


systematic_name: M10633
exact_source: Table 3S: 1% cutoff
source_species_code: HS
GEO_id: GSE2350
contributor: Jean Junior
contrib_organization: MSigDB Team
description_brief:
  Genes which comprise the top 1% of highly interconnected genes (major hubs) that account for most of gene interactions in the reconstructed regulatory networks from expression profiles in B lymphocytes.

description_full:
  Cellular phenotypes are determined by the differential activity of networks linking coregulated genes. Available methods for the reverse engineering of such networks from genome-wide expression profiles have been successful only in the analysis of lower eukaryotes with simple genomes. Using a new method called ARACNe (algorithm for the reconstruction of accurate cellular networks), we report the reconstruction of regulatory networks from expression profiles of human B cells. The results are suggestive a hierarchical, scale-free network, where a few highly interconnected genes (hubs) account for most of the interactions. Validation of the network against available data led to the identification of MYC as a major hub, which controls a network comprising known target genes as well as new ones, which were biochemically validated. The newly identified MYC targets include some major hubs. This approach can be generally useful for the analysis of normal and pathologic networks in mammalian cells.


systematic_name: M17372
exact_source: GSE1897: top 100 down-regulated in Myc/Tgfa; convertied to human orthologs
source_species_code: MM
GEO_id: GSE1897
contributor: Yujin Hoshida
contrib_organization: Broad Institute
description_brief:
  Genes down-regulated in hepatocellular carcinoma (HCC) tissue of MYC and TGFA [GeneID=4609;7039] double transgenic mice.

description_full:
[cell repeats an earlier one in this file: 1235 characters]


description_brief: The cyclin D1 signature: genes whose expression correlated with the levels of CCND1 [GeneID=595].
systematic_name: M2935
exact_source: Fig 2
source_species_code: HS
contributor: Jean Junior
contrib_organization: MSigDB Team
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: M11840
exact_source: Table 1S
source_species_code: DR
contributor: Jennifer Shepard
contrib_organization: Broad Institute
description_brief:
  Human orthologs of genes down-regulated in zebra fish after knockdown of BMYB [GeneID=4605] by morpholino.

description_full:
  A major goal of cancer research has been to identify genes that contribute to cancer formation. The similar pathology between zebrafish and human tumors, as well as the past success of large-scale genetic screens in uncovering human disease genes, makes zebrafish an ideal system in which to find such new genes. Here, we show that a zebrafish forward genetic screen uncovered multiple cell proliferation mutants including one mutant, crash&burn (crb), that represents a loss-of-function mutation in bmyb, a transcriptional regulator and member of a putative proto-oncogene family. crb mutant embryos have defects in mitotic progression and spindle formation, and exhibit genome instability. Regulation of cyclin B levels by bmyb appears to be the mechanism of mitotic accumulation in crb. Carcinogenesis studies reveal increased cancer susceptibility in adult crb heterozygotes. Gene-expression signatures associated with loss of bmyb in zebrafish are also correlated with conserved signatures in human tumor samples, and down-regulation of the B-myb signature genes is associated with retention of p53 function. Our findings show that zebrafish screens can uncover cancer pathways, and demonstrate that loss of function of bmyb is associated with cancer.


description_brief: Primary up-regulated targets of TP53 [GeneID=7157] in the H1299 (lung cancer) cell line.
systematic_name: M16229
exact_source: Table 1
source_species_code: HS
contributor: Pablo Tamayo
contrib_organization: MSigDB Team
description_full:
  The transcriptional program regulated by the tumor suppressor p53 was analysed using oligonucleotide microarrays. A human lung cancer cell line that expresses the temperature sensitive murine p53 was utilized to quantitate mRNA levels of various genes at different time points after shifting the temperature to 32 degrees C. Inhibition of protein synthesis by cycloheximide (CHX) was used to distinguish between primary and secondary target genes regulated by p53. In the absence of CHX, 259 and 125 genes were up or down-regulated respectively; only 38 and 24 of these genes were up and down-regulated by p53 also in the presence of CHX and are considered primary targets in this cell line. Cluster analysis of these data using the super paramagnetic clustering (SPC) algorithm demonstrate that the primary genes can be distinguished as a single cluster among a large pool of p53 regulated genes. This procedure identified additional genes that co-cluster with the primary targets and can also be classified as such genes. In addition to cell cycle (e.g. p21, TGF-beta, Cyclin E) and apoptosis (e.g. Fas, Bak, IAP) related genes, the primary targets of p53 include genes involved in many aspects of cell function, including cell adhesion (e.g. Thymosin, Smoothelin), signaling (e.g. H-Ras, Diacylglycerol kinase), transcription (e.g. ATF3, LISCH7), neuronal growth (e.g. Ninjurin, NSCL2) and DNA repair (e.g. BTG2, DDB2). The results suggest that p53 activates concerted opposing signals and exerts its effect through a diverse network of transcriptional changes that collectively alter the cell phenotype in response to stress.


systematic_name: M15973
exact_source: unknown
source_species_code: DR
contributor: Jennifer Shepard
contrib_organization: Broad Institute
description_brief:
  Human orthologs of BMYB [GeneID=4605] target genes in zebra fish, identified as commonly changed in the BMYB loss of function mutant crb ('crush and burn') and after knockdown of BMYB by morpholino.

description_full:
  A major goal of cancer research has been to identify genes that contribute to cancer formation. The similar pathology between zebrafish and human tumors, as well as the past success of large-scale genetic screens in uncovering human disease genes, makes zebrafish an ideal system in which to find such new genes. Here, we show that a zebrafish forward genetic screen uncovered multiple cell proliferation mutants including one mutant, crash&burn (crb), that represents a loss-of-function mutation in bmyb, a transcriptional regulator and member of a putative proto-oncogene family. crb mutant embryos have defects in mitotic progression and spindle formation, and exhibit genome instability. Regulation of cyclin B levels by bmyb appears to be the mechanism of mitotic accumulation in crb. Carcinogenesis studies reveal increased cancer susceptibility in adult crb heterozygotes. Gene-expression signatures associated with loss of bmyb in zebrafish are also correlated with conserved signatures in human tumor samples, and down-regulation of the B-myb signature genes is associated with retention of p53 function. Our findings show that zebrafish screens can uncover cancer pathways, and demonstrate that loss of function of bmyb is associated with cancer.


systematic_name: M19467
exact_source: GSE569: bottom 100 from COLON_TNFA DERMAL_TNFA ILIAC_TNFA AORTIC_TNFA LUNG_TNFA
source_species_code: HS
GEO_id: GSE569
contributor: Yujin Hoshida
contrib_organization: Broad Institute
description_brief:
  Genes down-regulated in five primary endothelial cell types (lung, aortic, iliac, dermal, and colon) by TNF [GeneID=7124].

description_full:
  To investigate the potential molecular mediators of tissue-specific recruitment, we explored the influence of different cytokine challenges on gene expression regulation in five primary endothelial cells (ECs), representing two different phenotypes: iliac artery and aortic (macrovascular); lung, colon and dermal (microvascular). We challenged ECs with cytokines that elicit different patterns of inflammatory and immune responses in immune cells: tumor necrosis factor (TNF-alpha), interferon-gamma (IFN-gamma) or interleukin-4 (IL-4), and used microarrays containing approximately 40,000 unique cDNAs, to assess changes in differential gene expression relative to untreated cells. Five hundred and sixty three sequences changed by at least 2.5 fold in one or more of the 15 possible EC /cytokine combinations. The list included highly regulated adhesion molecules, chemokines, cytokines, metalloproteases, and IFN-gamma-induced genes. Overall, IFN-gamma caused the largest number of gene expression changes and its profile was least correlated with IL-4. In addition to clusters that were predominantly EC/cytokine specific, we also observed several clusters that were regulated by more than one cytokine across several ECs. Furthermore, we identified genes that were reciprocally expressed in response to different cytokines that could serve as markers of inflammatory and immune expression. These results confirm the importance of microenvironment in primary ECs that could have important applications in developing targeted therapies for vascular diseases.


systematic_name: M5071
exact_source: Table 4: genes downregulated in G2 in comparison with G1
source_species_code: HS
contributor: Yujin Hoshida
contrib_organization: Broad Institute
description_brief:
  Genes up-regulated during transition from G1 (well differentiated tumor, infected with HCV) to G2 (moderately differentiated tumor, infected with HCV) in the development of hepatocellular carcinoma.

description_full:
[cell repeats an earlier one in this file: 1084 characters]


systematic_name: M10814
exact_source: Table 2A: HuGeneFL and Hu95Av2
source_species_code: HS
contributor: Jean Junior
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in a breast cancer cell line resistant to tamoxifen [PubChem=5376] compared to the parental line sensitive to the drug.

description_full:
  The reasons why human mammary tumors become resistant to tamoxifen therapy are mainly unknown. Changes in gene expression may occur as cells acquire resistance to antiestrogens. We therefore undertook a comparative gene expression analysis of tamoxifen-sensitive and tamoxifen-resistant human breast cancer in vivo models using Affymetrix oligonucleotide arrays to analyze differential gene expression. Total RNAs from the tamoxifen-sensitive patient-derived mammary carcinoma xenograft MaCa 3366 and the tamoxifen-resistant model MaCa 3366/TAM were hybridized to Affymetrix HuGeneFL and to Hu95Av2 arrays. Pairwise comparisons and clustering algorithms were applied to identify differentially expressed genes and patterns of gene expression. As revealed by cluster analysis, the tamoxifen-sensitive and the tamoxifen-resistant breast carcinomas differed regarding their gene expression pattern. More than 100 transcripts are changed in abundance in MaCa 3366/TAM as compared with MaCa 3366. Among the genes that are differentially expressed in the tamoxifen-resistant tumors, there are several IFN-inducible and estrogen-responsive genes, and genes known to be involved in breast carcinogenesis. The genes neuronatin (NNAT) and bone marrow stem cell antigen 2 (BST2) were sharply up-regulated in MaCa 3366/TAM. The differential expression of four genes (NNAT, BST2, IGFBP5, and BCAS1) was confirmed by Taqman PCR. Our results provide the starting point for deriving markers for tamoxifen resistance by differential gene expression profiling in a human breast cancer model of acquired tamoxifen resistance. Finally, genes whose expression profiles are distinctly changed between the two xenograft lines will be further evaluated as potential targets for diagnostic or therapeutic approaches of tamoxifen-resistant breast cancer.


systematic_name: M2148
exact_source: unknown
source_species_code: DR
contributor: Jennifer Shepard
contrib_organization: Broad Institute
description_brief:
  Human orthologs of genes down-regulated in the crb ('crash and burn') zebrafish mutant that represents a loss-of-function mutation in BMYB [GeneID=4605].

description_full:
[cell repeats an earlier one in this file: 1256 characters]


systematic_name: M13763
exact_source: Table 1
source_species_code: HS
contributor: Yujin Hoshida
contrib_organization: Broad Institute
description_brief:
  Genes up-regulated in primary hepatocytes and Hep3B (hepatocyte) cells in response to IFNA [GeneID=3439].

description_full:
  BACKGROUND & AIMS: Interferon (IFN)-alpha therapy is currently the primary choice for viral hepatitis and a promising treatment for hepatocellular carcinoma (HCC). Primary mouse and rat hepatocytes respond poorly to IFN-alpha stimulation. Thus, it is very important to examine the IFN-alpha signal pathway in primary human hepatocytes. METHODS: The IFN-alpha-activated signals and genes in primary human hepatocytes and hepatoma cells were examined by Western blotting and microarray analyses. RESULTS: Primary human hepatocytes respond very well to IFN-alpha stimulation as shown by activation of multiple signal transducer and activator of transcription factor (STAT) 1, 2, 3, 5, and multiple genes. The differential response to IFN-alpha stimulation in primary human and mouse hepatocytes may be caused by expression of predominant functional IFN-alpha receptor 2c (IFNAR2c) in primary human hepatocytes vs. expression of predominant inhibitory IFNAR2a in mouse hepatocytes. Microarray analyses of primary human hepatocytes show that IFN-alpha up-regulates about 44 genes by over 2-fold and down-regulates about 9 genes by 50%. The up-regulated genes include a variety of antiviral and tumor suppressors/proapoptotic genes. The down-regulated genes include c-myc and c-Met, the hepatocyte growth factor (HGF) receptor. Down-regulation of c-Met is caused by IFN-alpha suppression of the c-Met promoter through down-regulation of Sp1 binding and results in attenuation of HGF-induced signals and cell proliferation. CONCLUSIONS: IFN-alpha directly targets human hepatocytes, followed by activation of multiple STATs and regulation of a wide variety of genes, which may contribute to the antiviral and antitumor activities of IFN-alpha in human liver.


systematic_name: M1409
exact_source: Table 3S: up-regulated genes
source_species_code: HS
contributor: Kate Stafford
contrib_organization: MSigDB Team
description_brief:
  Cell proliferation genes up-regulated by histone deacetylase (HDAC) inhibitors SAHA and depsipeptide [PubChem=5311;5352062].

description_full:
  Histone deacetylase inhibitors (HDACis) inhibit tumor cell growth and survival, possibly through their ability to regulate the expression of specific proliferative and/or apoptotic genes. However, the HDACi-regulated genes necessary and/or sufficient for their biological effects remain undefined. We demonstrate that the HDACis suberoylanilide hydroxamic acid (SAHA) and depsipeptide regulate a highly overlapping gene set with at least 22% of genes showing altered expression over a 16-h culture period. SAHA and depsipeptide coordinately regulated the expression of several genes within distinct apoptosis and cell cycle pathways. Multiple genes within the Myc, type beta TGF, cyclin/cyclin-dependent kinase, TNF, Bcl-2, and caspase pathways were regulated in a manner that favored induction of apoptosis and decreased cellular proliferation. APAF-1, a gene central to the intrinsic apoptotic pathway, was induced by SAHA and depsipeptide and shown to be important, but not essential, for HDACi-induced cell death. Overexpression of p16(INK4A) and arrest of cells in G(1) can suppress HDACi-mediated apoptosis. Although p16(INK4A) did not affect the genome-wide transcription changes mediated by SAHA, a small number of apoptotic genes, including BCLXL and B-MYB, were differentially regulated in a manner consistent with attenuated HDACi-mediated apoptosis in arrested cells. We demonstrate that different HDACi alter transcription of a large and common set of genes that control diverse molecular pathways important for cell survival and proliferation. The ability of HDACi to target multiple apoptotic and cell proliferation pathways may provide a competitive advantage over other chemotherapeutic agents because suppression/loss of a single pathway may not confer resistance to these agents.


systematic_name: M4707
exact_source: Table 5: genes upregulated in G3 in comparison with G2
source_species_code: HS
contributor: Yujin Hoshida
contrib_organization: Broad Institute
description_brief:
  Genes down-regulated during transition from G2 (moderately differentiated tumor, infected with HCV) to G3 (poorly differentiated tumor, infected with HCV) in the development of hepatocellular carcinoma.

description_full:
[cell repeats an earlier one in this file: 1084 characters]


systematic_name: M3274
exact_source: Fig 2: upper panel
source_species_code: HS
contributor: Jean Junior
contrib_organization: MSigDB Team
description_brief:
  Top up-regulated marker genes for medulloblastoma classification: desmoplastic vs classic morphology.

description_full:
  Embryonal tumours of the central nervous system (CNS) represent a heterogeneous group of tumours about which little is known biologically, and whose diagnosis, on the basis of morphologic appearance alone, is controversial. Medulloblastomas, for example, are the most common malignant brain tumour of childhood, but their pathogenesis is unknown, their relationship to other embryonal CNS tumours is debated, and patients' response to therapy is difficult to predict. We approached these problems by developing a classification system based on DNA microarray gene expression data derived from 99 patient samples. Here we demonstrate that medulloblastomas are molecularly distinct from other brain tumours including primitive neuroectodermal tumours (PNETs), atypical teratoid/rhabdoid tumours (AT/RTs) and malignant gliomas. Previously unrecognized evidence supporting the derivation of medulloblastomas from cerebellar granule cells through activation of the Sonic Hedgehog (SHH) pathway was also revealed. We show further that the clinical outcome of children with medulloblastomas is highly predictable on the basis of the gene expression profiles of their tumours at diagnosis.


systematic_name: M10209
exact_source: Table 1S
source_species_code: DR
contributor: Jennifer Shepard
contrib_organization: Broad Institute
description_brief:
  Human orthologs of genes up-regulated in zebra fish after knockdown of BMYB [GeneID=4605] by morpholino.

description_full:
[cell repeats an earlier one in this file: 1256 characters]


systematic_name: M18562
exact_source: Table 2S
source_species_code: HS
contributor: Kate Stafford
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in response to both hypoxia and overexpression of an active form of HIF1A [GeneID=3091].

description_full:
  Hypoxia-inducible factor 1 (HIF-1) activates transcription of genes encoding angiogenic growth factors, which are secreted by hypoxic cells and stimulate endothelial cells, leading to angiogenesis. To determine whether HIF-1 also mediates cell-autonomous responses to hypoxia, we have compared gene expression profiles in arterial endothelial cells cultured under nonhypoxic versus hypoxic conditions and in nonhypoxic cells infected with adenovirus encoding beta-galactosidase versus a constitutively active form of HIF-1alpha (AdCA5). There were 245 gene probes that showed at least 1.5-fold increase in expression in response to hypoxia and in response to AdCA5; 325 gene probes showed at least 1.5-fold decrease in expression in response to hypoxia and in response to AdCA5. The largest category of genes down-regulated by both hypoxia and AdCA5 encoded proteins involved in cell growth/proliferation. Many genes up-regulated by both hypoxia and AdCA5 encoded cytokines/growth factors, receptors, and other signaling proteins. Transcription factors accounted for the largest group of HIF-1-regulated genes, indicating that HIF-1 controls a network of transcriptional responses to hypoxia in endothelial cells. Infection of endothelial cells with AdCA5 under nonhypoxic conditions was sufficient to induce increased basement membrane invasion and tube formation similar to the responses induced by hypoxia, indicating that HIF-1 mediates cell-autonomous activation of endothelial cells.


systematic_name: M1414
exact_source: Table 1: Discriminating score < 0
source_species_code: HS
contributor: Kate Stafford
contrib_organization: MSigDB Team
description_brief:
  Down-regulated genes discriminating multiple myeloma samples by type of immunoglobulin they produce: IgG vs IgA.

description_full:
[cell repeats an earlier one in this file: 1711 characters]


systematic_name: M5636
exact_source: GSE1897: top 100 down-regulated in Myc/E2f1; convertied to human orthologs
source_species_code: MM
GEO_id: GSE1897
contributor: Yujin Hoshida
contrib_organization: Broad Institute
description_brief:
  Genes down-regulated in hepatocellular carcinoma (HCC) from MYC and E2F1 [GeneID=4609;1869] double transgenic mice.

description_full:
[cell repeats an earlier one in this file: 1235 characters]


systematic_name: M13903
exact_source: Table 1S
source_species_code: HS
contributor: Pablo Tamayo
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in LNCaP cells (prostate cancer) in response to synthetic androgen R1881 [PubChem=13766].

description_full:
  The human prostate gland is an important target organ of androgenic hormones. Testosterone and dihydrotestosterone interact with the androgen receptor to regulate vital aspects of prostate growth and function including cellular proliferation, differentiation, apoptosis, metabolism, and secretory activity. Our objective in this study was to characterize the temporal program of transcription that reflects the cellular response to androgens and to identify specific androgen-regulated genes (ARGs) or gene networks that participate in these responses. We used cDNA microarrays representing about 20,000 distinct human genes to profile androgen-responsive transcripts in the LNCaP adenocarcinoma cell line and identified 146 genes with transcript alterations more than 3-fold. Of these, 103 encode proteins with described functional roles, and 43 represent transcripts that have yet to be characterized. Temporal gene expression profiles grouped the ARGs into four distinct cohorts. Five uncharacterized ARGs demonstrated exclusive or high expression levels in the prostate relative to other tissues studied. A search of available DNA sequence upstream of 28 ARGs identified 25 with homology to the androgen response-element consensus-binding motif. These results identify previously uncharacterized and unsuspected genes whose expression levels are directly or indirectly regulated by androgens; further, they provide a comprehensive temporal view of the transcriptional program of human androgen-responsive cells.


systematic_name: M9826
exact_source: Table 2S: correlation <= -0.3
source_species_code: HS
contributor: Jean Junior
contrib_organization: MSigDB Team
description_brief:
  Genes whose expression is significantly and negatively correlated with poor breast cancer clinical outcome (defined as developing distant metastases in less than 5 years).

description_full:
[cell repeats an earlier one in this file: 1349 characters]


systematic_name: M8244
exact_source: Table 1S
source_species_code: HS
contributor: Kate Stafford
contrib_organization: MSigDB Team
description_brief:
  Genes changed in INA-6 cells (multiple myeloma, MM) by re-addition of IL6 [GeneID=3569] after its initial withdrawal for 12h.

description_full:
  Interleukin 6 (IL-6) is a growth and survival factor for multiple myeloma cells. As we report here, the IL-6-dependent human myeloma cell line INA-6 responds with a remarkably rapid and complete apoptosis to cytokine withdrawal. Among the antiapoptotic members of the B-cell lymphoma-2 (Bcl-2) family of apoptosis regulators, only myeloid cell factor-1 (Mcl-1) was slightly induced by IL-6. Overexpression studies demonstrated, however, that IL-6 does not exert its survival effect primarily through this pathway. The IL-6 signal transduction pathways required for survival and the target genes controlled by them were analyzed by using mutated receptor chimeras. The activation of signal transducer and activator of transcription 3 (Stat3) turned out to be obligatory for the survival of INA-6 cells. The same held true for survival and growth of XG-1 myeloma cells. Gene expression profiling of INA-6 cells by using oligonucleotide microarrays revealed many novel IL-6 target genes, among them several genes coding for transcriptional regulators involved in B-lymphocyte differentiation as well as for growth factors and receptors potentially implicated in autocrine or paracrine growth control. Regulation of most IL-6 target genes required the activation of Stat3, underscoring its central role for IL-6 signal transduction. Taken together, our data provide evidence for the existence of an as yet unknown Stat3-dependent survival pathway in myeloma cells.


systematic_name: M8510
exact_source: Fig 2: lower panel
source_species_code: HS
contributor: Jean Junior
contrib_organization: MSigDB Team
description_brief:
  Top down-regulated marker genes for medulloblastoma classification: desmoplastic vs classic morphology.

description_full:
  Embryonal tumours of the central nervous system (CNS) represent a heterogeneous group of tumours about which little is known biologically, and whose diagnosis, on the basis of morphologic appearance alone, is controversial. Medulloblastomas, for example, are the most common malignant brain tumour of childhood, but their pathogenesis is unknown, their relationship to other embryonal CNS tumours is debated, and patients' response to therapy is difficult to predict. We approached these problems by developing a classification system based on DNA microarray gene expression data derived from 99 patient samples. Here we demonstrate that medulloblastomas are molecularly distinct from other brain tumours including primitive neuroectodermal tumours (PNETs), atypical teratoid/rhabdoid tumours (AT/RTs) and malignant gliomas. Previously unrecognized evidence supporting the derivation of medulloblastomas from cerebellar granule cells through activation of the Sonic Hedgehog (SHH) pathway was also revealed. We show further that the clinical outcome of children with medulloblastomas is highly predictable on the basis of the gene expression profiles of their tumours at diagnosis.


systematic_name: M6752
exact_source: Table 4
source_species_code: HS
GEO_id: GSE997,GSE567
contributor: Kate Stafford
contrib_organization: MSigDB Team
description_brief:
  Genes essential to the development of megakaryocytes, as expressed in normal cells and essential thrombocythemic cells (ET).

description_full:
  Gene expression profiles of bone marrow (BM) CD34-derived megakaryocytic cells (MKs) were compared in patients with essential thrombocythemia (ET) and healthy subjects using oligonucleotide microarray analysis to identify differentially expressed genes and disease-specific transcripts. We found that proapoptotic genes such as BAX, BNIP3, and BNIP3L were down-regulated in ET MKs together with genes that are components of the mitochondrial permeability transition pore complex, a system with a pivotal role in apoptosis. Conversely, antiapoptotic genes such as IGF1-R and CFLAR were up-regulated in the malignant cells, as was the SDF1 gene, which favors cell survival. On the basis of the array results, we characterized apoptosis of normal and ET MKs by time-course evaluation of annexin-V and sub-G1 peak DNA stainings of immature and mature MKs after culture in serum-free medium with an optimal thrombopoietin concentration, and annexin-V-positive MKs only, with decreasing thrombopoietin concentrations. ET MKs were more resistant to apoptosis than their normal counterparts. We conclude that imbalance between proliferation and apoptosis seems to be an important step in malignant ET megakaryocytopoiesis.


systematic_name: M5133
exact_source: Table 1: fold induction > 0
source_species_code: HS
contributor: Yujin Hoshida
contrib_organization: Broad Institute
description_brief:
  Genes up-regulated in Jurkat cells (T lymphocyte) by expression of a constitutively active form of IRF3 [GeneID=3661].

description_full:
  Ubiquitously expressed interferon regulatory factor 3 (IRF-3) is directly activated after virus infection and functions as a key activator of the immediate-early alpha/beta interferon (IFN) genes, as well as the RANTES chemokine gene. In the present study, a tetracycline-inducible expression system expressing a constitutively active form of IRF-3 (IRF-3 5D) was combined with DNA microarray analysis to identify target genes regulated by IRF-3. Changes in mRNA expression profiles of 8,556 genes were monitored after Tet-inducible expression of IRF-3 5D. Among the genes upregulated by IRF-3 were transcripts for several known IFN-stimulated genes (ISGs). Subsequent analysis revealed that IRF-3 directly induced the expression of ISG56 in an IFN-independent manner through the IFN-stimulated responsive elements (ISREs) of the ISG56 promoter. These results demonstrate that, in addition to its role in the formation of a functional immediate-early IFN-beta enhanceosome, IRF-3 is able to discriminate among ISRE-containing genes involved in the establishment of the antiviral state as a direct response to virus infection.


systematic_name: M19681
exact_source: Final annotated Gene list PBL C vs Tx up in Tx
source_species_code: HS
GEO_id: GSE1563
contributor: Jean Junior
contrib_organization: MSigDB Team
description_brief:
  Genes upregulated in peripheral blood lymphocytes (PBL) from patients with well functioning kidneys more than 1-year post transplant compared to those from normal living kidney donors.

description_full:
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systematic_name: M18264
exact_source: Suppl. file: all_pathways/OXPHOS_HG-U133A_probes
source_species_code: HS
contributor: Vamsi Mootha
contrib_organization: Broad Institute
description_brief:
  Genes involved in oxidative phosphorylation; based on literature and sequence annotation resources and converted to Affymetrix HG-U133A probe sets.

description_full:
  DNA microarrays can be used to identify gene expression changes characteristic of human disease. This is challenging, however, when relevant differences are subtle at the level of individual genes. We introduce an analytical strategy, Gene Set Enrichment Analysis, designed to detect modest but coordinate changes in the expression of groups of functionally related genes. Using this approach, we identify a set of genes involved in oxidative phosphorylation whose expression is coordinately decreased in human diabetic muscle. Expression of these genes is high at sites of insulin-mediated glucose disposal, activated by PGC-1alpha and correlated with total-body aerobic capacity. Our results associate this gene set with clinically important variation in human metabolism and illustrate the value of pathway relationships in the analysis of genomic profiling experiments.


systematic_name: M3682
exact_source: Final annotated Gene list PBL Tx vs AR down in AR
source_species_code: HS
GEO_id: GSE1563
contributor: Jean Junior
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in peripheral blood lymphocytes (PBL) from patients with acute transplant rejection compared to those from patients with well functioning kidneys more than 1-year post transplant.

description_full:
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systematic_name: M4551
exact_source: GSE569: top 100 of COLON_IFNG DERMAL_IFNG ILIAC_IFNG AORTIC_IFNG LUNG_IFNG
source_species_code: HS
GEO_id: GSE569
contributor: Yujin Hoshida
contrib_organization: Broad Institute
description_brief:
  Genes up-regulated in five primary endothelial cell types (lung, aortic, iliac, dermal, and colon) by IFNG [GeneID=3458].

description_full:
  To investigate the potential molecular mediators of tissue-specific recruitment, we explored the influence of different cytokine challenges on gene expression regulation in five primary endothelial cells (ECs), representing two different phenotypes: iliac artery and aortic (macrovascular); lung, colon and dermal (microvascular). We challenged ECs with cytokines that elicit different patterns of inflammatory and immune responses in immune cells: tumor necrosis factor (TNF-alpha), interferon-gamma (IFN-gamma) or interleukin-4 (IL-4), and used microarrays containing approximately 40,000 unique cDNAs, to assess changes in differential gene expression relative to untreated cells. Five hundred and sixty three sequences changed by at least 2.5 fold in one or more of the 15 possible EC /cytokine combinations. The list included highly regulated adhesion molecules, chemokines, cytokines, metalloproteases, and IFN-gamma-induced genes. Overall, IFN-gamma caused the largest number of gene expression changes and its profile was least correlated with IL-4. In addition to clusters that were predominantly EC/cytokine specific, we also observed several clusters that were regulated by more than one cytokine across several ECs. Furthermore, we identified genes that were reciprocally expressed in response to different cytokines that could serve as markers of inflammatory and immune expression. These results confirm the importance of microenvironment in primary ECs that could have important applications in developing targeted therapies for vascular diseases.


systematic_name: M17466
exact_source: GSE569: top 100 from COLON_TNFA DERMAL_TNFA ILIAC_TNFA AORTIC_TNFA LUNG_TNFA
source_species_code: HS
GEO_id: GSE569
contributor: Yujin Hoshida
contrib_organization: Broad Institute
description_brief:
  Genes up-regulated in five primary endothelial cell types (lung, aortic, iliac, dermal, and colon) by TNF [GeneID=7124].

description_full:
  To investigate the potential molecular mediators of tissue-specific recruitment, we explored the influence of different cytokine challenges on gene expression regulation in five primary endothelial cells (ECs), representing two different phenotypes: iliac artery and aortic (macrovascular); lung, colon and dermal (microvascular). We challenged ECs with cytokines that elicit different patterns of inflammatory and immune responses in immune cells: tumor necrosis factor (TNF-alpha), interferon-gamma (IFN-gamma) or interleukin-4 (IL-4), and used microarrays containing approximately 40,000 unique cDNAs, to assess changes in differential gene expression relative to untreated cells. Five hundred and sixty three sequences changed by at least 2.5 fold in one or more of the 15 possible EC /cytokine combinations. The list included highly regulated adhesion molecules, chemokines, cytokines, metalloproteases, and IFN-gamma-induced genes. Overall, IFN-gamma caused the largest number of gene expression changes and its profile was least correlated with IL-4. In addition to clusters that were predominantly EC/cytokine specific, we also observed several clusters that were regulated by more than one cytokine across several ECs. Furthermore, we identified genes that were reciprocally expressed in response to different cytokines that could serve as markers of inflammatory and immune expression. These results confirm the importance of microenvironment in primary ECs that could have important applications in developing targeted therapies for vascular diseases.


systematic_name: M1424
exact_source: GSE1897: top 100 down-regulated in DENA; converted to human orthologs
source_species_code: MM
GEO_id: GSE1897
contributor: Yujin Hoshida
contrib_organization: Broad Institute
description_brief:
  Genes down-regulated in hepatocellular carcinoma (HCC) induced by diethylnitrosamine (DENA) [PubChem=5921].

description_full:
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systematic_name: M9583
exact_source: GSE569: bottom 100 of COLON_IFNG DERMAL_IFNG ILIAC_IFNG AORTIC_IFNG LUNG_IFNG
source_species_code: HS
GEO_id: GSE569
contributor: Yujin Hoshida
contrib_organization: Broad Institute
description_brief:
  Genes down-regulated in five primary endothelial cell types (lung, aortic, iliac, dermal, and colon) by IFNG [GeneID=3458].

description_full:
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systematic_name: M18496
exact_source: GSE1897: top 100 down-regulated in Myc; converted to human orthologs
source_species_code: MM
GEO_id: GSE1897
contributor: Yujin Hoshida
contrib_organization: Broad Institute
description_brief:
  Genes down-regulated in hepatocellular carcinoma (HCC) induced by overexpression of MYC [GeneID=4609].

description_full:
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description_brief: Genes up-regulated in peripheral B lymphocytes after incubation with IL4 [GeneID=3565] for 4 h.
systematic_name: M10558
exact_source: Table 1S
source_species_code: HS
contributor: Kate Stafford
contrib_organization: MSigDB Team
description_full:
  Diffuse large B-cell lymphomas (DLBCLs) can be subclassified into germinal center B-cell (GCB)-like and activated B-cell (ABC)-like tumors characterized by long and short survival, respectively. In contrast to ABC-like DLBCL, GCB-like tumors exhibit high expression of components of the interleukin 4 (IL-4) signaling pathway and of IL-4 target genes such as BCL6 and HGAL, whose high expression independently predicts better survival. These observations suggest distinct activity of the IL-4 signaling pathway in DLBCL subtypes. Herein, we demonstrate similar IL-4 expression but qualitatively different IL-4 effects on GCB-like and ABC-like DLBCL. In GCB-like DLBCL, IL-4 induces expression of its target genes, activates signal transducers and activators of transcription 6 (STAT6) signaling, and increases cell proliferation. In contrast, in the ABC-like DLBCL, IL-4 activates AKT, decreases cell proliferation by cell cycle arrest, and does not induce gene expression due to aberrant Janus kinase (JAK)-STAT6 signaling attributed to STAT6 dephosphorylation. We found distinct expression profiles of tyrosine phosphatases in DLBCL subtypes and identified putative STAT6 tyrosine phosphatases-protein tyrosine phosphatase nonreceptor type 1 (PTPN1) and PTPN2, whose expression is significantly higher in ABC-like DLBCL. These differences in tyrosine phosphatase expression might underlie distinct expression profiles of some of the IL-4 target genes and could contribute to a different clinical outcome of patients with GCB-like and ABC-like DLBCLs.


systematic_name: M4175
exact_source: Fig 2: the LYL+ panel
source_species_code: HS
contributor: Jean Junior
contrib_organization: MSigDB Team
description_brief:
  Nearest neighbors of LYL1 [GeneID=4066], based on the close agreement of their expression profiles with that of LYL1 in pediatric T cell acute lymphoblastic leukemia (T-ALL).

description_full:
  Human T cell leukemias can arise from oncogenes activated by specific chromosomal translocations involving the T cell receptor genes. Here we show that five different T cell oncogenes (HOX11, TAL1, LYL1, LMO1, and LMO2) are often aberrantly expressed in the absence of chromosomal abnormalities. Using oligonucleotide microarrays, we identified several gene expression signatures that were indicative of leukemic arrest at specific stages of normal thymocyte development: LYL1+ signature (pro-T), HOX11+ (early cortical thymocyte), and TAL1+ (late cortical thymocyte). Hierarchical clustering analysis of gene expression signatures grouped samples according to their shared oncogenic pathways and identified HOX11L2 activation as a novel event in T cell leukemogenesis. These findings have clinical importance, since HOX11 activation is significantly associated with a favorable prognosis, while expression of TAL1, LYL1, or, surprisingly, HOX11L2 confers a much worse response to treatment. Our results illustrate the power of gene expression profiles to elucidate transformation pathways relevant to human leukemia.


systematic_name: M500
exact_source: Table 2S: correlation >= 0.3
source_species_code: HS
contributor: Jean Junior
contrib_organization: MSigDB Team
description_brief:
  Genes whose expression is significantly and positively correlated with poor breast cancer clinical outcome (defined as developing distant metastases in less than 5 years).

description_full:
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description_brief: Genes up-regulated in 293T (transformed fetal renal cell) upon expression of MYC [GeneID=4609].
systematic_name: M5955
exact_source: Table 1: induced genes
source_species_code: HS
contributor: Yujin Hoshida
contrib_organization: Broad Institute
description_full:
  MYC affects normal and neoplastic cell proliferation by altering gene expression, but the precise pathways remain unclear. We used oligonucleotide microarray analysis of 6,416 genes and expressed sequence tags to determine changes in gene expression caused by activation of c-MYC in primary human fibroblasts. In these experiments, 27 genes were consistently induced, and 9 genes were repressed. The identity of the genes revealed that MYC may affect many aspects of cell physiology altered in transformed cells: cell growth, cell cycle, adhesion, and cytoskeletal organization. Identified targets possibly linked to MYC's effects on cell growth include the nucleolar proteins nucleolin and fibrillarin, as well as the eukaryotic initiation factor 5A. Among the cell cycle genes identified as targets, the G1 cyclin D2 and the cyclin-dependent kinase binding protein CksHs2 were induced whereas the cyclin-dependent kinase inhibitor p21(Cip1) was repressed. A role for MYC in regulating cell adhesion and structure is suggested by repression of genes encoding the extracellular matrix proteins fibronectin and collagen, and the cytoskeletal protein tropomyosin. A possible mechanism for MYC-mediated apoptosis was revealed by identification of the tumor necrosis factor receptor associated protein TRAP1 as a MYC target. Finally, two immunophilins, peptidyl-prolyl cis-trans isomerase F and FKBP52, the latter of which plays a role in cell division in Arabidopsis, were up-regulated by MYC. We also explored pattern-matching methods as an alternative approach for identifying MYC target genes. The genes that displayed an expression profile most similar to endogenous Myc in microarray-based expression profiling of myeloid differentiation models were highly enriched for MYC target genes.


systematic_name: M259
exact_source: Table 1S
source_species_code: HS
contributor: Kate Stafford
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in response to both hypoxia and overexpression of an active form of HIF1A [GeneID=3091].

description_full:
  Hypoxia-inducible factor 1 (HIF-1) activates transcription of genes encoding angiogenic growth factors, which are secreted by hypoxic cells and stimulate endothelial cells, leading to angiogenesis. To determine whether HIF-1 also mediates cell-autonomous responses to hypoxia, we have compared gene expression profiles in arterial endothelial cells cultured under nonhypoxic versus hypoxic conditions and in nonhypoxic cells infected with adenovirus encoding beta-galactosidase versus a constitutively active form of HIF-1alpha (AdCA5). There were 245 gene probes that showed at least 1.5-fold increase in expression in response to hypoxia and in response to AdCA5; 325 gene probes showed at least 1.5-fold decrease in expression in response to hypoxia and in response to AdCA5. The largest category of genes down-regulated by both hypoxia and AdCA5 encoded proteins involved in cell growth/proliferation. Many genes up-regulated by both hypoxia and AdCA5 encoded cytokines/growth factors, receptors, and other signaling proteins. Transcription factors accounted for the largest group of HIF-1-regulated genes, indicating that HIF-1 controls a network of transcriptional responses to hypoxia in endothelial cells. Infection of endothelial cells with AdCA5 under nonhypoxic conditions was sufficient to induce increased basement membrane invasion and tube formation similar to the responses induced by hypoxia, indicating that HIF-1 mediates cell-autonomous activation of endothelial cells.


systematic_name: M4493
exact_source: Fig. 3
source_species_code: HS
contributor: Yujin Hoshida
contrib_organization: Broad Institute
description_brief:
  Genes whose promoters were bound by E2F1 and E2F4 [GeneID=1869;1874] in the primary fibroblasts WI-38, by ChIP on chip assay.

description_full:
  The E2F transcription factor family is known to play a key role in the timely expression of genes required for cell cycle progression and proliferation, but only a few E2F target genes have been identified. We explored the possibility that E2F regulators play a broader role by identifying additional genes bound by E2F in living human cells. A protocol was developed to identify genomic binding sites for DNA-binding factors in mammalian cells that combines immunoprecipitation of cross-linked protein-DNA complexes with DNA microarray analysis. Among approximately 1200 genes expressed during cell cycle entry, we found that the promoters of 127 were bound by the E2F4 transcription factor in primary fibroblasts. A subset of these targets was also bound by E2F1. Most previously identified target genes known to have roles in DNA replication and cell cycle control and represented on the microarray were confirmed by this analysis. We also identified a remarkable cadre of genes with no previous connection to E2F regulation, including genes that encode components of the DNA damage checkpoint and repair pathways, as well as factors involved in chromatin assembly/condensation, chromosome segregation, and the mitotic spindle checkpoint. Our data indicate that E2F directly links cell cycle progression with the coordinate regulation of genes essential for both the synthesis of DNA as well as its surveillance.


systematic_name: M104
exact_source: Suppl. Data: section 3; DLBCL versus FL Distinction; Distinction = DLBCL
source_species_code: HS
contributor: Jean Junior
contrib_organization: MSigDB Team
description_brief:
  Top 50 up-regulated markers distinguishing diffuse large B-cell lymphoma (DLBCL) from follicular lymphoma (FL) samples.

description_full:
[cell repeats an earlier one in this file: 1284 characters]


systematic_name: M1421
exact_source: Table 3S: down-regulated genes
source_species_code: HS
contributor: Kate Stafford
contrib_organization: MSigDB Team
description_brief:
  Cell proliferation genes down-regulated by histone deacetylase (HDAC) inhibitors SAHA and depsipeptide [PubChem=5311;5352062].

description_full:
  Histone deacetylase inhibitors (HDACis) inhibit tumor cell growth and survival, possibly through their ability to regulate the expression of specific proliferative and/or apoptotic genes. However, the HDACi-regulated genes necessary and/or sufficient for their biological effects remain undefined. We demonstrate that the HDACis suberoylanilide hydroxamic acid (SAHA) and depsipeptide regulate a highly overlapping gene set with at least 22% of genes showing altered expression over a 16-h culture period. SAHA and depsipeptide coordinately regulated the expression of several genes within distinct apoptosis and cell cycle pathways. Multiple genes within the Myc, type beta TGF, cyclin/cyclin-dependent kinase, TNF, Bcl-2, and caspase pathways were regulated in a manner that favored induction of apoptosis and decreased cellular proliferation. APAF-1, a gene central to the intrinsic apoptotic pathway, was induced by SAHA and depsipeptide and shown to be important, but not essential, for HDACi-induced cell death. Overexpression of p16(INK4A) and arrest of cells in G(1) can suppress HDACi-mediated apoptosis. Although p16(INK4A) did not affect the genome-wide transcription changes mediated by SAHA, a small number of apoptotic genes, including BCLXL and B-MYB, were differentially regulated in a manner consistent with attenuated HDACi-mediated apoptosis in arrested cells. We demonstrate that different HDACi alter transcription of a large and common set of genes that control diverse molecular pathways important for cell survival and proliferation. The ability of HDACi to target multiple apoptotic and cell proliferation pathways may provide a competitive advantage over other chemotherapeutic agents because suppression/loss of a single pathway may not confer resistance to these agents.


systematic_name: M15171
exact_source: Table 2
source_species_code: HS
contributor: Kate Stafford
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in adult T-cell leukemia (ATL) cells compared to T lymphocytes from healthy controls.

description_full:
  Adult T-cell leukemia (ATL) caused by human T-cell leukemia virus type 1 (HTLV-1) infection, occurs in 2% to 4% of the HTLV-1 carriers with a long latent period, suggesting that additional alterations participate in the development of ATL. To characterize and identify novel markers of ATL, we examined the expression profiles of more than 12 000 genes in 8 cases of acute-type ATL using microarray. One hundred ninety-two genes containing interleukin 2 (IL-2) receptor alpha were up-regulated more than 2-fold compared with CD4(+) and CD4(+)CD45RO(+) T cells, and tumor suppressor in lung cancer 1 (TSLC1), caveolin 1, and prostaglandin D2 synthase showed increased expression of more than 30-fold. TSLC1 is a cell adhesion molecule originally identified as a tumor suppressor in the lung but lacks its expression in normal or activated T cells. We confirmed ectopic expression of the TSLC1 in all acute-type ATL cells and in 7 of 10 ATL- or HTLV-1-infected T-cell lines. Introduction of TSLC1 into a human ATL cell line ED enhanced both self-aggregation and adhesion ability to vascular endothelial cells. These results suggested that the ectopic expression of TSLC1 could provide a novel marker for acute-type ATL and may participate in tissue invasion, a characteristic feature of the malignant ATL cells.


systematic_name: M15346
exact_source: GSE1897: top 100 down-regulated in E2f1; converted to human orthologs
source_species_code: MM
GEO_id: GSE1897
contributor: Yujin Hoshida
contrib_organization: Broad Institute
description_brief:
  Genes down-regulated in hepatocellular carcinoma (HCC) induced by overexpression of E2F1 [GeneID=1869].

description_full:
[cell repeats an earlier one in this file: 1235 characters]


description_brief: Genes up-regulated in Hc cells (normal hepatocyte) by TNF [GeneID=7124].
systematic_name: M15412
exact_source: Table 1
source_species_code: HS
contributor: Yujin Hoshida
contrib_organization: Broad Institute
description_full:
  Using a cDNA microarray analysis, we identified x-ray-inducible immediate early response factor-1 (IEX-1) as a proapoptotic gene which was induced by TNF-alpha and also depend on NF-kappaB activation in Hc human hepatocytes. In these cells only the original form of IEX-1, termed IEX-1S, but not its longer transcript IEX-1L, was expressed. Overexpression of IEX-1S resulted in promotion of TNF-alpha-induced apoptosis in Hc cells expressing a mutant form of IkappaB. This proapoptotic action can be explained by its inhibitory findings on survival signals; inhibition of TNF-alpha-induced activation and expression of phosphatidylinositol 3-kinase (PI3K)/Akt, and also blockage of expression of Mcl-1, an antiapoptotic Bcl-2 family member which is located downstream of Akt, was inhibited by IEX-1S. LY 294002, an inhibitor of PI3K, increased IEX-1S expression induced by TNF-alpha and accelerated TNF-alpha-induced apoptosis in IkappaB-treated Hc cells. Overexpression of the dominant-negative Akt enhanced, but the constitutively active Akt suppressed, TNF-alpha-induced IEX-1S expression, suggesting that PI3K/Akt negatively regulated IEX-1S expression. These results demonstrate that NF-kappaB-dependent recruitment of IEX-1S may play a proapoptotic role in TNF-alpha-stimulated hepatocytes through blockage of the PI3K/Akt pathway. Moreover, the reciprocal cross-talk between IEX-1S and PI3K/Akt may closely be involved in the regulation of TNF-alpha-induced hepatocyte apoptosis.


systematic_name: M11516
exact_source: Table 2
source_species_code: HS
GEO_id: GSE1036
contributor: Kevin Vogelsang
contrib_organization: MSigDB Team
description_brief:
  Selected genes changed in K562 (immortalized erythroleukemia) cells induced by hemin [PubChem=26945] treatment to express erythroid properties.

description_full:
  Understanding regulation of fetal and embryonic hemoglobin expression is critical, since their expression decreases clinical severity in sickle cell disease and beta-thalassemia. K562 cells, a human erythroleukemia cell line, can differentiate along erythroid or megakaryocytic lineages and serve as a model for regulation of fetal/embryonic globin expression. We used microarray expression profiling to characterize transcriptomes from K562 cells treated for various times with hemin, an inducer of erythroid commitment. Approximately 5,000 genes were expressed irrespective of treatment. Comparative expression analysis (CEA) identified 899 genes as differentially expressed; analysis by the self-organizing map (SOM) algorithm clustered 425 genes into 8 distinct expression patterns, 322 of which were shared by both analyses. Differential expression of a subset of genes was validated by real-time RT-PCR. Analysis of 5'-flanking regions from differentially expressed genes by PAINT v3.0 software showed enrichment in specific transcription regulatory elements (TREs), some localizing to different expression clusters. This finding suggests coordinate regulation of cluster members by specific TREs. Finally, our findings provide new insights into rate-limiting steps in the appearance of heme-containing hemoglobin tetramers in these cells.


description_brief: Genes up-regulated in HEL cells (erythroleukemia) upon expression of ELF4 [GeneID=2000].
systematic_name: M8716
exact_source: Table 1: Increased
source_species_code: HS
contributor: Kevin Vogelsang
contrib_organization: MSigDB Team
description_full:
  Myeloid ELF1-like factor (MEF), also known as ELF4, is a member of the ETS family of transcription factors which is expressed in hematopoietic cells. MEF-deficient mice have defects in natural killer cell and natural killer T cell development, suggesting a role for MEF in regulating innate immunity. MEF also functions in myeloid cells, where it can transactivate target genes. To identify MEF target genes in a myeloid environment, we created an inducible expression system and used oligonucleotide microarrays to examine the transcript profile of HEL cells after induction of MEF expression. Sixteen genes were reproducibly turned on or off more than 2-fold, 8 h after induction of MEF expression, and we examined one of the genes, interleukin-8 (IL-8), in greater detail. IL-8 is a CXC chemokine involved in neutrophil chemoattraction, angiogenesis, and stem cell mobilization. It is expressed by several tumor types, and its expression is regulated primarily transcriptionally. The IL-8 promoter contains three ETS binding sites, and we identified the specific site that binds MEF and is required for MEF responsiveness. MEF, but not the closely related ETS factors PEA3, ETS1, ETS2, ELF1, or PU.1, strongly activates the IL-8 promoter. MEF overexpression is sufficient to induce IL-8 protein expression, and reduction in MEF expression (using RNA interference) results in decreased IL-8 levels. These data demonstrates that MEF is an important regulator of IL-8 expression.


systematic_name: M1276
exact_source: Table 2B
source_species_code: HS
contributor: Kevin Vogelsang
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated synergistically in NB4 cells (acute promyelocytic leukemia, APL) by tretinoin and NSC682994 [PubChem=444795;388304].

description_full:
  Differentiation induction is an effective therapy for acute promyelocytic leukemia (APL), which dramatically responds to all-trans-retinoic acid (ATRA). Recent studies have indicated that combinatorial use of retinoid and nonretinoid compounds, such as histone deacetylase inhibitors, arsenics, and PKA agonists, has higher therapeutic value in this disease and potentially in other malignancies. In a screen of 370 compounds, we identified benzodithiophene analogues as potent enhancers of ATRA-induced APL cell differentiation. These effects were not associated with changes in global histone acetylation and, for the most potent compounds, were exerted at very low nanomolar concentrations, and were paralleled by enhancement of some, but not all, ATRA-modulated gene expressions. Investigating the mechanism underlying the effects of these drugs on ATRA-induced APL cell differentiation, we have shown that benzodithiophenes enhance ATRA-mediated dissociation and association of corepressor N-CoR and coactivator p300 acetyltransferase, respectively, with retinoic acid receptor (RAR) alpha proteins. These data suggest that benzodithiophenes act at the level of receptor activation, possibly by affecting posttranslational modification of the receptor (and/or coregulators), thus leading to an enhancement in ATRA-mediated effects on gene expression and APL cell differentiation. Given the specificities of these low benzodithiophene concentrations for PML-RARalpha and RARalpha, these drugs may be useful for combinatorial differentiation therapy of APL and possibly other acute myelogenous leukemia subtypes in which the overall ATRA signaling is suppressed.


systematic_name: M11695
exact_source: Table 2
source_species_code: HS
GEO_id: GSE1153
contributor: Kevin Vogelsang
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated by estradiol (E2) [PubChem=5757] in U2OS cells (osteosarcoma) expressing ESR1 or ESR2 [GeneID=2099;2100].

description_full:
  Estrogens exert many important effects in bone, a tissue that contains both estrogen receptors alpha and beta (ERalpha and ERbeta). To compare the actions of these receptors, we generated U2OS human osteosarcoma cells stably expressing ERalpha or ERbeta, at levels comparable with those in osteoblasts, and we characterized their response to 17beta-estradiol (E2) over time using Affymetrix GeneChip microarrays to determine the expression of approximately 12,000 genes, followed by quantitative PCR verification of the regulation of selected genes. Of the approximately 100 regulated genes we identified, some were stimulated by E2 equally through ERalpha and ERbeta, whereas others were selectively stimulated via ERalpha or ERbeta. The E2-regulated genes showed three distinct temporal patterns of expression over the 48-h time course studied. Of the functional categories of the E2-regulated genes, most numerous were those encoding cytokines and factors associated with immune response, signal transduction, and cell migration and cytoskeleton regulation, indicating that E2 can exert effects on multiple pathways in these osteoblast-like cell lines. Of note, E2 up-regulated several genes associated with cell motility selectively via ERbeta, in keeping with the selective E2 enhancement of the motility of ERbeta-containing cells. On genes regulated equally by E2 via ERalpha or ERbeta, the phytoestrogen genistein preferentially stimulated gene expression via ERbeta. These studies indicate both common as well as distinct target genes for these two ERs, and identify many novel genes not previously known to be under estrogen regulation.


systematic_name: M9193
exact_source: Table 4S
source_species_code: HS
contributor: Kevin Vogelsang
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in normal bone marrow plasma cells (BMPC) compared to polyclonal plasmablasts (PPC) that also distinguished multiple myeloma (MM) samples by expression of levels of TACI [GeneID=23495].

description_full:
  B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) have been shown to promote multiple myeloma (MM) cell growth. We show that the main site of production for BAFF and APRIL is the bone marrow (BM) environment, and that production is mainly by monocytes and neutrophils. In addition, osteoclasts produce very high levels of APRIL, unlike BM stromal cells. Myeloma cells (MMCs) express TACI (transmembrane activator and calcium modulator and cyclophilin ligand interactor), the receptor of BAFF/APRIL, at varying levels. TACI expression is a good indicator of a BAFF-binding receptor. Expression data of purified MMCs from 65 newly diagnosed patients have been generated using Affymetrix microarrays and were analyzed by supervised clustering of groups with higher (TACI(hi)) versus lower (TACI(lo)) TACI expression levels. Patients in the TACI(lo) group had clinical parameters associated with bad prognosis. A set of 659 genes was differentially expressed between TACI(hi) and TACI(lo) MMCs. This set makes it possible to efficiently classify TACI(hi) and TACI(lo) MMCs in an independent cohort of 40 patients. TACI(hi) MMCs displayed a mature plasma cell gene signature, indicating dependence on the BM environment. In contrast, the TACI(lo) group had a gene signature of plasmablasts, suggesting an attenuated dependence on the BM environment. Taken together, our findings suggest using gene expression profiling to identify the group of patients who might benefit most from treatment with BAFF/APRIL inhibitors.


systematic_name: M8537
exact_source: Table 4
source_species_code: HS
contributor: Kevin Vogelsang
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in lymph nodes from patients with mantle cell lymphoma (MCL) compared to the non-malignant hyperplastic lymph nodes.

description_full:
  An imbalance between cellular apoptosis and survival may be critical for the pathogenesis of lymphoma. Therefore, the gene expression pattern in lymph node preparations from patients with mantle cell lymphoma (MCL) was compared to the pattern in nonmalignant hyperplastic lymph nodes (HLs). Oligonucleotide microarray analysis was performed comparing 5 MCLs to 4 HLs using high-density microarrays. The expression data were analyzed using Genespring software. For confirmation, the expression of selected genes was analyzed by real-time polymerase chain reaction using the RNA extracted from 16 MCL and 12 HL samples. The focus was on 42 genes that were at least 3-fold down-regulated in MCL; in addition to the B-cell leukemia 2 (BCL2) system other apoptotic pathways were altered in MCL. The FAS-associated via death domain (FADD) gene that acts downstream of the FAS cascade as a key gene to induce apoptosis was more than 10-fold down-regulated in MCL. Furthermore, the death-associated protein 6 (DAXX) gene, the caspase 2 (CASP2) gene, and the RIPK1 domain containing adapter with death domain (RAIDD) gene, which are key genes in other proapoptotic pathways, were also decreased in the MCL samples. The suggestion is made that in addition to the known overexpression of cyclin D1, which drives entry into the cell cycle, disturbances of pathways associated with apoptosis contribute to the development of MCL. (Blood. 2001;98:787-794)


description_brief: Liver selective genes
systematic_name: M13283
exact_source: Supplement 3c
source_species_code: HS
contributor: Kevin Vogelsang
contrib_organization: MSigDB Team
description_full:
  This study creates a compendium of gene expression in normal human tissues suitable as a reference for defining basic organ systems biology. Using oligonucleotide microarrays, we analyze 59 samples representing 19 distinct tissue types. Of approximately 7,000 genes analyzed, 451 genes are expressed in all tissue types and designated as housekeeping genes. These genes display significant variation in expression levels among tissues and are sufficient for discerning tissue-specific expression signatures, indicative of fundamental differences in biochemical processes. In addition, subsets of tissue-selective genes are identified that define key biological processes characterizing each organ. This compendium highlights similarities and differences among organ systems and different individuals and also provides a publicly available resource (Human Gene Expression Index, the HuGE Index, http://www.hugeindex.org) for future studies of pathophysiology.


description_brief: Genes down-regulated in T lymphocytes overexpressing TERT [GeneID=7015] off a retrovirus vector.
systematic_name: M2891
exact_source: Table 2
source_species_code: HS
GEO_id: GSE2230
contributor: Kevin Vogelsang
contrib_organization: MSigDB Team
description_full:
  Little is known about the long-term consequences of overexpression of the human telomerase reverse transcriptase (hTERT) gene in T lymphocytes. To address this issue, we transduced polyclonal as well as clonally derived populations of naive and memory CD44 T cells from 2 healthy donors (aged 24 and 34 years) with retroviral vectors encoding green fluorescence protein (GFP) and hTERT (GFP-hTERT) or GFP alone. After transduction, cells were sorted on the basis of GFP expression and cultured in vitro until senescence. T cells transduced with hTERT exhibited high stable telomerase activity throughout the culture period. Relative to GFP controls, minor changes in overall gene expression were observed yet the proliferative lifespan of the hTERT-transduced populations was significantly increased and the rate of telomere loss was lower. Nevertheless, hTERT-transduced cells showed progressive telomere loss and had shorter telomeres at senescence than controls (2.3 +/- 0.3 kilobase [kb] versus 3.4 +/- 0.1 kb). Furthermore, a population of cells with 4N DNA consisting of binucleated cells with connected nuclei emerged in the hTERT-transduced cells prior to senescence. We conclude that overexpression of hTERT in CD4+ T cells provides a proliferative advantage independent of the average telomere length but does not prevent eventual genetic instability and replicative senescence.


systematic_name: M7715
exact_source: Table 3S: negatively associated
source_species_code: HS
contributor: Kevin Vogelsang
contrib_organization: MSigDB Team
description_brief:
  Top 100 genes negatively associated with T-cell acute lymphoblastic leukemia MLL T-ALL) expressing MLL-ENL fusion [GeneID=4297;4298].

description_full:
  Rearrangements of the MLL locus, located on human chromosome 11q23, are frequent in both infant and therapy-related leukemias. Gene expression analysis of MLL-rearranged B-precursor acute lymphoblastic leukemias (MLL B-ALLs) has identified these cases as a unique subtype of leukemia, characterized by the expression of genes associated with both lymphoid and myeloid hematopoietic lineages. Here we show that MLL fusions also generate a distinct genetic subtype of T-lineage ALL (MLL T-ALL), in which leukemic cells are characterized by an early arrest in thymocyte differentiation, with suggestive evidence of commitment to the gammadelta lineage. Interestingly, multiple genes linked to cell proliferation (eg, PCNA, MYC, CDK2, and POLA) were down-regulated in MLL-fusion samples, relative to those transformed by other T-ALL oncogenes (P <.000 001, Fisher exact test). Overall, MLL T-ALL cases consistently demonstrated increased levels of expression of a subset of major HOX genes--HOXA9, HOXA10, and HOXC6--and the MEIS1 HOX coregulator (P <.008, one-sided Wilcoxon test), a pattern of gene expression that was reiterated in MLL B-ALLs. However, expression of myeloid lineage genes, previously reported in MLL B-ALLs, was not identified in T-lineage cases with this abnormality, suggesting that myeloid gene dysregulation is dispensable in leukemic transformation mediated by MLL fusion proteins. Our findings implicate dysregulation of HOX gene family members as a dominant mechanism of leukemic transformation induced by chimeric MLL oncogenes.


systematic_name: M12139
exact_source: Table 2S
source_species_code: HS
contributor: Kevin Vogelsang
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in acute promyelocytic leukemia (APL) patients with mutated FLT3 [GeneID=2322].

description_full:
  The prognostic significance of FLT3 mutations in acute promyelocytic leukemia (APL) is not firmly established and is of particular interest given the opportunities for targeted therapies using FLT3 inhibitors. We studied 203 patients with PML-RARA-positive APL; 43% of the patients had an FLT3 mutation (65 internal tandem duplications [ITDs], 19 D835/I836, 4 ITD+D835/I836). Both mutations were associated with higher white blood cell (WBC) count at presentation; 75% of the patients with WBC counts of 10 x 10(9)/L or greater had mutant FLT3. FLT3/ITDs were correlated with M3v subtype (P < .001), bcr3 PML breakpoint (P < .001), and expression of reciprocal RARA-PML transcripts (P = .01). Microarray analysis revealed differences in expression profiles among patients with FLT3/ITD, D835/I836, and wild-type FLT3. Patients with mutant FLT3 had a higher rate of induction death (19% vs 9%; P = .04, but no significant difference in relapse risk (28% vs 23%; P = .5) or overall survival (59% vs 67%; P = .2) at 5 years. In in vitro differentiation assays using primary APL blasts (n = 6), the FLT3 inhibitor CEP-701 had a greater effect on cell survival/proliferation in FLT3/ITD+ cells, but this inhibition was reduced in the presence of ATRA. Furthermore, in the presence of CEP-701, ATRA-induced differentiation was reduced in FLT3/ITD+ cells. These data carry implications for the use of FLT3 inhibitors as frontline therapy for APL.


systematic_name: M3169
exact_source: Table 5
source_species_code: HS
contributor: Kevin Vogelsang
contrib_organization: MSigDB Team
description_brief:
  ES/PNET (Ewing sarcoma; primitive neuroectodermal tumors) markers up-regulated in neuroblastoma cell lines expressing ESWR1-FLI1 [GeneID=2130;2313] fusion protein.

description_full:
  Neuroblastoma (NB) and the Ewing sarcoma (ES)/peripheral primitive neuroectodermal tumor (PNET) family are pediatric cancers derived from neural crest cells. Although NBs display features of the sympathetic nervous system, ES/PNETs express markers consistent with parasympathetic differentiation. To examine the control of these differentiation markers, we generated NB x ES/PNET somatic cell hybrids. NB-specific markers were suppressed in the hybrids, whereas ES/PNET-specific markers were unaffected. These results suggested that the Ews/Fli-1 fusion gene, resulting from a translocation unique to ES/PNETs, might account for the loss of NB-specific markers. To test this hypothesis, we generated two different NB cell lines that stably expressed the Ews/Fli-1 gene. We observed that heterologous expression of the Ews/Fli-1 protein led to the suppression of NB-specific markers and de novo expression of ES/PNET markers. To determine the extent of changes in differentiation, we used the Affymetrix GeneChip Array system to observe global transcriptional changes of genes. This analysis revealed that the gene expression pattern of the Ews/Fli-1-expressing NB cells resembled that observed in pooled ES/PNET cell lines and differed significantly from the NB parental cells. Therefore, we propose that Ews/Fli-1 contributes to the etiology of ES/PNET by subverting the differentiation program of its neural crest precursor cell to a less differentiated and more proliferative state.


systematic_name: M4888
exact_source: Table 2S: Subgroup = PR
source_species_code: HS
GEO_id: GSE2658
contributor: Kevin Vogelsang
contrib_organization: MSigDB Team
description_brief:
  Top 50 up-regulated genes in cluster PR of multiple myeloma samples characterized by increased expression of proliferation and cell cycle genes.

description_full:
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systematic_name: M19872
exact_source: Table 2
source_species_code: HS
contributor: Kevin Vogelsang
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in KCL22 cells (chronic myelogenous leukemia, CML, with BCR-ABL1 [GeneID=613;25] fusion) by expression of CEBPA [GeneID=1050].

description_full:
  The transcription factor C/EBPalpha plays a critical role in the process of granulocytic differentiation. Recently, mutations that abrogated transcriptional activation of C/EBPalpha were detected in acute myeloid leukemia patient samples. Moreover, the progression of chronic myelogenous leukemia (CML) to blast crisis in patients was correlated with down-modulation of C/EBPalpha. The KCL22 cell line, derived from BCR-ABL+ CML in blast crisis, expressed wild-type C/EBPepsilon protein but not a functional C/EBPalpha, -beta, and -gamma. Restoration of C/EBPalpha expression in KCL22 cells triggered a profound proliferative arrest, a block in the G2/M phase of the cell cycle and a gradual increase in apoptosis. Within 3 days of inducing expression of C/EBPalpha, a remarkable neutrophilic differentiation of the KCL22 blast cells occurred as shown by morphologic changes, induction of expression of CD11b, primary, secondary, and tertiary granule proteins, and granulocyte colony-stimulating factor receptor. Using high density oligonucleotide microarrays, the gene expression profile of KCL22 cells stably transfected with C/EBPalpha was compared with that of empty vector, and we identified genes not previously known to be regulated by C/EBPalpha. These included the up-regulation of those genes important for regulation of hematopoietic stem cell homing, granulocytic differentiation, and cell cycle, whereas down-regulation occurred for genes coding for signaling molecules and transcription factors that are implicated in regulation of proliferation and differentiation of hematopoietic cells. Our study showed that restoration of C/EBPalpha expression in BCR-ABL+ leukemic cells in blast crisis is sufficient for rapid neutrophil differentiation suggesting a potential therapeutic role for ectopic transfer of C/EBPalpha in acute phase of CML.


systematic_name: M1456
exact_source: Table 3
source_species_code: MM
contributor: Kevin Vogelsang
contrib_organization: MSigDB Team
description_brief:
  Genes commonly expressed in long term hematopoietic stem cells (HSC) and multipotent progenitors (MPP).

description_full:
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systematic_name: M18077
exact_source: Table 4
source_species_code: HS
contributor: Kevin Vogelsang
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in immunoglobulin light chain amyloidosis plasma cells (ALPC) compared to multiple myeloma (MM) cells.

description_full:
  Immunoglobulin light chain amyloidosis (AL) is characterized by a clonal expansion of plasma cells within the bone marrow. Gene expression analysis was used to identify a unique molecular profile for AL using enriched plasma cells (CD138+) from the bone marrow of 24 patients with AL and 28 patients with multiple myeloma (MM) and 6 healthy controls. Class prediction analysis (PAM) revealed a subset of 12 genes, which included TNFRSF7 (CD27), SDF-1, and PSMA2, that distinguished between these 2 groups with an estimated and observed accuracy of classification of 92%. This model was validated with an independent dataset of 11 patients with AL and 12 patients with MM with 87% accuracy. Differential expression for the most discriminant genes in the 12-gene subset was validated using quantitative real-time polymerase chain reaction and protein expression analysis, which upheld the observations from the micro-array expression data. Functional analyses using a novel network mapping software revealed a number of potentially significant pathways that were dysregulated in patients with AL, with those regulating proliferation, apoptosis, cell signaling, chemotaxis, and migration being substantially represented. This study provides new insight into the molecular profile of clonal plasma cells and its functional relevance in the pathogenesis of light chain amyloidosis.


systematic_name: M5360
exact_source: Table 1
source_species_code: HS
contributor: Kevin Vogelsang
contrib_organization: MSigDB Team
description_brief:
  Up-regulated genes in the signature of adipose stromal cells (ADSC) immortalized by forced expression of telomerase (TERT) [GeneID=7015].

description_full:
  Expression of TERT, the catalytic protein subunit of the telomerase complex, can be used to generate cell lines that expand indefinitely and retain multilineage potential. We have created immortal adipose stromal cell lines (ATSCs) by stably transducing nonhuman primate-derived ATSCs with a retroviral vector expressing TERT. Transduced cells (ATSC-TERT) had an increased level of telomerase activity and increased mean telomere length in the absence of malignant cellular transformation. Long-term culture of the ATSC-TERT cells demonstrated that the cells retain the ability to undergo differentiation along multiple lineages such as adipogenic, chondrogenic, and neurogenic. Untransduced cells demonstrated markedly reduced multilineage and self-renewal potentials after 12 passages in vitro. To determine the functional role of telomerase during osteogenesis, we examined osteogenic differentiation potential of ATSC-TERT cells in vitro. Compared with naive ATSCs, which typically begin to accumulate calcium after 3-4 weeks of induction by osteogenic differentiation medium, ATSC-TERT cells were found to accumulate significant amounts of calcium after only 1 week of culture in osteogenic induction medium. The cells have increased production of osteoblastic markers, such as AP2, osteoblast-specific factor 2, chondroitin sulfate proteoglycan 4, and the tumor necrosis factor receptor superfamily, compared with control ATSCs, indicating that telomerase expression may aid in maintaining the osteogenic stem cell pool during in vitro expansion. These results show that ectopic expression of the telomerase gene in nonhuman primate ATSCs prevents senescence-associated impairment of osteoblast functions and that telomerase therapy may be a useful strategy for bone regeneration and repair.


systematic_name: M1459
exact_source: Table 3S: BLOOD VASCULAR EC
source_species_code: HS
contributor: Kevin Vogelsang
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in BEC (blood endothelial cells) compared to LEC (lymphatic endothelial cells).

description_full:
  Lymphatic vessels are essential for fluid homeostasis, immune surveillance and fat adsorption, and also serve as a major route for tumor metastasis in many types of cancer. We found that isolated human primary lymphatic and blood vascular endothelial cells (LECs and BECs, respectively) show interesting differences in gene expression relevant for their distinct functions in vivo. Although these phenotypes are stable in vitro and in vivo, overexpression of the homeobox transcription factor Prox-1 in the BECs was capable of inducing LEC-specific gene transcription in the BECs, and, surprisingly, Prox-1 suppressed the expression of approximately 40% of the BEC-specific genes. Prox-1 did not have global effects on the expression of LEC-specific genes in other cell types, except that it up-regulated cyclin E1 and E2 mRNAs and activated the cyclin e promoter in various cell types. These data suggest that Prox-1 acts as a cell proliferation inducer and a fate determination factor for the LECs. Furthermore, the data provide insights into the phenotypic diversity of endothelial cells and into the possibility of transcriptional reprogramming of differentiated endothelial cells.


systematic_name: M15969
exact_source: Table 1: cluster 1
source_species_code: HS
contributor: Kevin Vogelsang
contrib_organization: MSigDB Team
description_brief:
  Cluster 1: genes up-regulated by RB1, CDNK2A [GeneID=1029;5925], and one of the E2Fs (E2F1, E2F2, or E2F3 [GeneID=1869;1870;1871]).

description_full:
  Deregulation of the retinoblastoma protein (pRB) pathway is a hallmark of human cancer. The core members of this pathway include the tumor suppressor protein, pRB, which through binding to a number of cellular proteins, most notably members of the E2F transcription factor family, regulates progression through the cell division cycle. With the aim of identifying transcriptional changes provoked by deregulation of the pRB pathway, we have used cell lines that conditionally express a constitutively active phosphorylation site mutant of pRB (pRBDeltaCDK) or p16INK4A (p16). The expression of pRBDeltaCDK and p16 resulted in significant repression and activation of a large number of genes as measured by high density oligonucleotide array analysis. Transcriptional changes were found in genes that are essential for DNA replication and cell proliferation. In agreement with previous results, we found a high degree of overlap between genes regulated by p16 and pRB. Data we have obtained previously for E2F family members showed that 74 of the genes repressed by pRB and p16 were induced by the E2Fs and 23 genes that were induced by pRB and p16 were repressed by the E2Fs. Thus, we have identified 97 genes as physiological targets of the pRB pathway, and the further characterization of these genes should provide insights into how this pathway controls proliferation. We show that Gibbs sampling detects enrichment of several sequence motifs, including E2F consensus binding sites, in the upstream regions of these genes and use this enrichment in an in silico filtering process to refine microarray derived gene lists.


systematic_name: M14650
exact_source: Table 1S
source_species_code: HS
GEO_id: GSE5229
contributor: Kevin Vogelsang
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in primary keratinocytes by expression of constantly active NOTCH1 [GeneID=4851].

description_full:
  Notch signaling promotes commitment of keratinocytes to differentiation and suppresses tumorigenesis. p63, a p53 family member, has been implicated in establishment of the keratinocyte cell fate and/or maintenance of epithelial self-renewal. Here we show that p63 expression is suppressed by Notch1 activation in both mouse and human keratinocytes through a mechanism independent of cell cycle withdrawal and requiring down-modulation of selected interferon-responsive genes, including IRF7 and/or IRF3. In turn, elevated p63 expression counteracts the ability of Notch1 to restrict growth and promote differentiation. p63 functions as a selective modulator of Notch1-dependent transcription and function, with the Hes-1 gene as one of its direct negative targets. Thus, a complex cross-talk between Notch and p63 is involved in the balance between keratinocyte self-renewal and differentiation.


systematic_name: M1472
exact_source: Table 2S: BEC-specific suppressed by AdProx-1
source_species_code: HS
contributor: Kevin Vogelsang
contrib_organization: MSigDB Team
description_brief:
  Genes specific to BEC (blood endothelium cells) repressed in BEC by expression of PROX1 [GeneID=5629] off adenovirus vector.

description_full:
  Lymphatic vessels are essential for fluid homeostasis, immune surveillance and fat adsorption, and also serve as a major route for tumor metastasis in many types of cancer. We found that isolated human primary lymphatic and blood vascular endothelial cells (LECs and BECs, respectively) show interesting differences in gene expression relevant for their distinct functions in vivo. Although these phenotypes are stable in vitro and in vivo, overexpression of the homeobox transcription factor Prox-1 in the BECs was capable of inducing LEC-specific gene transcription in the BECs, and, surprisingly, Prox-1 suppressed the expression of approximately 40% of the BEC-specific genes. Prox-1 did not have global effects on the expression of LEC-specific genes in other cell types, except that it up-regulated cyclin E1 and E2 mRNAs and activated the cyclin e promoter in various cell types. These data suggest that Prox-1 acts as a cell proliferation inducer and a fate determination factor for the LECs. Furthermore, the data provide insights into the phenotypic diversity of endothelial cells and into the possibility of transcriptional reprogramming of differentiated endothelial cells.


systematic_name: M12175
exact_source: Table 1
source_species_code: HS
contributor: Kevin Vogelsang
contrib_organization: MSigDB Team
description_brief:
  Genes significantly up-regulated in the blood mononuclear cells from patients with systemic lupus erythematosus compared to those from healthy persons.

description_full:
  Systemic lupus erythematosus (SLE) is a prototype systemic autoimmune disease characterized by flares of high morbidity. Using oligonucleotide microarrays, we now show that active SLE can be distinguished by a remarkably homogeneous gene expression pattern with overexpression of granulopoiesis-related and interferon (IFN)-induced genes. Using the most stringent statistical analysis (Bonferroni correction), 15 genes were found highly up-regulated in SLE patients, 14 of which are targets of IFN and one, defensin DEFA-3, a major product of immature granulocytes. A more liberal correction (Benjamini and Hochberg correction) yielded 18 additional genes, 12 of which are IFN-regulated and 4 granulocyte-specific. Indeed immature neutrophils were identified in a large fraction of SLE patients white blood cells. High dose glucocorticoids, a standard treatment of disease flares, shuts down the interferon signature, further supporting the role of this cytokine in SLE. The expression of 10 genes correlated with disease activity according to the SLEDAI. The most striking correlation (P < 0.001, r = 0.55) was found with the formyl peptide receptor-like 1 protein that mediates chemotactic activities of defensins. Therefore, while the IFN signature confirms the central role of this cytokine in SLE, microarray analysis of blood cells reveals that immature granulocytes may be involved in SLE pathogenesis.


description_brief: Hypoxia response genes up-regulated in both astrocytes and HeLa cell line.
systematic_name: M11033
exact_source: Table 1S: Induced
source_species_code: HS
GEO_id: GSE4483,GSE3051,GSE3045
contributor: Kevin Vogelsang
contrib_organization: MSigDB Team
description_full:
  Oxygen is vital for the development and survival of mammals. In response to hypoxia, the brain initiates numerous adaptive responses at the organ level as well as at the molecular and cellular levels, including the alteration of gene expression. Astrocytes play critical roles in the proper functioning of the brain; thus the manner in which astrocytes respond to hypoxia is likely important in determining the outcome of brain hypoxia. Here, we used microarray gene expression profiling and data-analysis algorithms to identify and analyze hypoxia-responsive genes in primary human astrocytes. We also compared gene expression patterns in astrocytes with those in human HeLa cells and pulmonary artery endothelial cells (ECs). Remarkably, in astrocytes, five times as many genes were induced as suppressed, whereas in HeLa and pulmonary ECs, as many as or more genes were suppressed than induced. More genes encoding hypoxia-inducible functions, such as glycolytic enzymes and angiogenic growth factors, were strongly induced in astrocytes compared with HeLa cells. Furthermore, gene ontology and computational algorithms revealed that many target genes of the EGF and insulin signaling pathways and the transcriptional regulators Myc, Jun, and p53 were selectively altered by hypoxia in astrocytes. Indeed, Western blot analysis confirmed that two major signal transducers mediating insulin and EGF action, Akt and MEK1/2, were activated by hypoxia in astrocytes. These results provide a global view of the signaling and regulatory network mediating oxygen regulation in human astrocytes


systematic_name: M17193
exact_source: Table 2S
source_species_code: HS
contributor: Kevin Vogelsang
contrib_organization: MSigDB Team
description_brief:
  Down-regulated genes distinguishing in multiple myeloma (MM) samples with lower expression of TACI [GeneID=23495].

description_full:
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systematic_name: M3905
exact_source: Table 2D
source_species_code: HS
contributor: Kevin Vogelsang
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated synergistically in NB4 cells (acute promyelocytic leukemia, APL) by tretinoin and NSC682994 [PubChem=444795;388304].

description_full:
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systematic_name: M1495
exact_source: Table 2S: LEC-specific induced by AdProx-1
source_species_code: HS
contributor: Kevin Vogelsang
contrib_organization: MSigDB Team
description_brief:
  Genes specific to LEC (lymphatic endothelium cells) induced in BEC (blood endothelium cells) by expression of PROX1 [GeneID=5629] off adenovirus vector.

description_full:
[cell repeats an earlier one in this file: 1185 characters]


description_brief: Genes up-regulated in normal fibroblasts under hypoxia conditions.
systematic_name: M1496
exact_source: Table 3
source_species_code: HS
contributor: John Newman
contrib_organization: University of Washington
description_full:
  Little is known about the detail of hypoxia-responsive gene expression patterns in advanced age, even though aging is thought to be partially associated with a decreased response to hypoxia. In the present study, we identified several hypoxia-inducible genes and investigated the effect of aging on hypoxic gene expression profiles using cDNA microarray analysis of young/old human diploid fibroblasts. Of 7458 genes in the microarray, we found that genes involved in angiogenesis, defense against oxidative stress, and transcription regulation are severely impaired in senescent cell, which is consistent with the fact that aged cells have attenuated responses to various stimuli.


systematic_name: M18085
exact_source: Table 2
source_species_code: HS
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Genes up-regulated in T24 cells (bladder carcinoma) after treatment with decitabine (5-aza-2'-deoxycytidine) [PubChem=451668].

description_full:
  Hypermethylation of the promoters of cancer-related genes is often associated with their inactivation during tumorigenesis. Several preclinical and clinical trials have been developed to use DNA methylation inhibitors, such as 5-aza-2'-deoxycytidine (5-Aza-CdR) in attempts to reactivate silenced genes in human cancers. We used high-density oligonucleotide gene expression microarrays to examine the effects of 5-Aza-CdR treatment on human fibroblast cells (LD419) and a human bladder tumor cell line (T24). Data obtained 8 days after recovery from 5-Aza-CdR treatment showed that more genes were induced in tumorigenic cells (61 genes induced; >or=4-fold) than nontumorigenic cells (34 genes induced; >or= 4-fold). Approximately 60% of induced genes did not have CpG islands within their 5' regions, suggesting that some genes activated by 5-Aza-CdR may not result from the direct inhibition of promoter methylation. Interestingly, a high percentage of genes activated in both cell types belonged to the IFN signaling pathway, confirming data from other tumor cell types.


systematic_name: M1491
exact_source: Table 1, 2: Progeria: FoldD < 0
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in fibroblasts from patients with Hutchinson-Gilford progeria (premature aging), compared to those from normal young individuals.

description_full:
  Messenger RNA levels were measured in actively dividing fibroblasts isolated from young, middle-age, and old-age humans and humans with progeria, a rare genetic disorder characterized by accelerated aging. Genes whose expression is associated with age-related phenotypes and diseases were identified. The data also suggest that an underlying mechanism of the aging process involves increasing errors in the mitotic machinery of dividing cells in the postreproductive stage of life. We propose that this dysfunction leads to chromosomal pathologies that result in misregulation of genes involved in the aging process.


systematic_name: M6122
exact_source: Table 1S: 20hpi >= 3 & Diff Call [20 hpi] = I, MI
source_species_code: HS
GEO_id: GSE675
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Genes up-regulated in primary fibroblast cell culture after infection with HCMV (AD169 strain) at 20 h time point that were not up-regulated at the previous time point, 18 h.

description_full:
  The effect of human cytomegalovirus (HCMV) infection on cellular mRNA accumulation was analyzed by gene chip technology. During a 48-h time course after infection of human diploid fibroblasts, 1,425 cellular mRNAs were found to be up-regulated or down-regulated by threefold or greater in at least two consecutive time points. Several classes of genes were prominently affected, including interferon response genes, cell cycle regulators, apoptosis regulators, inflammatory pathway genes, and immune regulators. The number of mRNAs that were up-regulated or down-regulated were roughly equal over the complete time course. However, for the first 8 h after infection, the number of up-regulated mRNAs was significantly less than the number of down-regulated mRNAs. By analyzing the mRNA expression profile of cells infected in the presence of cycloheximide, it was found that a minimum of 25 mRNAs were modulated by HCMV in the absence of protein synthesis. These included mRNAs encoded by a small number of interferon-responsive genes, as well as beta interferon itself. Cellular mRNA levels in cytomegalovirus-infected cells were compared to the levels in cells infected with UV-inactivated virus. The inactivated virus caused the up-regulation of a much greater number of mRNAs, many of which encoded proteins with antiviral roles, such as interferon-responsive genes and proinflammatory cytokines. These data argue that one or more newly synthesized viral gene products block the induction of antiviral pathways that are triggered by HCMV binding and entry.


description_brief: Genes up-regulated in primary adipocytes compared to preadipocytes.
systematic_name: M15476
exact_source: Table 1
source_species_code: HS
contributor: John Newman
contrib_organization: University of Washington
description_full:
  Uncontrolled expansion of adipose tissue leads to obesity, a public health epidemic affecting >30% of adult Americans. Adipose mass increases in part through the recruitment and differentiation of an existing pool of preadipocytes (PA) into adipocytes (AD). Most studies investigating adipogenesis used primarily murine cell lines; much less is known about the relevant processes that occur in humans. Therefore, characterization of genes associated with adipocyte development is key to understanding the pathogenesis of obesity and developing treatments for this disorder. To address this issue, we performed large-scale analyses of human adipose gene expression using microarray technology. Differential gene expression between PA and AD was analyzed in 6 female patients using human cDNA microarray slides and data analyzed using the Stanford Microarray Database. Statistical analysis for the gene expression was performed using the SAS mixed models. Compared with PA, several genes involved in lipid metabolism were overexpressed in AD, including fatty acid binding protein, adipose differentiation-related protein, lipoprotein lipase, perilipin, and adipose most abundant transcript 1. Novel genes expressed in adipocytes included E2F5 transcriptional factor and SMARC (SWI/SNF-related, matrix associated, actin-dependent regulator of chromatin). PA predominantly expressed genes encoding extracellular matrix components such as fibronectin, matrix metalloprotein, and novel proteins such as lysyl oxidase. Despite the high differential expression of some of these genes, many did not differ significantly likely due to high variability and limited statistical power. A comprehensive list of differential gene expression is presented according to cellular function. In conclusion, these studies offer an overview of the gene expression profiles in PA and AD and identify new genes with potentially important functions in adipose tissue development and obesity that merit further investigation.


systematic_name: M11383
exact_source: Table 1S: 16hpi >= 3 & Diff Call [16hpi] = I, MI
source_species_code: HS
GEO_id: GSE675
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Genes up-regulated in primary fibroblast cell culture after infection with HCMV (AD169 strain) at 16 h time point that were not up-regulated at the previous time point, 14 h.

description_full:
  The effect of human cytomegalovirus (HCMV) infection on cellular mRNA accumulation was analyzed by gene chip technology. During a 48-h time course after infection of human diploid fibroblasts, 1,425 cellular mRNAs were found to be up-regulated or down-regulated by threefold or greater in at least two consecutive time points. Several classes of genes were prominently affected, including interferon response genes, cell cycle regulators, apoptosis regulators, inflammatory pathway genes, and immune regulators. The number of mRNAs that were up-regulated or down-regulated were roughly equal over the complete time course. However, for the first 8 h after infection, the number of up-regulated mRNAs was significantly less than the number of down-regulated mRNAs. By analyzing the mRNA expression profile of cells infected in the presence of cycloheximide, it was found that a minimum of 25 mRNAs were modulated by HCMV in the absence of protein synthesis. These included mRNAs encoded by a small number of interferon-responsive genes, as well as beta interferon itself. Cellular mRNA levels in cytomegalovirus-infected cells were compared to the levels in cells infected with UV-inactivated virus. The inactivated virus caused the up-regulation of a much greater number of mRNAs, many of which encoded proteins with antiviral roles, such as interferon-responsive genes and proinflammatory cytokines. These data argue that one or more newly synthesized viral gene products block the induction of antiviral pathways that are triggered by HCMV binding and entry.


description_brief: Genes up-regulated in HUVEC cells (endothelium) at 2 h after VEGFA [GeneID=7422] stimulation.
systematic_name: M13319
exact_source: Table 2
source_species_code: HS
contributor: John Newman
contrib_organization: University of Washington
description_full:
  Vascular endothelial growth factor (VEGF) is one of the most important factors that stimulate angiogenesis and vascular permeability. To clarify the role of VEGF, we analysed a human cDNA chip containing 7267 human genes to identify genes induced by VEGF in human umbilical vein endothelial cells (HUVECs). One hundred thirty-nine cDNAs, including ninety-nine previously known and forty poorly characterized or novel sequences, were increased more than two-fold by VEGF within twenty-four hours of stimulation. Among them, only five are known to regulate angiogenesis: cyclooxygenase 2 (COX2), heparin-binding epidermal growth factor-like growth factor, early growth response 1 (EGR 1), CYR61, and angiopoietin 2. Fifty-three genes induced within the first two hours were thought to be directly induced by VEGF. Of these, Down syndrome candidate region 1 (maximum induction = 6.1-fold) was the most profoundly induced, followed by Mifl (KIAA0025; 5.5-fold), COX2 (4.7-fold), EGR 3 (3.7-fold), EGR 2 (3.2-fold), bactericidal/permeability-increasing protein (3.1-fold), and CD1B antigen, b polypeptide (3.1-fold). In addition to the genes mentioned above, there were many poorly characterized or novel genes induced by VEGF. Further analysis of these genes may aid in the elucidation of the molecular mechanisms of angiogenesis or vascular permeability stimulated by VEGF.


systematic_name: M1501
exact_source: Table 1: Group 1A
source_species_code: HS
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Genes basally silent, with hypermethylated promoters, up-regulated by the combination of TSA and decitabine [PubChem=5562;451668] in RKO cells (colorectal cancer).

description_full:
  Aberrant hypermethylation of gene promoters is a major mechanism associated with inactivation of tumor-suppressor genes in cancer. We previously showed this transcriptional silencing to be mediated by both methylation and histone deacetylase activity, with methylation being dominant. Here, we have used cDNA microarray analysis to screen for genes that are epigenetically silenced in human colorectal cancer. By screening over 10,000 genes, we show that our approach can identify a substantial number of genes with promoter hypermethylation in a given cancer; these are distinct from genes with unmethylated promoters, for which increased expression is produced by histone deacetylase inhibition alone. Many of the hypermethylated genes we identified have high potential for roles in tumorigenesis by virtue of their predicted function and chromosome position. We also identified a group of genes that are preferentially hypermethylated in colorectal cancer and gastric cancer. One of these genes, SFRP1, belongs to a gene family; we show that hypermethylation of four genes in this family occurs very frequently in colorectal cancer, providing for (i) a unique potential mechanism for loss of tumor-suppressor gene function and (ii) construction of a molecular marker panel that could detect virtually all colorectal cancer.


description_brief: Genes identified as hypermethylated in SW48 cells (colon cancer).
systematic_name: M14473
exact_source: Table 1
source_species_code: HS
GEO_id: GSE2664,GSE2653
contributor: John Newman
contrib_organization: University of Washington
description_full:
  Cytosine methylation is required for mammalian development and is often perturbed in human cancer. To determine how this epigenetic modification is distributed in the genomes of primary and transformed cells, we used an immunocapturing approach followed by DNA microarray analysis to generate methylation profiles of all human chromosomes at 80-kb resolution and for a large set of CpG islands. In primary cells we identified broad genomic regions of differential methylation with higher levels in gene-rich neighborhoods. Female and male cells had indistinguishable profiles for autosomes but differences on the X chromosome. The inactive X chromosome (Xi) was hypermethylated at only a subset of gene-rich regions and, unexpectedly, overall hypomethylated relative to its active counterpart. The chromosomal methylation profile of transformed cells was similar to that of primary cells. Nevertheless, we detected large genomic segments with hypomethylation in the transformed cell residing in gene-poor areas. Furthermore, analysis of 6,000 CpG islands showed that only a small set of promoters was methylated differentially, suggesting that aberrant methylation of CpG island promoters in malignancy might be less frequent than previously hypothesized.


systematic_name: M1499
exact_source: Table 1: week 4 >= 1
source_species_code: HS
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Genes up-regulated in NCI-H2170 cells (lung cancer) upon induction of resistance to cisplatin [PubChem=2767].

description_full:
  In recent years, most cDNA microarray studies of chemotherapeutic drug resistance have not considered the temporal pattern of gene expression. The objective of this study was to examine systematically changes in gene expression of NCI-H226 and NCI-H2170 lung cancer cells treated weekly with IC10 doses of cisplatin. NCI-H226 lung cancer cells were treated weekly with an IC10 dose of cisplatin. Candidate genes with a fold change of 2.0 or more were identified from this study. A second experiment was conducted by exposing NCI-H2170 cells to cisplatin doses that were increased in week 4 and decreased in week 5. Overall, 44 genes were differentially expressed in both the NCI-H226 and NCI-H2170 cell lines. In the NCI-H2170 cell line, 24 genes had a twofold gene expression change from weeks 3 to 4. Real-time PCR found a significant correlation of the gene expression changes for seven genes of interest. This small time-ordered series identified novel genes associated with cisplatin resistance. This kind of analysis should be viewed as a first step towards building gene-regulatory networks.


systematic_name: M347
exact_source: Table 4
source_species_code: HS
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Oxidative stress genes down-regulated in ARPE-19 cells (retinal pigmented epithelium) in response to HNE and H2O2 [PubChem=5283344;784].

description_full:
[cell repeats an earlier one in this file: 1321 characters]


systematic_name: M1520
exact_source: Table 2
source_species_code: HS
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Genes up-regulated in HeLa cells (cervical carcinoma) at 4 h after stimulation with TNF [GeneID=7124].

description_full:
  Tumor necrosis factor alpha (TNF alpha) is a proinflammatory cytokine with important roles in regulating inflammatory responses as well as cell cycle proliferation and apoptosis. Although TNFalpha stimulates apoptosis, it also activates the transcription factor NF-kappa B, and studies have shown that inhibition of NF-kappa B potentiates the cytotoxicity of TNFalpha. Since several chemotherapy agents act like TNFalpha to both promote apoptosis and activate NF-kappa B, understanding the role of NF-kappa B in suppressing apoptosis may have significant clinical applications. To understand the effects of stimulation with TNFalpha and the role of NF-kappa B in regulating this response, a 23k human cDNA microarray was used to screen TNFalpha-inducible genes in HeLa cells. Real-time PCR verified expression changes in 16 of these genes and revealed three distinct temporal patterns of expression after TNFalpha stimulation. Using RNA interference to disrupt expression of the p65 subunit of NF-kappa B, all but two of the genes were shown to depend on this transcription factor for their expression, which correlated well with the existence of NF-kappa B binding sites in most of their promoters. Inflammatory, proapoptotic, and antiapoptotic genes were all shown to be regulated by NF-kappa B, demonstrating the wide variety of targets activated by NF-kappa B signaling and the necessity of differentiating among these genes for therapeutic purposes.


systematic_name: M19130
exact_source: Table 1S: 16hpi <= -3 & Diff Call [16 hpi] = D, MD
source_species_code: HS
GEO_id: GSE675
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Genes down-regulated in primary fibroblast cell culture after infection with HCMV (AD169 strain) at 16 h time point that were not down-regulated at the previous time point, 14 h.

description_full:
  The effect of human cytomegalovirus (HCMV) infection on cellular mRNA accumulation was analyzed by gene chip technology. During a 48-h time course after infection of human diploid fibroblasts, 1,425 cellular mRNAs were found to be up-regulated or down-regulated by threefold or greater in at least two consecutive time points. Several classes of genes were prominently affected, including interferon response genes, cell cycle regulators, apoptosis regulators, inflammatory pathway genes, and immune regulators. The number of mRNAs that were up-regulated or down-regulated were roughly equal over the complete time course. However, for the first 8 h after infection, the number of up-regulated mRNAs was significantly less than the number of down-regulated mRNAs. By analyzing the mRNA expression profile of cells infected in the presence of cycloheximide, it was found that a minimum of 25 mRNAs were modulated by HCMV in the absence of protein synthesis. These included mRNAs encoded by a small number of interferon-responsive genes, as well as beta interferon itself. Cellular mRNA levels in cytomegalovirus-infected cells were compared to the levels in cells infected with UV-inactivated virus. The inactivated virus caused the up-regulation of a much greater number of mRNAs, many of which encoded proteins with antiviral roles, such as interferon-responsive genes and proinflammatory cytokines. These data argue that one or more newly synthesized viral gene products block the induction of antiviral pathways that are triggered by HCMV binding and entry.


systematic_name: M1521
exact_source: Table 1: 6h
source_species_code: HS
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Genes up-regulated in MMEC cells (myometrial endothelium) at 6 h after VEGFA [GeneID=7422] stimulation.

description_full:
  There is evidence that the vasculature of different organs display different functional characteristics in response to cytokines and growth factors. The aim of this study was to use cDNA gene expression microarray to analyse changes in gene expression following stimulation of myometrial microvascular endothelial cells (MMECs) with vascular endothelial growth factor (VEGF). Primary isolates of MMECs were obtained from fresh hysterectomy specimens and purified with magnetic beads. Cells were stimulated with 15 ng/ml VEGF for 3, 6 and 12 h, and two unstimulated experiments served as controls. A total of six arrays was performed over these time-points. A total of 110 genes were identified as up-regulated by VEGF, 19% of which (21 genes) have previously been reported as up-regulated by VEGF or by angiogenesis. Among the novel genes to be up-regulated by VEGF were brain-derived growth factor, oxytocin receptor and estrogen sulphotransferase. The significance of the genes identified in the physiological and pathological functioning of the myometrial vasculature is discussed.


systematic_name: M1345
exact_source: Fig. 2A
source_species_code: HS
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Genes commonly up-regulated in cancer relative to normal tissue, according to the meta-analysis of the OncoMine gene expression database.

description_full:
  Many studies have used DNA microarrays to identify the gene expression signatures of human cancer, yet the critical features of these often unmanageably large signatures remain elusive. To address this, we developed a statistical method, comparative metaprofiling, which identifies and assesses the intersection of multiple gene expression signatures from a diverse collection of microarray data sets. We collected and analyzed 40 published cancer microarray data sets, comprising 38 million gene expression measurements from >3,700 cancer samples. From this, we characterized a common transcriptional profile that is universally activated in most cancer types relative to the normal tissues from which they arose, likely reflecting essential transcriptional features of neoplastic transformation. In addition, we characterized a transcriptional profile that is commonly activated in various types of undifferentiated cancer, suggesting common molecular mechanisms by which cancer cells progress and avoid differentiation. Finally, we validated these transcriptional profiles on independent data sets.


description_brief: Genes known to be induced by hypoxia
systematic_name: M10508
exact_source: Box 1
source_species_code: HS
contributor: John Newman
contrib_organization: University of Washington
description_full:
  Cells undergo a variety of biological responses when placed in hypoxic conditions, including activation of signalling pathways that regulate proliferation, angiogenesis and death. Cancer cells have adapted these pathways, allowing tumours to survive and even grow under hypoxic conditions, and tumour hypoxia is associated with poor prognosis and resistance to radiation therapy. Many elements of the hypoxia-response pathway are therefore good candidates for therapeutic targeting.


systematic_name: M8416
exact_source: Table 1S: 10hpi <= -3 & Diff Call [10 hpi] = D, MD
source_species_code: HS
GEO_id: GSE675
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Genes down-regulated in primary fibroblast cell culture after infection with HCMV (AD169 strain) at 10 h time point that were not down-regulated at the previous time point, 8 h.

description_full:
[cell repeats an earlier one in this file: 1560 characters]


