# gene_set_details

systematic_name: M4270
exact_source: Table 9S
source_species_code: RM
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Downregulated in the vastus lateralis muscle of middle aged rhesus monkeys subjected to caloric restriction since young adulthood vs age matched controls

description_full:
  In laboratory rodents, caloric restriction (CR) retards several age-dependent physiological and biochemical changes in skeletal muscle, including increased steady-state levels of oxidative damage to lipids, DNA, and proteins. We have previously used high-density oligonucleotide arrays to show that CR can prevent or delay most of the major age-related transcriptional alterations in the gastrocnemius muscle of C57BL/6 mice. Here we report the effects of aging and adult-onset CR on the gene expression profile of 7,070 genes in the vastus lateralis muscle from rhesus monkeys. Gene expression analysis of aged rhesus monkeys (mean age of 26 years) was compared with that of young animals (mean age of 8 years). Aging resulted in a selective up-regulation of transcripts involved in inflammation and oxidative stress, and a down-regulation of genes involved in mitochondrial electron transport and oxidative phosphorylation. Middle-aged monkeys (mean age of 20 years) subjected to CR since early adulthood (mean age of 11 years) were studied to determine the gene expression profile induced by CR. CR resulted in an up-regulation of cytoskeletal protein-encoding genes, and also a decrease in the expression of genes involved in mitochondrial bioenergetics. Surprisingly, we did not observe any evidence for an inhibitory effect of adult-onset CR on age-related changes in gene expression. These results indicate that the induction of an oxidative stress-induced transcriptional response may be a common feature of aging in skeletal muscle of rodents and primates, but the extent to which CR modifies these responses may be species-specific.


systematic_name: M11837
exact_source: Table 5S: Fold change < -1
source_species_code: HS
GEO_id: GSE362
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Genes whose expression decreases with age in normal kidney, excluding those with higher expression in blood.

description_full:
  In this study, we found 985 genes that change expression in the cortex and the medulla of the kidney with age. Some of the genes whose transcripts increase in abundance with age are known to be specifically expressed in immune cells, suggesting that immune surveillance or inflammation increases with age. The age-regulated genes show a similar aging profile in the cortex and the medulla, suggesting a common underlying mechanism for aging. Expression profiles of these age-regulated genes mark not only age, but also the relative health and physiology of the kidney in older individuals. Finally, the set of aging-regulated kidney genes suggests specific mechanisms and pathways that may play a role in kidney degeneration with age.


description_brief: Genes up-regulated in HL-60 cells (promyeloid leukemia) by cantharidin [PubChem=6708701].
systematic_name: M14118
exact_source: Table 2
source_species_code: HS
contributor: John Newman
contrib_organization: University of Washington
description_full:
  Cantharidin is a natural toxin that has antitumor properties and causes leukocytosis as well as increasing sensitivity of tumor cells resistant to other chemotherapeutic agents. There is limited information, however, on the molecular pharmacological mechanisms of cantharidin on human cancer cells. We have used cDNA microarrays to identify gene expression changes in HL-60 promyeloid leukemia cells exposed to cantharidin. Cantharidin-treated cells not only decreased expression of genes coding for proteins involved in DNA replication (e.g., DNA polymerase delta), DNA repair (e.g., FANCG, ERCC), energy metabolism (e.g., isocitrate dehydrogenase alpha, ADP/ATP translocase), but also decreased expression of genes coding for proteins that have oncogenic activity (e.g., c-myc, GTPase) or show tumor-specific expression (e.g., phosphatidylinositol 3-kinase). In contrast, these treated cells overexpressed several genes that encode intracellular and secreted growth-inhibitory proteins (e.g., BTG2, MCP-3) as well as proapoptotic genes (e.g., ATL-derived PMA-responsive peptide). Our findings suggest that alterations in specific genes functionally related to cell proliferation or apoptosis may be responsible for cantharidin-mediated cytotoxicity. We also found that exposure of HL-60 cells to cantharidin resulted in the decreased expression of multidrug resistance-associated protein genes (e.g., ABCA3, MOAT-B), suggesting that cantharidin may be used as an oncotherapy sensitizer, and the increased expression of genes in modulating cytokine production and inflammatory response (e.g., NFIL-3, N-formylpeptide receptor), which may partly explain the stimulating effects on leukocytosis. Our data provide new insight into the molecular mechanisms of cantharidin.


systematic_name: M12051
exact_source: Table 1: fold < 0
source_species_code: HS
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Genes down-regulated in normal keratinocytes immortalized by infection with the high risk HPV31 (human papilloma virus) strain.

description_full:
  Human papillomaviruses (HPVs) infect keratinocytes and induce proliferative lesions. In infected cells, viral gene products alter the activities of cellular proteins, such as Rb and p53, resulting in altered cell cycle response. It is likely that HPV gene products also alter expression of cellular genes. In this study we used microarray analysis to examine the global changes in gene expression induced by high-risk HPV type 31 (HPV31). Among 7,075 known genes and ESTs (expressed sequence tags) tested, we found that 178 were upregulated and 150 were downregulated twofold or more in HPV31 cells compared to normal human keratinocytes. While no specific pattern could be deduced from the list of genes that were upregulated, downregulated genes could be classified to three groups: genes that are involved in the regulation of cell growth, genes that are specifically expressed in keratinocytes, and genes whose expression is increased in response to interferon stimulation. The basal level of expression of several interferon-responsive genes was found to be downregulated in HPV31 cells by both microarray analysis and Northern blot analysis in different HPV31 cell lines. When cells were treated with alpha or gamma interferon, expression of interferon-inducible genes was impaired. At high doses of interferon, the effects were less pronounced. Among the genes repressed by HPV31 was the signal transducer and activator of transcription (Stat-1), which plays a major role in mediating the interferon response. Suppression of Stat-1 expression may contribute to a suppressed response to interferon as well as immune evasion.


systematic_name: M14098
exact_source: Table 1S: 24hpi <= -3 & Diff Call [24 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 24 h time point that were not down-regulated at the previous time point, 20 h.

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


systematic_name: M12948
exact_source: Table 3: ratio < 0
source_species_code: HS
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Genes down-regulated in MCF7 cells (breast cancer) after treatment with the oxydants: hydrogen peroxyde, menadione, and t-butyl hydroperoxyde [PubChem=784;4055;6410].

description_full:
  Global gene expression patterns in breast cancer cells after treatment with oxidants (hydrogen peroxide, menadione, and t-butyl hydroperoxide) were investigated in three replicate experiments. RNA collected after treatment (at 1, 3, 7, and 24 h) rather than after a single time point, enabled an analysis of gene expression patterns. Using a 17,000 microarray, template-based clustering and multidimensional scaling analysis of the gene expression over the entire time course identified 421 genes as being either up- or down-regulated by the three oxidants. In contrast, only 127 genes were identified for any single time point and a 2-fold change criteria. Surprisingly, the patterns of gene induction were highly similar among the three oxidants; however, differences were observed, particularly with respect to p53, IL-6, and heat-shock related genes. Replicate experiments increased the statistical confidence of the study, whereas changes in gene expression patterns over a time course demonstrated significant additional information versus a single time point. Analyzing the three oxidants simultaneously by template cluster analysis identified genes that heretofore have not been associated with oxidative stress.


systematic_name: M13251
exact_source: Table 1S: 14hpi <= -3 & Diff Call [14 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 14 h time point that were not down-regulated at the previous time point, 12 h.

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


systematic_name: M10695
exact_source: Table 1S: 8hpi >= 3 & Diff Call [8hpi] = 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 point after infection with HCMV (AD169 strain) at 8 h time point that were not up-regulated at the previous time point, 6 h.

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


systematic_name: M1545
exact_source: Table 1: 12h
source_species_code: HS
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Genes up-regulated in MMEC cells (myometrial endothelium) at 12 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: M5601
exact_source: Table 1S: 20 hpi <= -3 & Diff Call [20 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 20 h time point that were not down-regulated at the previous time point, 18 h.

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


systematic_name: M1554
exact_source: Table 1: pCMV-BRG1 24 h > 0
source_species_code: HS
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Genes up-regulated in H1299 cells (lung cancer) by expression of SMARCA4 [GeneID=6597] off a plasmid vector.

description_full:
  BRG1, also called SMARCA4, is the catalytic subunit of the SWI/SNF chromatin-remodelling complex and influences transcriptional regulation by disrupting histone-DNA contacts in an ATP-dependent manner. BRG1 and other members of the SWI/SNF complex become inactivated in tumours, implying a role in cancer development. To understand the contribution of BRG1 to lung tumourigenesis, we restored BRG1 in H1299 lung cancer cells and used cDNA microarray analysis to identify changes in gene expression. Forty-three transcripts became activated, whereas two were repressed. Chromatin immunoprecipitation of resulting candidate genes revealed that the CYP3A4 and ZNF185 promoters recruited BRG1 and that recruitment to the CYP3A4 promoter was specific to this gene and did not involve the CYP3A5 or CYP3A7 family members. Moreover, specifically BRG1 but not its homologue BRM was recruited to the CYP3A4 and ZNF185 promoters. To explore their potential relevance in lung tumours, levels of CYP3A4 and ZNF185 transcripts were evaluated in seven additional lung cancer cell lines. CYP3A4 was undetectable in any of the lung cancer cells tested, and only the CYP3A5 family member was present in the A549 and Calu-3 cells. In contrast, the amount of ZNF185 transcript clearly varied among lung cancer cell lines and severely reduced levels were observed in BRG1-deficient cells, except those of A427. We extended these observations to 27 lung primary tumours using real-time RT-PCR (TaqMan) and observed that four (15%) and 14 (52%) of them had BRG1 and ZNF185 downregulation, respectively, when compared with normal lung. No significant correlation between reduced levels of BRG1 and ZNF185 was observed, indicating that additional mechanisms to BRG1 inactivation may contribute to the loss of ZNF185 expression in lung tumours. In conclusion, our results provide evidence that transcriptional activation of ZNF185 and CYP3A4 is mediated by direct association of BRG1 with their promoters and also indicate that a decreased level of ZNF185 is a common feature of lung tumours and may be of biological relevance in lung carcinogenesis.


systematic_name: M19622
exact_source: Table 1
source_species_code: HS
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Genes up-regulated in HK-2 cells kidney tubular epithelium) under hypoxia and down-regulated on re-oxygenation.

description_full:
  Epithelial cells of the kidney represent a primary target for hypoxic injury in ischemic acute renal failure (ARF); however, the underlying transcriptional mechanism(s) remain undefined. In this study, human proximal tubular epithelial cells (HK-2) exposed to hypoxia in vitro demonstrated a non-lethal but dysfunctional phenotype, closely reflective of the epithelial pathobiology of ARF. HK-2 cells exposed to hypoxia demonstrated increased paracellular permeability, decreased proliferation, loss of tight junctional integrity, and significant actin disassembly in the absence of cell death. Microarray analysis of transcriptomic changes underlying this response identified a distinct cohort of 48 genes with a closely shared hypoxia-dependent expression profile. Within this hypoxia-sensitive cluster were genes identified previously as hypoxia-inducible factor-1 (HIF-1)-dependent (e.g. vascular endothelial growth factor and adrenomedullin) as well as genes not previously known to be hypoxia-responsive (e.g. stanniocalcin 2). In hypoxia, HIF-1 bound to evolutionarily conserved hypoxia-response elements (HRE) in the promoters of these genes as well as to the HRE consensus motif. A further subset of these genes, not associated with transcriptional regulation by HIF-1, was also present, suggesting alternative HIF-1-independent pathways. Overexpression of HIF-1 alpha in normoxia induced the expression of a significant number of the hypoxia-dependent genes; however, it did not induce the pathophysiologic epithelial response. In summary, hypoxia-elicited alterations in renal proximal tubular epithelial cells in vitro closely resemble the epithelial pathophysiology of ARF. Our data indicate that although this event may rely heavily on HIF-1-dependent gene transcription, it is likely that separate hypoxia-dependent transcriptional regulators also play a role.


description_brief: Genes whose promoters contain TP53 [GeneID=7157] response elements.
systematic_name: M16284
exact_source: Table 1
source_species_code: HS
contributor: John Newman
contrib_organization: University of Washington
description_full:
  Little is known about the mechanisms that regulate differential transactivation by p53. We developed a system in the yeast Saccharomyces cerevisiae that addresses p53 transactivation capacity from 26 different p53 response elements (REs) under conditions where all other factors, such as chromatin, are kept constant. The system relies on a tightly regulated promoter (rheostatable) that can provide for a broad range of p53 expression. The p53 transactivation capacity toward each 20- to 22-bp-long RE could be ranked by using a simple phenotypic assay. Surprisingly, there was as much as a 1,000-fold difference in transactivation. There was no correlation between the functional rank and statistical predictions of binding energy of the REs. Instead we found that the central sequence element in an RE greatly affects p53 transactivation capacity, possibly because of DNA structural properties. Our results suggest that intrinsic DNA binding affinity and p53 protein levels are important contributors to p53-induced differential transactivation. These results are also relevant to understanding the regulation by other families of transcription factors that recognize several sequence-related response elements and/or have tightly regulated expression. We found that p53 had weak activity towards half the apoptotic REs. In addition, p53 alleles associated with familial breast cancer, previously classified as wild type, showed subtle differences in transactivation capacity towards several REs.


systematic_name: M1561
exact_source: Table 2S
source_species_code: HS
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Genes down-regulated in BJ cells (foreskin fibroblasts) immortalized by expression of TERT [GeneID=7015].

description_full:
  Reconstitution of telomerase activity by ectopic expression of telomerase reverse transcriptase (hTERT) results in an immortal phenotype in various types of normal human cells, including fibroblasts. Despite lack of transformation characteristics, it is unclear whether hTERT-immortalized cells are physiologically and biochemically the same as their normal counterparts. Here, we compared the gene expression profiles of normal and hTERT-immortalized fibroblasts by using a cDNA microarray containing 20,736 cDNA clones and identified 172 dysregulated genes or expressed sequence tags (ESTs). One of the highly expressed genes in the hTERT-immortalized fibroblasts (hTERT-BJ cells) encodes epiregulin, a potent growth factor. Blockade of epiregulin reduced the growth of hTERT-BJ cells and colony formation of hTERT-transformed fibroblasts. Moreover, inhibition of epiregulin function in immortal hTERT-BJ cells triggered a senescence program. Our results suggest that both activation of telomerase and subsequent induction of epiregulin are required for sustained cell proliferation. Given the significant difference in gene expression profiles between normal and hTERT-immortalized fibroblasts and the close relationship between epiregulin and tumorigenesis, we conclude that hTERT-immortalized cells may not replace their normal counterparts for studies of normal cell biology and that the use of hTERT for expansion of normal human cells for therapeutic purposes must be approached with caution.


systematic_name: M1037
exact_source: Table 3, 3A
source_species_code: HS
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Genes up-regulated in gastric cancer cell lines: doxorubicin [PubChem=31703] resistant vs sensitive.

description_full:
[cell repeats an earlier one in this file: 1503 characters]


systematic_name: M12144
exact_source: Table 1S: 48hpi <= 3 & Diff Call [48hpi] = 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 48 h time point that were not down-regulated at the previous time point, 24 h.

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


systematic_name: M19929
exact_source: Table 1S: 48hpi >= 3 & Diff Call [48hpi] = 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 48 h time point that were not up-regulated at the previous time point, 24 h.

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


systematic_name: M7846
exact_source: Table 1S: 8hpi <= -3 & Diff Call [8hpi] = 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 point after infection with HCMV (AD169 strain) at 8 h time point that were not down-regulated at the previous time point, 6 h.

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


systematic_name: M4767
exact_source: Table 1: Cluster 2
source_species_code: HS
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Cluster 2: ECM related genes up-regulated in dermal fibroblasts within 30 min after TGFB1 [GeneID=7040] addition; reached a plateau after that.

description_full:
[cell repeats an earlier one in this file: 1532 characters]


systematic_name: M7429
exact_source: Table 3: 24 h down-regulated
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in T98G cells (glioma, express MGMT [GeneID=4255]) by carmustine [PubChem=2578] at 24 h.

description_full:
[cell repeats an earlier one in this file: 1725 characters]


systematic_name: M8365
exact_source: Fig. 3
source_species_code: HS
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Genes commonly up-regulated in undifferentiated cancer relative to well-differentiated cancer, based on 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.


systematic_name: M17225
exact_source: Table 1S: 14hpi >= 3 & Diff Call [14hpi] = 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 14 h time point that were not up-regulated at the previous time point, 12 h.

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


systematic_name: M16026
exact_source: Table 1: Cluster 1
source_species_code: HS
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Cluster 1: ECM related genes up-regulated in dermal fibroblasts within 30 min after TGFB1 [GeneID=7040] addition, and which kept increasing with time.

description_full:
[cell repeats an earlier one in this file: 1532 characters]


description_brief: Up-regulated at any timepoint following infection of primary human foreskin fibroblasts with CMV
systematic_name: M19630
exact_source: Table 1: U
source_species_code: HS
contributor: John Newman
contrib_organization: University of Washington
description_full:
  Mechanistic insights to viral replication and pathogenesis generally have come from the analysis of viral gene products, either by studying their biochemical activities and interactions individually or by creating mutant viruses and analyzing their phenotype. Now it is possible to identify and catalog the host cell genes whose mRNA levels change in response to a pathogen. We have used DNA array technology to monitor the level of approximately 6,600 human mRNAs in uninfected as compared with human cytomegalovirus-infected cells. The level of 258 mRNAs changed by a factor of 4 or more before the onset of viral DNA replication. Several of these mRNAs encode gene products that might play key roles in virus-induced pathogenesis, identifying them as intriguing targets for further study.


systematic_name: M4737
exact_source: Table 1: Clusters 1-3
source_species_code: HS
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  ECM related genes up-regulated early (within 30 min) in dermal fibroblasts after addition of TGFB1 [GeneID=7040].

description_full:
[cell repeats an earlier one in this file: 1532 characters]


systematic_name: M6641
exact_source: Table 1S: 18hpi >= 3 & Diff Call [18hpi] = I, MI
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 18 h time point that were not down-regulated at the previous time point, 16 h.

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


systematic_name: M1587
exact_source: Table 1: Cluster 4
source_species_code: HS
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Genes in cluster 4: immediate down-regulation in HFW cells (fibroblast) by sodium arsenite [PubChem=26435].

description_full:
[cell repeats an earlier one in this file: 1227 characters]


systematic_name: M15069
exact_source: Table 3
source_species_code: HS
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Genes up-regulated in A549 cells (lung carcinoma) upon infection with RSV (respiratory syncytial virus) and up-regulated by further treatment with ribavirin [PubChem=5064].

description_full:
  Respiratory syncytial virus (RSV) is a mucosa-restricted virus that is a leading cause of epidemic respiratory tract infections in children. RSV replication is a potent activator of the epithelial-cell genomic response, influencing the expression of a spectrum of cellular pathways, including proinflammatory chemokines of the CC, CXC, and CX(3)C subclasses. Ribavirin (1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide) is a nontoxic antiviral agent currently licensed for the treatment of severe RSV lower respiratory tract infections. Because ribavirin treatment reduces the cytopathic effect in infected cells, we used high-density microarrays to investigate the hypothesis that ribavirin modifies the virus-induced epithelial genomic response to replicating virus. Ribavirin treatment administered in concentrations of 10 to 100 micro g/ml potently inhibited RSV transcription, thereby reducing the level of RSV N transcripts to approximately 13% of levels in nontreated cells. We observed that in both the absence and the presence of ribavirin, RSV infection induced global alterations in the host epithelial cell, affecting approximately 49% of the approximately 6,650 expressed genes detectable by the microarray. Ribavirin influences the expression of only 7.5% of the RSV-inducible genes (total number of genes, 272), suggesting that the epithelial-cell genetic program initiated by viral infection is independent of high-level RSV replication. Hierarchical clustering of the ribavirin-regulated genes identified four expression patterns. In one group, ribavirin inhibited the expression of the RSV-inducible CC chemokines MIP-1 alpha and -1 beta, which are important in RSV-induced pulmonary pathology, and interferon (IFN), a cytokine important in the mucosal immune response. In a second group, ribavirin further up-regulated a set of RSV- and IFN-stimulated response genes (ISGs) encoding antiviral proteins (MxA and p56), complement products, acute-phase response factors, and the STAT and IRF transcription factors. Because IFN-beta expression itself was reduced in the ribavirin-treated cells, we further investigated the mechanism for up-regulation of the IFN-signaling pathway. Enhanced expression of IFI 6-16, IFI 9-27, MxA/p78, STAT-1 alpha, STAT-1 beta, IRF-7B, and TAP-1-LMP2 transcripts were independently reproduced by Northern blot analysis. Ribavirin-enhanced TAP-1-LMP2 expression was a transcriptional event where site mutations of the IFN-stimulated response element (ISRE) blocked RSV and ribavirin-inducible promoter activity. Furthermore, ribavirin up-regulated the transcriptional activity of a reporter gene selectively driven by the ISRE. In specific DNA pull-down assays, we observed that ribavirin enhanced RSV-induced STAT-1 binding to the ISRE. We conclude that ribavirin potentiates virus-induced ISRE signaling to enhance the expression of antiviral ISGs, suggesting a mechanism for the efficacy of combined treatment with ribavirin and IFN in other chronic viral diseases.


systematic_name: M15187
exact_source: Table 2S: Cluster d6
source_species_code: HS
GEO_id: GSE713
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Cluster d6: genes progressively down-regulated in WS1 cells (fibroblast) through 18 h after irradiation with high dose UV-C.

description_full:
[cell repeats an earlier one in this file: 1467 characters]


systematic_name: M5388
exact_source: Table 1S: 18hpi <= -3 & Diff Call [18 hpi] = D, MD
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 18 h time point that were not up-regulated at the previous time point, 16 h.

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


systematic_name: M1603
exact_source: Table 1
source_species_code: HS
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Genes up-regulated in HeLa cells (cervical carcinoma) at 30 min 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: M12459
exact_source: Table 3
source_species_code: HS
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Cancer related genes down-regulated in any of four hepatoma cell lines following 24 h treatment with TSA [PubChem=5562].

description_full:
  OBJECTIVE: Histone deacetylase (HDAC) inhibitors have been reported to induce cell growth arrest, apoptosis and differentiation in tumor cells. The effect of the HDAC inhibitor, trichostatin A (TSA), on hepatoma cells, however, has not been well studied. In this study, we examined cell viability and gene expression profile in hepatoma cell lines treated with TSA. METHODS: To study cell growth inhibition and induction of apoptosis by TSA on human hepatoma cell lines including HuH7, Hep3B, HepG2, and PLC/PRF/5, cells were treated with TSA at various concentrations and analyzed by the 3-(4, 5-dimethyl-2-thiazolyl)-2H-tetrazolium bromide (MTT) and TUNEL assays, respectively. Changes in gene expression profile after exposure to TSA were assessed using a cDNA microarray consisting of 557 distinct cDNA of cancer-related genes. The levels of acetylated histones were examined by the chromatin immunoprecipitation (ChIP) assay using anti-acetylated histone H3 or H4 antibody. RESULTS: The MTT assay demonstrated that TSA showed cell growth inhibition not only in a concentration-dependent but also a time-dependent manner on all cell lines studied. The TUNEL assay also revealed the potential of TSA to induce apoptosis. The microarray analysis revealed that 8 genes including collagen type 1, alpha2 (COL1A2), insulin-like growth factor binding protein 2 (IGFBP2), integrin, alpha7 (ITGA7), basigin (BSG), quiescin Q6 (QSCN6), superoxide dismutase 3, extracellular (SOD3), nerve growth factor receptor (NGFR), and p53-induced protein (PIG11) exhibited substantial induction (ratio >2.0) after TSA treatment in multiple cell lines. ChIP assay, in general, showed a good correlation between the expression level of mRNA and levels of acetylated histones in these upregulated genes. CONCLUSIONS: This study showed cell growth inhibition and the gene expression profile in hepatoma cell lines exposed to TSA. The alteration in levels of acetylated histones was closely associated with expression of specific cancer-related genes in hepatoma cells.


systematic_name: M2257
exact_source: Table 1
source_species_code: HS
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Cellular genes up-regulated in forskin fibroblasts by expression of CMV EI86 protein off an adenovirus vector.

description_full:
  We have previously reported that the immediate early (IE)-86 protein of human cytomegalovirus (HCMV) pushes the cell cycle toward S phase but inhibits cell division [Murphy, E. A., Streblow, D. N., Nelson, J. A. & Stinski, M. F. (2000) J. Virol. 74, 7108-7118]. We determined the cellular genes activated by the IE86 protein in permissive human fibroblast cells. A 4-fold or greater increase in the steady-state RNA from many cellular genes that regulate the cell cycle, the enzymes for DNA precursor synthesis, and the initiation of cellular DNA replication was detected by high-density DNA microarray analysis. Northern blot analysis confirmed the DNA microarray data. The viral IE86 protein induced a significant increase in the cellular steady-state RNA level from the B-myb, cyclin E, cdk-2, E2F-1, ribonucleotide reductase 1, ribonucleotide reductase 2, thymidylate synthetase, MCM3, and MCM7 genes, but actin RNA was not affected. Cellular genes regulated by the E2F transcription factors were strongly activated by the IE86 protein. In most cases, the cellular genes induced by the IE86 protein were also induced by HCMV infection. This study demonstrates the global array of cellular genes activated by the IE86 protein that pushes progression of the cell cycle from G0/G1 toward the G1/S transition point.


systematic_name: M972
exact_source: unknown
source_species_code: MM
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Up-regulated at 4 hours following treatment of mouse lymphocytes (TK 3.7.2C) with a high dose of methyl methanesulfonate (MMS)

description_full:
  Exposure to DNA-damaging agents can elicit a variety of stress-related responses that may alter the gene expression of numerous biological pathways. We used Affymetrix microarrays to detect gene expression changes in mouse lymphoma (L5178Y) and human lymphoblastoid (TK6) cells in response to methyl methanesulfonate (MMS; a prototypical alkylating agent) and bleomycin (a prototypical oxidative mutagen). Cells were treated for 4 hr, and RNA was isolated either at the end of the treatment or after a 20-hr recovery period. Two concentrations of each agent were used based on cytotoxicity levels and Tk mutant frequencies. Our microarray data analysis indicated that MMS and bleomycin gene expression responses were considerably different in mouse cells versus human cells. The results also suggested that more comprehensive cellular responses to MMS and bleomycin occurred in TK6 cells than in L5178Y cells. In contrast to L5178Y cells, the response of TK6 cells to MMS and bleomycin was characterized by the induction of p53-dependent genes that are involved in DNA repair, cell cycle regulation, and apoptosis. It appears that the induction of DNA damage by MMS in human TK6 cells mediated cytotoxicity and led to decreased cell survival. This may explain the greater sensitivity of TK6 cells to cytotoxic effects of MMS compared to L5178Y cells. Bleomycin exerted comparable cytotoxic effects in the two cell lines. Overall, these studies were unable to identify distinctive gene expression changes that differentiated bleomycin from MMS in either TK6 cells or mouse lymphoma cells.


systematic_name: M6302
exact_source: Table 1
source_species_code: HS
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Genes down-regulated in LD419 cells (fibroblast) 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: M3506
exact_source: Fig. 7A: arrow down
source_species_code: HS
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Down-regulated in CD4+ [GeneID=920] T lymphocytes after 4 h treatment with 100 nM TSA [PubChem=5562].

description_full:
  BACKGROUND: Histone deacetylase inhibitors (HDACIs) induce hyperacetylation of core histones modulating chromatin structure and affecting gene expression. These compounds are also able to induce growth arrest, cell differentiation, and apoptotic cell death of tumor cells in vitro as well as in vivo. Even though several genes modulated by HDAC inhibition have been identified, those genes clearly responsible for the biological effects of these drugs have remained elusive. We investigated the pharmacological effect of the HDACI and potential anti-cancer agent Trichostatin A (TSA) on primary T cells. METHODS: To ascertain the effect of TSA on resting and activated T cells we used a model system where an enriched cell population consisting of primary T-cells was stimulated in vitro with immobilized anti-CD3/anti-CD28 antibodies whilst exposed to pharmacological concentrations of Trichostatin A. RESULTS: We found that this drug causes a rapid decline in cytokine expression, accumulation of cells in the G1 phase of the cell cycle, and induces apoptotic cell death. The mitochondrial respiratory chain (MRC) plays a critical role in the apoptotic response to TSA, as dissipation of mitochondrial membrane potential and reactive oxygen species (ROS) scavengers block TSA-induced T-cell death. Treatment of T cells with TSA results in the altered expression of a subset of genes involved in T cell responses, as assessed by microarray gene expression profiling. We also observed up- as well as down-regulation of various costimulatory/adhesion molecules, such as CD28 and CD154, important for T-cell function. CONCLUSIONS: Taken together, our findings indicate that HDAC inhibitors have an immunomodulatory potential that may contribute to the potency and specificity of these antineoplastic compounds and might be useful in the treatment of autoimmune disorders.


systematic_name: M15382
exact_source: Table 1S: 10hpi >= 3 & Diff Call [10hpi] = 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 10 h time point that were not up-regulated at the previous time point, 8 h.

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


systematic_name: M1618
exact_source: Suppl. file BRG1resp.xls
source_species_code: HS
GEO_id: GSE2966
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Genes up-regulated in SW-13 cells (kidney cancer) by transient expression of SMARCA4 [GeneID=6597] at 24 h off a plasmid vector.

description_full:
  The mammalian BAF complex regulates gene expression by modifying chromatin structure. In this report, we identify 80 genes activated and 2 genes repressed by the BAF complex in SW-13 cells. We find that prior binding of NFI/CTF to the NFI/CTF binding site in CSF1 promoter is required for the recruitment of the BAF complex and the BAF-dependent activation of the promoter. Furthermore, the activation of the CSF1 promoter requires Z-DNA-forming sequences that are converted to Z-DNA structure upon activation by the BAF complex. The BAF complex facilitates Z-DNA formation in a nucleosomal template in vitro. We propose a model in which the BAF complex promotes Z-DNA formation which, in turn, stabilizes the open chromatin structure at the CSF1 promoter.


systematic_name: M8834
exact_source: Table 1: week 4 < 1
source_species_code: HS
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Genes down-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: M10142
exact_source: Table 1: full names changed to symbols
source_species_code: RN
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  DNA replication genes up-regulated in a Rat-1a cell line (fibroblast) by expression of E2F1 [GeneID=1869].

description_full:
  The transcription factor E2F-1 plays a pivotal role in the regulation of G1/S transition in higher eukaryotes cell cycle. We used a cell line containing an inducible E2F-1 and oligonucleotide microarray analysis to identify novel E2F target genes. We show that E2F-1 up-regulates the expression of a number of genes coding for components of the DNA replication machinery. Among them is the gene coding for the 32 Kd subunit of replication protein A (RPA2). Replication protein A is the most abundant single strand DNA binding complex and it is essential for DNA replication. We demonstrate that RPA2 is a novel E2F target gene whose expression can be directly regulated by E2F-1 via E2F binding sites in its promoter. In addition, expression of Topoisomerase IIalpha and subunit IV of DNA polymerase alpha is also up-regulated upon E2F-1 induction. Taken together, these results provide novel links between components of the DNA replication machinery and the cell growth regulatory pathway involving the Rb tumor suppressor and E2F.


systematic_name: M11572
exact_source: Table 1S: 12hpi >= 3 & Diff Call [12hpi] = 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 12 h time point that were not up-regulated at the previous time point, 10 h.

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


systematic_name: M7013
exact_source: Table 8S
source_species_code: RM
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Upregulated in the vastus lateralis muscle of middle aged rhesus monkeys subjected to caloric restriction since young adulthood vs age matched controls

description_full:
[cell repeats an earlier one in this file: 1642 characters]


systematic_name: M9066
exact_source: Table 2: 48 h down-regulated
source_species_code: HS
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Genes down-regulated in A172 cells (glioma, does not express MGMT [GeneID=4255]) by carmustine [PubChem=2578] at 48 h.

description_full:
[cell repeats an earlier one in this file: 1725 characters]


systematic_name: M8382
exact_source: Suppl. File 2: cluster 5
source_species_code: HS
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Cluster 5: genes up-regulated in SW260 cells (colon cancer) by curcumin and sulindac [PubChem=969516;5352].

description_full:
[cell repeats an earlier one in this file: 2217 characters]


systematic_name: M14728
exact_source: Table 1S: 6hpi >= 3 & Diff Call [6hpi] = 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 point after infection with HCMV (AD169 strain) at 6 h time point that were not up-regulated at the previous time point, 4 h.

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


systematic_name: M9375
exact_source: Table 2S: Cluster#=G1
source_species_code: HS
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Cluster G1: genes most highly up-regulated in NHEK cells (normal keratinocyte) between 6 h and 12 h after UV-B irradiation.

description_full:
[cell repeats an earlier one in this file: 2087 characters]


description_brief: Genes that are transcriptionally regulated by HIF1A [GeneID=3091].
systematic_name: M12299
exact_source: Table 1
source_species_code: HS
contributor: John Newman
contrib_organization: University of Washington
description_full:
  Hypoxia-inducible factor 1 (HIF-1) activates transcription of genes encoding proteins that mediate adaptive responses to reduced oxygen availability. The HIF-1beta subunit is constitutively expressed, whereas the HIF-1alpha subunit is subject to ubiquitination and proteasomal degradation, a process that is inhibited under hypoxic conditions. Recent data indicate that HIF-1 plays major roles in the prevention of myocardial and cerebral ischemia and in the pathogenesis of pulmonary hypertension and cancer. Modulation of HIF-1 activity by genetic or pharmacological means could provide a novel therapeutic approach to these common causes of mortality.


systematic_name: M19511
exact_source: Table 1S: fold change > 0
source_species_code: HS
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Genes up-regulated in fibroblasts with defective XPC [GeneID=7508] in response to cisplatin [PubChem=2767].

description_full:
  XPC is an important DNA damage recognition protein involved in DNA nucleotide excision repair. We have studied the role of the XPC protein in cisplatin treatment-mediated cell cycle regulation. Through the comparison of microarray data obtained from human normal fibroblasts and two individual XPC-defective cell lines, 486 genes were identified as XPC-responsive genes in the cisplatin treatment (with a minimal 1.5-fold change) and 297 of these genes were further mapped to biological pathways and gene ontologies. The cell cycle and cell proliferation-related genes were the most affected genes by the XPC defect in the cisplatin treatment. Many other cellular function genes were also affected by the XPC defect in the treatment. Western blot hybridization results revealed that the XPC defect reduced the p53 responses to the cisplatin treatment. The ability to activate caspase-3 was also attenuated in the XPC cells with the treatment. These results suggest that the XPC protein plays a critical role in initiating the cisplatin DNA damaging treatment-mediated signal transduction process, resulting in activation of the p53 pathway and cell cycle arrest that allow DNA repair and apoptosis to take place. These results reveal an important role of the XPC protein in the cancer prevention.


systematic_name: M1636
exact_source: Table 1: Cluster 3
source_species_code: HS
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Genes in cluster 3: delayed up-regulation in HFW cells (fibroblast) by sodium arsenite [PubChem=26435].

description_full:
[cell repeats an earlier one in this file: 1227 characters]


systematic_name: M16384
exact_source: Table 1: Down-regulated
source_species_code: HS
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Genes down-regulated in MFCF-7 cells (breast cancer) upon stable autocrine expression of HG1 [GeneID=2688].

description_full:
[cell repeats an earlier one in this file: 1275 characters]


systematic_name: M9556
exact_source: Table 3: 48 h down-regulated
source_species_code: HS
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Genes down-regulated in T98G cells (glioma, express MGMT [GeneID=4255]) by carmustine [PubChem=2578] at 48 h.

description_full:
[cell repeats an earlier one in this file: 1725 characters]


systematic_name: M12457
exact_source: Table 1,2: Middle Age: FoldD < 0
source_species_code: HS
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Genes down-regulated in fibroblasts from middle-age individuals, compared to those from the young donors.

description_full:
[cell repeats an earlier one in this file: 616 characters]


systematic_name: M12275
exact_source: Table 1S: 24hpi >= 3 & Diff Call [24 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 24 h time point that were not up-regulated at the previous time point, 20 h.

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


systematic_name: M10355
exact_source: Table 2
source_species_code: HS
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Genes up-regulated in MCV152 cells (ovarian cancer) treated with follicle stimulating hormone (FSH).

description_full:
  Epidemiologic data have implicated reproductive follicle-stimulating hormone (FSH) as a probable risk factor for ovarian cancer (OC) development. Although pituitary and sex hormones have been reported to regulate OC cell growth, no information is available on the influence of FSH on gene expression profiles during ovarian surface epithelial (OSE) cell proliferation. This study evaluated the effect of FSH treatment on cell proliferation of various OSE cell lines and gene expression profiles with FSH treatment. Follicle-stimulating hormone receptor (FSHR) was found at higher expression at both transcriptional and protein levels in ovarian cancerous tissues compared to normal tissues, and FSH was shown to promote cell growth in 3 OSE cell lines. Furthermore, it was also found that overexpression of FSHR in Chinese hamster ovary (CHO) cells leads to cell proliferation. Using cDNA MicroArray analysis on MCV152 cells with FSH treatment, 91 genes were found upregulated and 68 genes downregulated for more than 2-fold after FSH treatment. Most of the genes were related to metabolism, cell proliferation and oncogenes. Downregulated genes included tumor suppressor genes (RB1, BRCA1, BS69) and the genes related to cell proliferation control. Pathway analysis found that FSH activates certain important enzymes in sterol biosynthesis pathways. FSH-induced gene expression profiles on MCV152 cells support the standing hypothesis that FSH is a probable risk factor for ovarian cancerous development.


systematic_name: M10311
exact_source: Table 1S: 2hpi =< -3 & Diff Call [6hpi] = 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 point after infection with HCMV (AD169 strain) at 6 h time point that were not down-regulated at the previous time point, 4 h.

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


systematic_name: M5775
exact_source: Table 1S: 12hpi <= -3 & Diff Call [12 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 12 h time point that were not down-regulated at the previous time point, 10 h.

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


systematic_name: M5622
exact_source: Table 2S: Cluster#=G2
source_species_code: HS
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Cluster G2: genes increasingly up-regulated in NHEK cells (normal keratinocyte) and reaching maximum levels at 12 h and 24 h after UV-B irradiation.

description_full:
[cell repeats an earlier one in this file: 2087 characters]


systematic_name: M1673
exact_source: Table 1: 3h
source_species_code: HS
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Genes up-regulated in MMEC cells (myometrial endothelium) at 3 h after VEGFA [GeneID=7422] stimulation.

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


systematic_name: M8349
exact_source: Suppl. file: CHS & Igrovs with common trend: down
source_species_code: HS
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Genes down-regulated in chondrosarcoma and ovarian carcinoma cell lines which developed resistance to trabectedin [PubChem=3199].

description_full:
  ET-743 (Yondelis(TM), Trabectedin) isolated from the tunicate Ecteinascidia turbinata, is being tested in phase II clinical trials in Europe and the United States of America (USA). Studies with different solid tumours have shown antitumour activity in advanced, pre-treated sarcomas as well as in drug-resistant breast and ovarian cancer. The primary mechanism of action for ET-743 has not been fully elucidated and different models have been suggested to explain its molecular mechanism of action. ET-743 binds tightly to the minor groove of DNA and previous data have suggested that ET-743 acts by interfering with RNA transcription. To further investigate the mechanism of in vitro drug resistance, we evaluated the gene expression profile in ovarian and chondrosarcoma cell lines selected for resistance to ET-743. We found 70 genes whose expression was modulated in both drug-resistant cell lines when compared with their respective parental drug-sensitive cell lines. This pattern of gene expression seems to be selective for ET-743-resistant cells, since ovarian cancer cells resistant to paclitaxel did not share the same gene expression changes. Data presented in this study reveal different molecular pathways that could be involved in the cellular mechanism of ET-743 resistance.


systematic_name: M2069
exact_source: Table 1S: myc
source_species_code: HS
GEO_id: GSE3151
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes selected in supervised analyses to discriminate cells expressing c-Myc [GeneID=4609] from control cells expressing GFP.

description_full:
[cell repeats an earlier one in this file: 1717 characters]


systematic_name: M12029
exact_source: Table 1S: Ras
source_species_code: HS
GEO_id: GSE3151
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes selected in supervised analyses to discriminate cells expressing activated HRAS [GeneID=3265] oncogene from control cells expressing GFP.

description_full:
[cell repeats an earlier one in this file: 1717 characters]


systematic_name: M17363
exact_source: Table 3S
source_species_code: HS
GEO_id: GSE4003
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Immune response genes up-regulated in zenograft tumors formed by SNU-601 cells (gastric cancer) made to express LRRC3B [GeneID=116135].

description_full:
  Leucine-rich repeat-containing 3B (LRRC3B) is an evolutionarily highly conserved leucine-rich repeat-containing protein, but its biological significance is unknown. Using restriction landmark genomic scanning and pyrosequencing, we found that the promoter region of LRRC3B was aberrantly methylated in gastric cancer. Gastric cancer cell lines displayed epigenetic silencing of LRRC3B, but treatment with the DNA methylation inhibitor 5-aza-2'-deoxycytidine and/or the histone deacetylase inhibitor trichostatin A increased LRRC3B expression in gastric cancer cell lines. Real-time reverse transcription-PCR analysis of 96 paired primary gastric tumors and normal adjacent tissues showed that LRRC3B expression was reduced in 88.5% of gastric tumors compared with normal adjacent tissues. Pyrosequencing analysis of the promoter region revealed that LRRC3B was significantly hypermethylated in gastric tumors. Stable transfection of LRRC3B in SNU-601 cells, a gastric cancer cell line, inhibited anchorage-dependent and anchorage-independent colony formation, and LRRC3B expression suppressed tumorigenesis in nude mice. Microarray analysis of LRRC3B-expressing xenograft tumors showed induction of immune response-related genes and IFN signaling genes. H&E-stained sections of LRRC3B-expressing xenograft tumors showed lymphocyte infiltration in the region. We suggest that LRRC3B is a putative tumor suppressor gene that is silenced in gastric cancers by epigenetic mechanisms and that LRRC3B silencing in cancer may play an important role in tumor escape from immune surveillance.


systematic_name: M12522
exact_source: Suppl. Data File 1: HER2-18_Group1
source_species_code: HS
GEO_id: GSE8139,GSE8141,GSE8140
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  The 'group 1 set' of genes associated with acquired endocrine therapy resistance in breast tumors expressing ESR1 and ERBB2 [GeneID=2099;2064].

description_full:
  The effectiveness of therapies targeting specific pathways in breast cancer, such as the estrogen receptor or HER2, is limited because many tumors manifest resistance, either de novo or acquired, during the course of treatment. To investigate molecular mechanisms of resistance, we used two xenograft models of estrogen receptor-positive (ER+) breast cancer, one with and one without HER2 overexpression (MCF7/HER2-18 and MCF7 wt, respectively). Mice with established tumors were assigned to the following treatment groups: estrogen supplementation (E2), estrogen deprivation (ED), ED plus tamoxifen (Tam), all with or without the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib (G). Another group received ED plus the antiestrogen fulvestrant (MCF7 wt only). Tumors with acquired or de novo resistance to these endocrine therapies were profiled for gene expression and compared with tumors in the E2 control group. One class of genes underexpressed in endocrine-resistant tumors (relative to E2-treated tumors) were estrogen inducible in vitro and associated with ER+ human breast cancers (luminal subtype). Another class of genes overexpressed in tumors with acquired resistance in both models represented transcriptional targets of HER2 signaling and was associated with ER-/HER2+ human cancers (ERBB2+ subtype). A third class of genes overexpressed in MCF7/HER2-18 tumors exhibiting de novo resistance to tamoxifen was associated with ER+ human cancers but not with estrogen-regulated genes. Thus, in response to various endocrine therapy regimens, these xenograft breast tumors shut down classic estrogen signaling and activate alternative pathways such as HER2 that contribute to treatment resistance. Over time, the molecular phenotype of breast cancer can change.


systematic_name: M3062
exact_source: Suppl. Data File 1: HER2-18_Group2
source_species_code: HS
GEO_id: GSE8139,GSE8141,GSE8140
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  The 'group 2 set' of genes associated with acquired endocrine therapy resistance in breast tumors expressing ESR1 and ERBB2 [GeneID=2099;2064].

description_full:
[cell repeats an earlier one in this file: 1792 characters]


systematic_name: M6386
exact_source: Suppl. Data File 1: WT_Group4
source_species_code: HS
GEO_id: GSE8139,GSE8141,GSE8140
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  The 'group 4 set' of genes associated with acquired endocrine therapy resistance in breast tumors expressing ESR1 but not ERBB2 [GeneID=2099;2064].

description_full:
[cell repeats an earlier one in this file: 1792 characters]


systematic_name: M2662
exact_source: Table 1
source_species_code: HS
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Selected electrophile and drug detoxication genes down-regulated in A549 and H460 cells (lung cancer) upon knockdown of NFE2L2 [GeneID=4780] by RNAi.

description_full:
  Nuclear factor erythroid-2-related factor 2 (Nrf2) is a redox-sensitive transcription factor that regulates the expression of electrophile and xenobiotic detoxification enzymes and efflux proteins, which confer cytoprotection against oxidative stress and apoptosis in normal cells. Loss of function mutations in the Nrf2 inhibitor, Kelch-like ECH-associated protein (Keap1), results in constitutive activation of Nrf2 function in non-small cell lung cancer. In this study, we show that constitutive activation of Nrf2 in lung cancer cells promotes tumorigenicity and contributes to chemoresistance by up-regulation of glutathione, thioredoxin, and the drug efflux pathways involved in detoxification of electrophiles and broad spectrum of drugs. RNAi-mediated reduction of Nrf2 expression in lung cancer cells induces generation of reactive oxygen species, suppresses tumor growth, and results in increased sensitivity to chemotherapeutic drug-induced cell death in vitro and in vivo. Inhibiting Nrf2 expression using naked siRNA duplexes in combination with carboplatin significantly inhibits tumor growth in a subcutaneous model of lung cancer. Thus, targeting Nrf2 activity in lung cancers, particularly those with Keap1 mutations, could be a promising strategy to inhibit tumor growth and circumvent chemoresistance.


systematic_name: M7488
exact_source: Figure 4B: red
source_species_code: HS
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Antigen processing and presentation genes up-regulated in JY cells (B lymphocytes) treated with TSA [PubChem=5562].

description_full:
  Histone deacetylases (HDAC) modify the architecture of chromatin, leading to decreased gene expression, an effect that is reversed by HDAC inhibition. The balance between deacetylation and acetylation is central to many biological events including the regulation of cell proliferation and cancer but also the differentiation of immune T cells. The effects of HDAC inhibition on the interaction between antitumor effector T cells and tumor cells are not known. Here, we studied presentation of a universal self-tumor antigen, telomerase reverse transcriptase, in human tumor cells during HDAC inhibition. We found that HDAC inhibition with trichostatin A was associated with a decreased presentation and diminished killing of tumor cells by CTLs. Using gene array analysis, we found that HDAC inhibition resulted in a decrease of genes coding for proteasome catalytic proteins and for tapasin, an endoplasmic reticulum resident protein involved in the MHC class I pathway of endogenous antigen presentation. Our findings indicate that epigenetic changes in tumor cells decrease self-tumor antigen presentation and contribute to reduced recognition and killing of tumor cells by cytotoxic T lymphocytes. This mechanism could contribute to tumor escape from immune surveillance.


systematic_name: M8341
exact_source: Figure 4B: blue
source_species_code: HS
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Antigen processing and presentation genes down-regulated in JY cells (B lymphocytes) treated with trichostatin A (TSA) [PubChem=5562].

description_full:
  Histone deacetylases (HDAC) modify the architecture of chromatin, leading to decreased gene expression, an effect that is reversed by HDAC inhibition. The balance between deacetylation and acetylation is central to many biological events including the regulation of cell proliferation and cancer but also the differentiation of immune T cells. The effects of HDAC inhibition on the interaction between antitumor effector T cells and tumor cells are not known. Here, we studied presentation of a universal self-tumor antigen, telomerase reverse transcriptase, in human tumor cells during HDAC inhibition. We found that HDAC inhibition with trichostatin A was associated with a decreased presentation and diminished killing of tumor cells by CTLs. Using gene array analysis, we found that HDAC inhibition resulted in a decrease of genes coding for proteasome catalytic proteins and for tapasin, an endoplasmic reticulum resident protein involved in the MHC class I pathway of endogenous antigen presentation. Our findings indicate that epigenetic changes in tumor cells decrease self-tumor antigen presentation and contribute to reduced recognition and killing of tumor cells by cytotoxic T lymphocytes. This mechanism could contribute to tumor escape from immune surveillance.


systematic_name: M1709
exact_source: Table 2S: HMGA1a
source_species_code: RN
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes changed in Rat1a cells (fibroblasts) by overexpression of  HMGA1 isoform a [GeneID=3159] off a plasmid vector.

description_full:
  Although HMGA1 (high-mobility group A1; formerly HMG-I/Y) is an oncogene that is widely overexpressed in aggressive cancers, the molecular mechanisms underlying transformation by HMGA1 are only beginning to emerge. HMGA1 encodes the HMGA1a and HMGA1b protein isoforms, which function in regulating gene expression. To determine how HMGA1 leads to neoplastic transformation, we looked for genes regulated by HMGA1 using gene expression profile analysis. Here, we show that the STAT3 gene, which encodes the signaling molecule signal transducer and activator of transcription 3 (STAT3), is a critical downstream target of HMGA1a. STAT3 mRNA and protein are up-regulated in fibroblasts overexpressing HMGA1a and activated STAT3 recapitulates the transforming activity of HMGA1a in fibroblasts. HMGA1a also binds directly to a conserved region of the STAT3 promoter in vivo in human leukemia cells by chromatin immunoprecipitation and activates transcription of the STAT3 promoter in transfection experiments. To determine if this pathway contributes to HMGA1-mediated transformation, we investigated STAT3 expression in our HMGA1a transgenic mice, all of which developed aggressive lymphoid malignancy. STAT3 expression was increased in the leukemia cells from our transgenics but not in control cells. Blocking STAT3 function induced apoptosis in the transgenic leukemia cells but not in controls. In primary human leukemia samples, there was a positive correlation between HMGA1a and STAT3 mRNA. Moreover, blocking STAT3 function in human leukemia or lymphoma cells led to decreased cellular motility and foci formation. Our results show that the HMGA1a-STAT3 axis is a potential Achilles heel that could be exploited therapeutically in hematopoietic and other malignancies overexpressing HMGA1a.


systematic_name: M1710
exact_source: Table 2S: HMGA1b
source_species_code: RN
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes changed in Rat1a cells (fibroblasts) by overexpression of  HMGA1 isoform b [GeneID=3159] off a plasmid vector.

description_full:
  Although HMGA1 (high-mobility group A1; formerly HMG-I/Y) is an oncogene that is widely overexpressed in aggressive cancers, the molecular mechanisms underlying transformation by HMGA1 are only beginning to emerge. HMGA1 encodes the HMGA1a and HMGA1b protein isoforms, which function in regulating gene expression. To determine how HMGA1 leads to neoplastic transformation, we looked for genes regulated by HMGA1 using gene expression profile analysis. Here, we show that the STAT3 gene, which encodes the signaling molecule signal transducer and activator of transcription 3 (STAT3), is a critical downstream target of HMGA1a. STAT3 mRNA and protein are up-regulated in fibroblasts overexpressing HMGA1a and activated STAT3 recapitulates the transforming activity of HMGA1a in fibroblasts. HMGA1a also binds directly to a conserved region of the STAT3 promoter in vivo in human leukemia cells by chromatin immunoprecipitation and activates transcription of the STAT3 promoter in transfection experiments. To determine if this pathway contributes to HMGA1-mediated transformation, we investigated STAT3 expression in our HMGA1a transgenic mice, all of which developed aggressive lymphoid malignancy. STAT3 expression was increased in the leukemia cells from our transgenics but not in control cells. Blocking STAT3 function induced apoptosis in the transgenic leukemia cells but not in controls. In primary human leukemia samples, there was a positive correlation between HMGA1a and STAT3 mRNA. Moreover, blocking STAT3 function in human leukemia or lymphoma cells led to decreased cellular motility and foci formation. Our results show that the HMGA1a-STAT3 axis is a potential Achilles heel that could be exploited therapeutically in hematopoietic and other malignancies overexpressing HMGA1a.


systematic_name: M14046
exact_source: Table 3, 2S: common up-regulated
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Common up-regulated transcripts in fibroblasts expressing either XP/CS or TDD mutant forms of ERCC3 [GeneID=2071], after UVC irradiation.

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


description_brief: Genes with promoters bound by E2F4 [GeneID=1874] in unstimulated hybridoma cells.
systematic_name: M1744
exact_source: Table 4S
source_species_code: MM
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_full:
  Foxp3+CD4+CD25+ regulatory T (T(reg)) cells are essential for the prevention of autoimmunity. T(reg) cells have an attenuated cytokine response to T-cell receptor stimulation, and can suppress the proliferation and effector function of neighbouring T cells. The forkhead transcription factor Foxp3 (forkhead box P3) is selectively expressed in T(reg) cells, is required for T(reg) development and function, and is sufficient to induce a T(reg) phenotype in conventional CD4+CD25- T cells. Mutations in Foxp3 cause severe, multi-organ autoimmunity in both human and mouse. FOXP3 can cooperate in a DNA-binding complex with NFAT (nuclear factor of activated T cells) to regulate the transcription of several known target genes. However, the global set of genes regulated directly by Foxp3 is not known and consequently, how this transcription factor controls the gene expression programme for T(reg) function is not understood. Here we identify Foxp3 target genes and report that many of these are key modulators of T-cell activation and function. Remarkably, the predominant, although not exclusive, effect of Foxp3 occupancy is to suppress the activation of target genes on T-cell stimulation. Foxp3 suppression of its targets appears to be crucial for the normal function of T(reg) cells, because overactive variants of some target genes are known to be associated with autoimmune disease.


systematic_name: M4034
exact_source: Table 2S
source_species_code: HS
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes expressed in at least one prostate cancer cell line but not in normal prostate epithelial cells or stromal cells

description_full:
  Hypomethylation of CpG dinucleotides in genomic DNA was one of the first somatic epigenetic alterations discovered in human cancers. DNA hypomethylation is postulated to occur very early in almost all human cancers, perhaps facilitating genetic instability and cancer initiation and progression. We therefore examined the nature, extent, and timing of DNA hypomethylation changes in human prostate cancer. Contrary to the prevailing view that global DNA hypomethylation changes occur extremely early in all human cancers, we show that reductions in (5me)C content in the genome occur very late in prostate cancer progression, appearing at a significant extent only at the stage of metastatic disease. Furthermore, we found that, whereas some LINE1 promoter hypomethylation does occur in primary prostate cancers compared with normal tissues, this LINE1 hypomethylation is significantly more pronounced in metastatic prostate cancer. Next, we carried out a tiered gene expression microarray and bisulfite genomic sequencing-based approach to identify genes that are silenced by CpG island methylation in normal prostate cells but become overexpressed in prostate cancer cells as a result of CpG island hypomethylation. Through this analysis, we show that a class of cancer testis antigen genes undergoes CpG island hypomethylation and overexpression in primary prostate cancers, but more so in metastatic prostate cancers. Finally, we show that DNA hypomethylation patterns are quite heterogeneous across different metastatic sites within the same patients. These findings provide evidence that DNA hypomethylation changes occur later in prostate carcinogenesis than the CpG island hypermethylation changes and occur heterogeneously during prostate cancer progression and metastatic dissemination.


systematic_name: M15835
exact_source: Table 1S
source_species_code: HS
GEO_id: GSE12708
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated SUM44/LCCTam cells (breast cancer) resistant to 4-hydroxytamoxifen [PubChem=63062] relative to the parental SUM44 cells sensitive to the drug.

description_full:
  One-third of all estrogen receptor (ER)-positive breast tumors treated with endocrine therapy fail to respond, and the remainder is likely to relapse in the future. Almost all data on endocrine resistance has been obtained in models of invasive ductal carcinoma (IDC). However, invasive lobular carcinomas (ILC) comprise up to 15% of newly diagnosed invasive breast cancers each year and, whereas the incidence of IDC has remained relatively constant during the last 20 years, the prevalence of ILC continues to increase among postmenopausal women. We report a new model of Tamoxifen (TAM)-resistant invasive lobular breast carcinoma cells that provides novel insights into the molecular mechanisms of endocrine resistance. SUM44 cells express ER and are sensitive to the growth inhibitory effects of antiestrogens. Selection for resistance to 4-hydroxytamoxifen led to the development of the SUM44/LCCTam cell line, which exhibits decreased expression of ERalpha and increased expression of the estrogen-related receptor gamma (ERRgamma). Knockdown of ERRgamma in SUM44/LCCTam cells by siRNA restores TAM sensitivity, and overexpression of ERRgamma blocks the growth-inhibitory effects of TAM in SUM44 and MDA-MB-134 VI lobular breast cancer cells. ERRgamma-driven transcription is also increased in SUM44/LCCTam, and inhibition of activator protein 1 (AP1) can restore or enhance TAM sensitivity. These data support a role for ERRgamma/AP1 signaling in the development of TAM resistance and suggest that expression of ERRgamma may be a marker of poor TAM response.


systematic_name: M19548
exact_source: Table 2S: Class 2 = CLASS 2
source_species_code: HS
GEO_id: GSE11266
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated by estradiol [PubChem=5757] and up-regulated by ESRRA [GeneID=2101] in MCF-7 cells (breast cancer).

description_full:
  Expression of estrogen-related receptor alpha (ERRalpha) has recently been shown to carry negative prognostic significance in breast and ovarian cancers. The specific role of this orphan nuclear receptor in tumor growth and progression, however, is yet to be fully understood. The significant homology between estrogen receptor alpha (ERalpha) and ERRalpha initially suggested that these receptors may have similar transcriptional targets. Using the well-characterized ERalpha-positive MCF-7 breast cancer cell line, we sought to gain a genome-wide picture of ERalpha-ERRalpha cross-talk using an unbiased microarray approach. In addition to generating a host of novel ERRalpha target genes, this study yielded the surprising result that most ERRalpha-regulated genes are unrelated to estrogen signaling. The relatively small number of genes regulated by both ERalpha and ERRalpha led us to expand our study to the more aggressive and less clinically treatable ERalpha-negative class of breast cancers. In this setting, we found that ERRalpha expression is required for the basal level of expression of many known and novel ERRalpha target genes. Introduction of a small interfering RNA directed to ERRalpha into the highly aggressive breast carcinoma MDA-MB-231 cell line dramatically reduced the migratory potential of these cells. Although stable knockdown of ERRalpha expression in MDA-MB-231 cells had no effect on in vitro cell proliferation, a significant reduction of tumor growth rate was observed when these cells were implanted as xenografts. Our results confirm a role for ERRalpha in breast cancer growth and highlight it as a potential therapeutic target for estrogen receptor-negative breast cancer.


systematic_name: M19002
exact_source: Table 2S: Class 3 = CLASS 3
source_species_code: HS
GEO_id: GSE11266
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated by estradiol [PubChem=5757] and down-regulated by ESRRA [GeneID=2101] in MCF-7 cells (breast cancer).

description_full:
  Expression of estrogen-related receptor alpha (ERRalpha) has recently been shown to carry negative prognostic significance in breast and ovarian cancers. The specific role of this orphan nuclear receptor in tumor growth and progression, however, is yet to be fully understood. The significant homology between estrogen receptor alpha (ERalpha) and ERRalpha initially suggested that these receptors may have similar transcriptional targets. Using the well-characterized ERalpha-positive MCF-7 breast cancer cell line, we sought to gain a genome-wide picture of ERalpha-ERRalpha cross-talk using an unbiased microarray approach. In addition to generating a host of novel ERRalpha target genes, this study yielded the surprising result that most ERRalpha-regulated genes are unrelated to estrogen signaling. The relatively small number of genes regulated by both ERalpha and ERRalpha led us to expand our study to the more aggressive and less clinically treatable ERalpha-negative class of breast cancers. In this setting, we found that ERRalpha expression is required for the basal level of expression of many known and novel ERRalpha target genes. Introduction of a small interfering RNA directed to ERRalpha into the highly aggressive breast carcinoma MDA-MB-231 cell line dramatically reduced the migratory potential of these cells. Although stable knockdown of ERRalpha expression in MDA-MB-231 cells had no effect on in vitro cell proliferation, a significant reduction of tumor growth rate was observed when these cells were implanted as xenografts. Our results confirm a role for ERRalpha in breast cancer growth and highlight it as a potential therapeutic target for estrogen receptor-negative breast cancer.


description_brief: Genes that comprise the mitochondria gene module
systematic_name: M15112
exact_source: Table 2S
source_species_code: HS
GEO_id: GSE5307,GSE8957
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_full:
  A major goal of cancer research is to match specific therapies to molecular targets in cancer. Genome-scale expression profiling has identified new subtypes of cancer based on consistent patterns of variation in gene expression, leading to improved prognostic predictions. However, how these new genetic subtypes of cancers should be treated is unknown. Here, we show that a gene module map can guide the prospective identification of targeted therapies for genetic subtypes of cancer. By visualizing genome-scale gene expression in cancer as combinations of activated and deactivated functional modules, gene module maps can reveal specific functional pathways associated with each subtype that might be susceptible to targeted therapies. We show that in human breast cancers, activation of a poor-prognosis wound signature is strongly associated with induction of both a mitochondria gene module and a proteasome gene module. We found that 3-bromopyruvic acid, which inhibits glycolysis, selectively killed breast cells expressing the mitochondria and wound signatures. In addition, inhibition of proteasome activity by bortezomib, a drug approved for human use in multiple myeloma, abrogated wound signature expression and selectively killed breast cells expressing the wound signature. Thus, gene module maps may enable rapid translation of complex genomic signatures in human disease to targeted therapeutic strategies.


systematic_name: M515
exact_source: Table 3.1S, 3.2S
source_species_code: HS
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Up-regulated genes displaying alternative splicing in MDA-MB-435 cells (breast cancer) whose metastatic potential has been reduced by expression of NME1 [GeneID=4830].

description_full:
  The role of Gemin5 in alternative mRNA splicing, tumor cell motility, and proteomic instability was investigated. Isotope Capture Affinity Tag proteomic analysis was conducted on MDA-MB-435 tumor cells transfected with either a control vector (C-100) or the Nm23-H1 metastasis suppressor (H1-177). Ingenuity pathway analysis revealed that RNA posttranscriptional processing was the most prominent class of differentially expressed proteins. Within this category, overexpression of Acinus1, Poly(a) binding protein, HNRPA2B1, Bop1, and Gemin5 was confirmed in less metastatic H1-177 cells. Overexpression of the latter four proteins was also observed in the lower metastatic antisense Ezrin transfectant of a murine osteosarcoma model system, confirming the general relevance of the trends. Gemin5, a component of the spliceosomal complex, was chosen for further study. Analysis of global mRNA splicing by SpliceArray chips revealed that 16 genes were differentially spliced in C-100 compared with H1-177 cells; transient transfection of gemin5 into C-100 cells restored the splice pattern to that of H1-177 cells. Alternative splicing patterns for the engulfment and cell motility 1 and thrombospondin 4 genes were confirmed by semiquantitative reverse transcription-PCR. Gemin5 overexpression coordinately reduced C-100 cell motility by 50%, and siRNA-mediated reduction of Gemin5 expression increased the motility of H1-177 cells by 2-fold (P < 0.004). The data provide the first demonstration that alterations in the expression of a spliceosome protein can effect both specific splicing events and tumor cell motility. The data also show that changes in mRNA splicing patterns accompany metastatic progression, which may contribute to proteome instability.


systematic_name: M9389
exact_source: Fig 1C: red cluster
source_species_code: HS
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes in the red cluster of protein kinases distinguishing between luminal A and basal breast cancer subtypes.

description_full:
  Breast cancer is a heterogeneous disease made of various molecular subtypes with different prognosis. However, evolution remains difficult to predict within some subtypes, such as luminal A, and treatment is not as adapted as it should be. Refinement of prognostic classification and identification of new therapeutic targets are needed. Using oligonucleotide microarrays, we profiled 227 breast cancers. We focused our analysis on two major breast cancer subtypes with opposite prognosis, luminal A (n = 80) and basal (n = 58), and on genes encoding protein kinases. Whole-kinome expression separated luminal A and basal tumors. The expression (measured by a kinase score) of 16 genes encoding serine/threonine kinases involved in mitosis distinguished two subgroups of luminal A tumors: Aa, of good prognosis and Ab, of poor prognosis. This classification and its prognostic effect were validated in 276 luminal A cases from three independent series profiled across different microarray platforms. The classification outperformed the current prognostic factors in univariate and multivariate analyses in both training and validation sets. The luminal Ab subgroup, characterized by high mitotic activity compared with luminal Aa tumors, displayed clinical characteristics and a kinase score intermediate between the luminal Aa subgroup and the luminal B subtype, suggesting a continuum in luminal tumors. Some of the mitotic kinases of the signature represent therapeutic targets under investigation. The identification of luminal A cases of poor prognosis should help select appropriate treatment, whereas the identification of a relevant kinase set provides potential targets.


systematic_name: M12692
exact_source: Fig 1C: green cluster
source_species_code: HS
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes in the green cluster of protein kinases distinguishing between luminal A and basal breast cancer subtypes.

description_full:
[cell repeats an earlier one in this file: 1679 characters]


systematic_name: M828
exact_source: Table 1S: lower in TamR tumor
source_species_code: HS
GEO_id: GSE7327
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in breast cancer tumors (formed by MCF-7 xenografts) resistant to tamoxifen [PubChem=5376].

description_full:
  Not all breast cancers respond to tamoxifen, and many develop resistance despite initial benefit. We used an in vivo model of estrogen receptor (ER)-positive breast cancer (MCF-7 xenografts) to investigate mechanisms of this resistance and develop strategies to circumvent it. Epidermal growth factor receptor (EGFR) and HER2, which were barely detected in control estrogen-treated tumors, increased slightly with tamoxifen and were markedly increased when tumors became resistant. Gefitinib, which inhibits EGFR/HER2, improved the antitumor effect of tamoxifen and delayed acquired resistance, but had no effect on estrogen-stimulated growth. Phosphorylated levels of p42/44 and p38 mitogen-activated protein kinases (both downstream of EGFR/HER2) were increased in the tamoxifen-resistant tumors and were suppressed by gefitinib. There was no apparent increase in phosphorylated AKT (also downstream of EGFR/HER2) in resistant tumors, but it was nonetheless suppressed by gefitinib. Phosphorylated insulin-like growth factor-IR (IGF-IR), which can interact with both EGFR and membrane ER, was elevated in the tamoxifen-resistant tumors compared with the sensitive group. However, ER-regulated gene products, including total IGF-IR itself and progesterone receptor, remained suppressed even at the time of acquired resistance. Tamoxifen's antagonism of classic ER genomic function was retained in these resistant tumors and even in tumors that overexpress HER2 (MCF-7 HER2/18) and are de novo tamoxifen-resistant. In conclusion, EGFR/HER2 may mediate tamoxifen resistance in ER-positive breast cancer despite continued suppression of ER genomic function by tamoxifen. IGF-IR expression remains dependent on ER but is activated in the tamoxifen-resistant tumors. This study provides a rationale to combine HER inhibitors with tamoxifen in clinical studies, even in tumors that do not initially overexpress EGFR/HER2.


systematic_name: M4288
exact_source: Table 4S: Mean exp > 0
source_species_code: HS
GEO_id: GSE8430
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in MCF10A cells (breast cancer) grown at low (mesenchymal phenotype) compared to those grown at high (epithelial, basal-like phenotype) confluency.

description_full:
  Epithelial-mesenchymal transition (EMT) is defined by the loss of epithelial characteristics and the acquisition of a mesenchymal phenotype. In carcinoma cells, EMT can be associated with increased aggressiveness, and invasive and metastatic potential. To assess the occurrence of EMT in human breast tumors, we conducted a tissue microarray-based immunohistochemical study in 479 invasive breast carcinomas and 12 carcinosarcomas using 28 different markers. Unsupervised hierarchical clustering of the tumors and statistical analysis showed that up-regulation of EMT markers (vimentin, smooth-muscle-actin, N-cadherin, and cadherin-11) and overexpression of proteins involved in extracellular matrix remodeling and invasion (SPARC, laminin, and fascin), together with reduction of characteristic epithelial markers (E-cadherin and cytokeratins), preferentially occur in breast tumors with the basal-like phenotype. Moreover, most breast carcinosarcomas also had a basal-like phenotype and showed expression of mesenchymal markers in their sarcomatous and epithelial components. To assess whether basal-like cells have intrinsic phenotypic plasticity for mesenchymal transition, we performed in vitro studies with the MCF10A cell line. In response to low cell density, MCF10A cells suffer spontaneous morphologic and phenotypic EMT-like changes, including cytoskeleton reorganization, vimentin and Slug up-regulation, cadherin switching, and diffuse cytosolic relocalization of the catenins. Moreover, these phenotypic changes are associated with modifications in the global genetic differentiation program characteristic of the EMT process. In summary, our data indicate that in breast tumors, EMT likely occurs within a specific genetic context, the basal phenotype, and suggests that this proclivity to mesenchymal transition may be related to the high aggressiveness and the characteristic metastatic spread of these tumors.


systematic_name: M13984
exact_source: Table 1: Up-regulated
source_species_code: HS
GEO_id: GSE8687,GSE8685
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated by IL2 [GeneID=3558] in cells derived from  CD4+ [GeneID=920] cutaneous T-cell lymphoma (CTCL).

description_full:
  In this study, we compared the effects of interleukin-2 (IL-2), IL-15, and IL-21 on gene expression, activation of cell signaling pathways, and functional properties of cells derived from CD4+ cutaneous T-cell lymphoma (CTCL). Whereas both IL-2 and IL-15 modulated, in a CTCL cell line, the expression of >1,000 gene transcripts by at least 2-fold, IL-21 up-regulated <40 genes. All three cytokines induced tyrosine phosphorylation of Jak1 and Jak3 in CTCL cell lines and native leukemic (Sezary) cells. However, only IL-2 and IL-15 strongly activated signal transducers and activators of transcription 5, phosphoinositide 3-kinase/Akt, and mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase/ERK signaling pathways in the cell lines and mitogen-primed native cells. In contrast, IL-21 selectively activated signal transducers and activators of transcription 3. Whereas all three cytokines protected CTCL cells from apoptosis, only IL-2 and IL-15 promoted their proliferation. The effects of the cytokine stimulation were Jak3 kinase- and Jak1 kinase- dependent. These findings document the vastly different effect of IL-2 and IL-15 versus IL-21 on CTCL cells. They also suggest two novel therapeutic approaches to CTCL and, possibly, other CD4+ T-cell lymphomas: inhibition of the Jak1/Jak3 kinase complex and, given the known strong immunostimulatory properties of IL-21 on CD8+ T, natural killer, and B cells, application of this cytokine to boost an immune response against malignant CD4+ T cells.


systematic_name: M13276
exact_source: Table 1: Down-regulated
source_species_code: HS
GEO_id: GSE8687,GSE8685
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated by IL2 [GeneID=3558] in cells derived from  CD4+ [GeneID=920] cutaneous T-cell lymphoma (CTCL).

description_full:
  In this study, we compared the effects of interleukin-2 (IL-2), IL-15, and IL-21 on gene expression, activation of cell signaling pathways, and functional properties of cells derived from CD4+ cutaneous T-cell lymphoma (CTCL). Whereas both IL-2 and IL-15 modulated, in a CTCL cell line, the expression of >1,000 gene transcripts by at least 2-fold, IL-21 up-regulated <40 genes. All three cytokines induced tyrosine phosphorylation of Jak1 and Jak3 in CTCL cell lines and native leukemic (Sezary) cells. However, only IL-2 and IL-15 strongly activated signal transducers and activators of transcription 5, phosphoinositide 3-kinase/Akt, and mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase/ERK signaling pathways in the cell lines and mitogen-primed native cells. In contrast, IL-21 selectively activated signal transducers and activators of transcription 3. Whereas all three cytokines protected CTCL cells from apoptosis, only IL-2 and IL-15 promoted their proliferation. The effects of the cytokine stimulation were Jak3 kinase- and Jak1 kinase- dependent. These findings document the vastly different effect of IL-2 and IL-15 versus IL-21 on CTCL cells. They also suggest two novel therapeutic approaches to CTCL and, possibly, other CD4+ T-cell lymphomas: inhibition of the Jak1/Jak3 kinase complex and, given the known strong immunostimulatory properties of IL-21 on CD8+ T, natural killer, and B cells, application of this cytokine to boost an immune response against malignant CD4+ T cells.


systematic_name: M6041
exact_source: Fig 3: E2-specific
source_species_code: HS
GEO_id: GSE10270
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  'Cancer prone response profile' (CPRP): genes changed in response to estradiol [PubChem=5757]  in epithelial cell cultures from patients at high risk of breast cancer.

description_full:
  Breast cancer outcome is highly variable. Whether inadvertent exposure to environmental xenobiotics evokes a biological response promoting cancer aggressiveness and a higher probability of tumor recurrence remains unknown. To determine specific molecular alterations which arise in high-risk breast tissue in the presence of the ubiquitous xenoestrogen, bisphenol A (BPA), we used nonmalignant random periareolar fine-needle aspirates in a novel functional assay. Early events induced by BPA in epithelial-stromal cocultures derived from the contralateral tissue of patients with breast cancer included gene expression patterns which facilitate apoptosis evasion, endurance of microenvironmental stress, and cell cycle deregulation without a detectable increase in cell numbers. This BPA response profile was significantly associated with breast tumors characterized by high histologic grade (P < 0.001) and large tumor size (P = 0.002), resulting in decreased recurrence-free patient survival (P < 0.001). Our assays show a biological fingerprint of probable prior exposure to endocrine-disrupting agents, and suggest a scenario in which their presence in the microenvironmental milieu of high-risk breast tissue could play a deterministic role in establishing and maintaining tumor aggressiveness and poor patient outcome.


systematic_name: M8655
exact_source: Fig 3: BPA-specific
source_species_code: HS
GEO_id: GSE10270
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  'Cancer prone response profile' (CPRP): genes changed in response to bisphenol A [PubChem=6623]  in epithelial cell cultures from patients at high risk of breast cancer.

description_full:
  Breast cancer outcome is highly variable. Whether inadvertent exposure to environmental xenobiotics evokes a biological response promoting cancer aggressiveness and a higher probability of tumor recurrence remains unknown. To determine specific molecular alterations which arise in high-risk breast tissue in the presence of the ubiquitous xenoestrogen, bisphenol A (BPA), we used nonmalignant random periareolar fine-needle aspirates in a novel functional assay. Early events induced by BPA in epithelial-stromal cocultures derived from the contralateral tissue of patients with breast cancer included gene expression patterns which facilitate apoptosis evasion, endurance of microenvironmental stress, and cell cycle deregulation without a detectable increase in cell numbers. This BPA response profile was significantly associated with breast tumors characterized by high histologic grade (P < 0.001) and large tumor size (P = 0.002), resulting in decreased recurrence-free patient survival (P < 0.001). Our assays show a biological fingerprint of probable prior exposure to endocrine-disrupting agents, and suggest a scenario in which their presence in the microenvironmental milieu of high-risk breast tissue could play a deterministic role in establishing and maintaining tumor aggressiveness and poor patient outcome.


systematic_name: M18086
exact_source: Fig 3: E2/BPA-common
source_species_code: HS
GEO_id: GSE10270
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  'Cancer prone response profile' (CPRP): genes common to estradiol and bisphenol A [PubChem=5757;6623]  response of epithelial cell cultures from patients at high risk of breast cancer.

description_full:
  Breast cancer outcome is highly variable. Whether inadvertent exposure to environmental xenobiotics evokes a biological response promoting cancer aggressiveness and a higher probability of tumor recurrence remains unknown. To determine specific molecular alterations which arise in high-risk breast tissue in the presence of the ubiquitous xenoestrogen, bisphenol A (BPA), we used nonmalignant random periareolar fine-needle aspirates in a novel functional assay. Early events induced by BPA in epithelial-stromal cocultures derived from the contralateral tissue of patients with breast cancer included gene expression patterns which facilitate apoptosis evasion, endurance of microenvironmental stress, and cell cycle deregulation without a detectable increase in cell numbers. This BPA response profile was significantly associated with breast tumors characterized by high histologic grade (P < 0.001) and large tumor size (P = 0.002), resulting in decreased recurrence-free patient survival (P < 0.001). Our assays show a biological fingerprint of probable prior exposure to endocrine-disrupting agents, and suggest a scenario in which their presence in the microenvironmental milieu of high-risk breast tissue could play a deterministic role in establishing and maintaining tumor aggressiveness and poor patient outcome.


systematic_name: M9611
exact_source: Table 3S
source_species_code: HS
GEO_id: GSE10911
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in derivatives of MCF-7aro cells (breast cancer) that developed resistance to tamoxifen [PubChem=5376] or  inhibitors of aromatase (CYP19A1) [GeneID=1588].

description_full:
  Acquired resistance to either tamoxifen or aromatase inhibitors (AI) develops after prolonged treatment in a majority of hormone-responsive breast cancers. In an attempt to further elucidate mechanisms of acquired resistance to AIs, MCF-7aro cells resistant to letrozole (T+LET R), anastrozole (T+ANA R), and exemestane (T+EXE R), as well as long-term estrogen deprived (LTEDaro) and tamoxifen-resistant (T+TAM R) lines were generated. This is the first complete panel of endocrine therapy-resistant cell lines, which were generated as multiple independent biological replicates for unbiased genome-wide analysis using affymetrix microarrays. Although similarities are apparent, microarray results clearly show gene signatures unique to AI-resistance were inherently different from LTEDaro and T+TAM R gene expression profiles. Based on hierarchical clustering, unique estrogen-responsive gene signatures vary depending on cell line, with some genes up-regulated in all lines versus other genes up-regulated only in the AI-resistant lines. Characterization of these resistant lines showed that LTEDaro, T+LET R, and T+ANA R cells contained a constitutively active estrogen receptor (ER)alpha that does not require estrogen for activation. This ligand-independent activation of ER was not observed in the parental cells, as well as T+EXE R and T+TAM R cells. Further characterization of these resistant lines was performed using cell cycle analysis, immunofluorescence experiments to visualize ER subcellular localization, as well as cross-resistance studies to determine second-line inhibitor response. Using this well-defined model system, our studies provide important information regarding differences in resistance mechanisms to AIs, TAM, and LTEDaro, which are critical in overcoming resistance when treating hormone-responsive breast cancers.


systematic_name: M12661
exact_source: Table 2B
source_species_code: HS
GEO_id: GSE8866
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes commonly down-regulated in SK-N-BE cells (neuroblastoma) after RNAi knockdown of CCND1 and CDK4 [GeneID=595;1019].

description_full:
  Genomic aberrations of Cyclin D1 (CCND1), CDK4, and CDK6 in neuroblastoma indicate that dysregulation of the G(1) entry checkpoint is an important cell cycle aberration in this pediatric tumor. Here, we report that analysis of Affymetrix expression data of primary neuroblastic tumors shows an extensive overexpression of Cyclin D1, which correlates with histologic subgroups. Immunohistochemical analysis showed overexpression of Cyclin D1 in neuroblasts and low Cyclin D1 expression in all cell types in ganglioneuroma. This suggests an involvement of G(1)-regulating genes in neuronal differentiation processes which we further evaluated using RNA interference against Cyclin D1 and its kinase partners CDK4 and CDK6 in several neuroblastoma cell lines. The Cyclin D1 and CDK4 knockdown resulted in pRb pathway inhibition as shown by an almost complete disappearance of CDK4/CDK6-specific pRb phosphorylation, reduction of E2F transcriptional activity, and a decrease of Cyclin A protein levels. Phenotype analysis showed a significant reduction in cell proliferation, a G(1)-specific cell cycle arrest, and, moreover, an extensive neuronal differentiation. Affymetrix microarray profiling of small interfering RNA-treated cells revealed a shift in expression profile toward a neuronal phenotype. Several new potential downstream players are identified. We conclude that neuroblastoma functionally depend on overexpression of G(1)-regulating genes to maintain their undifferentiated phenotype.


systematic_name: M11156
exact_source: Table 17S
source_species_code: HS
GEO_id: GSE10842
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in normal tissue adjacent to liver tumor, compared to the normal liver samples.

description_full:
[cell repeats an earlier one in this file: 1211 characters]


systematic_name: M11318
exact_source: Table 3S
source_species_code: HS
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in the MM1S cells (multiple myeloma) after treatment with aplidin [PubChem=44152164], a marine-derived compound with potential anti-cancer properties.

description_full:
  Despite recent progress in its treatment, multiple myeloma (MM) remains incurable, thus necessitating identification of novel anti-MM agents. We report that the marine-derived cyclodepsipeptide Aplidin exhibits, at clinically achievable concentrations, potent in vitro activity against primary MM tumor cells and a broad spectrum of human MM cell lines, including cells resistant to conventional (e.g., dexamethasone, alkylating agents, and anthracyclines) or novel (e.g., thalidomide and bortezomib) anti-MM agents. Aplidin is active against MM cells in the presence of proliferative/antiapoptotic cytokines or bone marrow stromal cells and has additive or synergistic effects with some of the established anti-MM agents. Mechanistically, a short in vitro exposure to Aplidin induces MM cell death, which involves activation of p38 and c-jun NH(2)-terminal kinase signaling, Fas/CD95 translocation to lipid rafts, and caspase activation. The anti-MM effect of Aplidin is associated with suppression of a constellation of proliferative/antiapoptotic genes (e.g., MYC, MYBL2, BUB1, MCM2, MCM4, MCM5, and survivin) and up-regulation of several potential regulators of apoptosis (including c-JUN, TRAIL, CASP9, and Smac). Aplidin exhibited in vivo anti-MM activity in a mouse xenograft model. The profile of the anti-MM activity of Aplidin in our preclinical models provided the framework for its clinical testing in MM, which has already provided favorable preliminary results.


systematic_name: M3102
exact_source: Fig 1S: erbb2 up
source_species_code: HS
GEO_id: GSE2034,GSE5327
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in the erbb2 subype of breast cancer samples, characterized by higher expression of ERBB2 [GeneID=2064].

description_full:
[cell repeats an earlier one in this file: 1595 characters]


systematic_name: M1518
exact_source: Table 1
source_species_code: HS
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in response to nutlin-3a [PubChem=216345], an inhibitor of MDM2 [GeneID=4193],  in skin fibroblast cultures after knockdown of TP53 [GeneID=7157] by RNAi.

description_full:
  Nutlin-3, an MDM2 inhibitor, activates p53, resulting in several types of cancer cells undergoing apoptosis. Although p53 is mutated or deleted in approximately 50% of all cancers, p53 is still functionally active in the other 50%. Consequently, nutlin-3 and similar drugs could be candidates for neoadjuvant therapy in cancers with a functional p53. Cellular senescence is also a phenotype induced by p53 activation and plays a critical role in protecting against tumor development. In this report, we found that nutlin-3a can induce senescence in normal human fibroblasts. Nutlin-3a activated and repressed a large number of p53-dependent genes, including those encoding microRNAs. mir-34a, mir-34b, and mir-34c, which have recently been shown to be downstream effectors of p53-mediated senescence, were up-regulated, and inhibitor of growth 2 (ING2) expression was suppressed by nutlin-3a treatment. Two candidates for a p53-DNA binding consensus sequence were found in the ING2 promoter regulatory region; thus, we performed chromatin immunoprecipitation and electrophoretic mobility shift assays and confirmed p53 binding directly to those sites. In addition, the luciferase activity of a construct containing the ING2 regulatory region was repressed after p53 activation. Antisense knockdown of ING2 induces p53-independent senescence, whereas overexpression of ING2 induces p53-dependent senescence. Taken together, we conclude that nutlin-3a induces senescence through p53 activation in normal human fibroblasts, and p53-mediated mir34a, mir34b, and mir34c up-regulation and ING2 down-regulation may be involved in the senescence pathway.


systematic_name: M6379
exact_source: Table 1
source_species_code: HS
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in response to nutlin-3a [PubChem=216345], an inhibitor of MDM2 [GeneID=4193],  in skin fibroblast cultures after knockdown of TP53 [GeneID=7157] by RNAi.

description_full:
  Nutlin-3, an MDM2 inhibitor, activates p53, resulting in several types of cancer cells undergoing apoptosis. Although p53 is mutated or deleted in approximately 50% of all cancers, p53 is still functionally active in the other 50%. Consequently, nutlin-3 and similar drugs could be candidates for neoadjuvant therapy in cancers with a functional p53. Cellular senescence is also a phenotype induced by p53 activation and plays a critical role in protecting against tumor development. In this report, we found that nutlin-3a can induce senescence in normal human fibroblasts. Nutlin-3a activated and repressed a large number of p53-dependent genes, including those encoding microRNAs. mir-34a, mir-34b, and mir-34c, which have recently been shown to be downstream effectors of p53-mediated senescence, were up-regulated, and inhibitor of growth 2 (ING2) expression was suppressed by nutlin-3a treatment. Two candidates for a p53-DNA binding consensus sequence were found in the ING2 promoter regulatory region; thus, we performed chromatin immunoprecipitation and electrophoretic mobility shift assays and confirmed p53 binding directly to those sites. In addition, the luciferase activity of a construct containing the ING2 regulatory region was repressed after p53 activation. Antisense knockdown of ING2 induces p53-independent senescence, whereas overexpression of ING2 induces p53-dependent senescence. Taken together, we conclude that nutlin-3a induces senescence through p53 activation in normal human fibroblasts, and p53-mediated mir34a, mir34b, and mir34c up-regulation and ING2 down-regulation may be involved in the senescence pathway.


systematic_name: M16490
exact_source: Table 1S: p53 upregulated
source_species_code: HS
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Apoptosis genes up-regulated by TP53 [GeneID=7157] in HCT116 cells (colon cancer) treated with thymoquinone [PubChem=10281].

description_full:
  There are few reports describing the role of p53-dependent gene repression in apoptotic cell death. To identify such apoptosis-associated p53 target genes, we used the pro-oxidant plant-derived drug thymoquinone and compared p53+/+ and p53-/- colon cancer cells HCT116. The p53 wild-type (wt) status correlated with more pronounced DNA damage and higher apoptosis after thymoquinone treatment. A significant up-regulation of the survival gene CHEK1 was observed in p53-/- cells in response to thymoquinone due to the lack of transcriptional repression of p53. In p53-/- cells, transfection with p53-wt vector and CHEK1 small interfering RNA treatment decreased CHEK1 mRNA and protein levels and restored apoptosis to the levels of the p53+/+ cells. p53-/- cells transplanted to nude mice treated with thymoquinone up-regulated CHEK1 expression and did not undergo apoptosis unlike p53+/+ cells. Immunofluorescence analysis revealed that the apoptosis resistance in p53-/- cells after thymoquinone treatment might be conveyed by shuttling of CHEK1 into the nucleus. We confirmed the in vivo existence of this CHEK1/p53 link in human colorectal cancer, showing that tumors lacking p53 had higher levels of CHEK1, which was accompanied by poorer apoptosis. CHEK1 overexpression was correlated with advanced tumor stages (P = 0.03), proximal tumor localization (P = 0.02), and worse prognosis (1.9-fold risk, univariate Cox regression; Kaplan-Meier, P = 0.04). We suggest that the inhibition of the stress response sensor CHEK1 might contribute to the antineoplastic activity of specific DNA-damaging drugs.


systematic_name: M3218
exact_source: Table 2S
source_species_code: HS
GEO_id: GSE10943,GSE9481
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Top 50 genes up-regulated in ovarian cancer progenitor cells (also known as side population, SP, cells) in response to interferon alpha (IFNA).

description_full:
  The side population (SP), recently identified in several normal tissues and in a variety of tumors based on its ability to extrude some fluorescent dyes, may comprise cells endowed with stem cell features. In this study, we investigated the presence of SP in epithelial ovarian cancer and found it in 9 of 27 primary tumor samples analyzed, as well as in 4 of 6 cultures from xenotransplants. SP cells from one xenograft bearing a large SP fraction were characterized in detail. SP cells had higher proliferation rates, were much less apoptotic compared with non-SP cells, and generated tumors more rapidly than non-SP cells. We also investigated the effects of IFN-alpha, a cytokine that has widely been used to treat solid tumors, on epithelial ovarian cancer cells and observed that IFN-alpha exerted marked antiproliferative and proapoptotic effects on primary cultures containing high numbers of SP cells. In vitro, IFN-alpha treatment invariably caused a dramatic reduction in SP size in tumor cell lines of different origins; moreover, IFN-alpha treatment of purified SP cells was associated with a distinctive change in their transcriptional profile. Gene therapy with human IFN-alpha resulted in regression of established tumors bearing a large SP fraction, which was not observed when tumors bearing low SP levels were treated. These findings could have relevant clinical implications because they imply that tumors bearing large SP numbers, albeit rare, could be sensitive to IFN-alpha treatment.


systematic_name: M11428
exact_source: Table 1S
source_species_code: HS
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Inflammatory cytokines, chemokines and their cognate receptors up-regulated in THP-1 cells (monocyte) after treatment with PSMD4 [GeneID=5710].

description_full:
  We previously showed that angiocidin, a tumor and vascular associated protein, is a potent inhibitor of angiogenesis and tumor growth. Angiocidin is a multidomain protein that exerts its antiangiogenic activity through multiple mechanisms, including effects on cell matrix interaction. Here, we describe another activity of angiocidin that may contribute to its antitumor activity. We show that angiocidin activates monocytes to secrete a mixture of proinflammatory cytokines and induces them to differentiate into macrophage-like cells. Using the monocytic cell line THP-1, we show that angiocidin induces the cells to become adherent and phagocytic, express macrophage markers, and secrete matrix metalloproteinase-9. Microarray analysis of control and angiocidin-treated THP-1 cells revealed that angiocidin up-regulated p105/p50, p100/p52, and rel B, components of the nuclear factor-kappaB (NF-kappaB) pathway. We confirmed the microarray data and showed that angiocidin induced phosphorylation of I kappa beta, p50, and p65 and translocation of p50 and p65 to the nucleus. We also showed that angiocidin activated up-stream mediators of NF-kappaB, such as the mitogen-activated protein kinase (MAPK) pathway and phosphoinositide-3 kinase (PI3K). Blockage of NF-kappaB and MAPK activation with small molecule inhibitors completely prevented angiocidin-mediated secretion of cytokines from THP-1 cells, but did not inhibit their adhesive phenotype. Blocking PI3K inhibited both secretion of cytokines, as well as the adhesive phenotype. These data suggest that angiocidin activates monocytes to secrete cytokines and differentiates them to a macrophage-like phenotype through at least two pathways mediated by MAPK and NF-kappaB, as well as PI3K.


systematic_name: M6335
exact_source: Fig. 1B
source_species_code: HS
GEO_id: GSE10240
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes changed in HBE cells (bronchial epithelium) after treatment with IL22 and IL17A [GeneID=50616;3605].

description_full:
  Emerging evidence supports the concept that T helper type 17 (T(H)17) cells, in addition to mediating autoimmunity, have key roles in mucosal immunity against extracellular pathogens. Interleukin-22 (IL-22) and IL-17A are both effector cytokines produced by the T(H)17 lineage, and both were crucial for maintaining local control of the Gram-negative pulmonary pathogen, Klebsiella pneumoniae. Although both cytokines regulated CXC chemokines and granulocyte colony-stimulating factor production in the lung, only IL-22 increased lung epithelial cell proliferation and increased transepithelial resistance to injury. These data support the concept that the T(H)17 cell lineage and its effector molecules have evolved to effect host defense against extracellular pathogens at mucosal sites.


description_brief: Genes up-regulated in MCF7-ADR cell line (breast cancer) resistant to docetaxel [PubChem=148124].
systematic_name: M10292
exact_source: Table 1
source_species_code: HS
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_full:
  Drug resistance acquired by cancer cells has led to treatment failure. To understand the regulatory network underlying docetaxel resistance in breast cancer cells and to identify molecular targets for therapy, we tested small interfering RNAs (siRNAs) against 36 genes whose expression was elevated in human nonresponders to docetaxel for the ability to promote apoptosis of docetaxel-resistant human breast cancer cells (MCF7-ADR cells). The results indicate that the downregulation of the gene encoding ribophorin [corrected] II (RPN2), which is part of an N-oligosaccharyl transferase complex, most efficiently induces apoptosis of MCF7-ADR cells in the presence of docetaxel. RPN2 silencing induced reduced glycosylation of the P-glycoprotein, as well as decreased membrane localization, thereby sensitizing MCF7-ADR cells to docetaxel. Moreover, in vivo delivery of siRNA specific for RPN2 markedly reduced tumor growth in two types of models for drug resistance. Thus, RPN2 silencing makes cancer cells hypersensitive response to docetaxel, and RPN2 might be a new target for RNA interference-based therapeutics against drug resistance.


systematic_name: M1819
exact_source: Fig. 4: Meiotic and DNA repair
source_species_code: MM
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Meitic and DNA repair genes important for female fertility, based on mouse models with female fertility defects.

description_full:
[cell repeats an earlier one in this file: 1515 characters]


systematic_name: M7854
exact_source: Fig. 3A
source_species_code: HS
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Differentially expressed genes in a panel of xenografts representing 8 common pediatric tumors compared to the normal tissues.

description_full:
  Human tumor xenografts have been used extensively for rapid screening of the efficacy of anticancer drugs for the past 35 years. The selection of appropriate xenograft models for drug testing has been largely empirical and has not incorporated a similarity to the tumor type of origin at the molecular level. This study is the first comprehensive analysis of the transcriptome of a large set of pediatric xenografts, which are currently used for preclinical drug testing. Suitable models representing the tumor type of origin were identified. It was found that the characteristic expression patterns of the primary tumors were maintained in the corresponding xenografts for the majority of samples. Because a prerequisite for developing rationally designed drugs is that the target is expressed at the protein level, we developed tissue arrays from these xenografts and corroborated that high mRNA levels yielded high protein levels for two tested genes. The web database and availability of tissue arrays will allow for the rapid confirmation of the expression of potential targets at both the mRNA and the protein level for molecularly targeted agents. The database will facilitate the identification of tumor markers predictive of response to tested agents as well as the discovery of new molecular targets.


systematic_name: M12827
exact_source: Table 4S
source_species_code: HS
GEO_id: E-MEXP-168
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in cultured stromal stem cells from adipose tissue, compared to the freshly isolated cells.

description_full:
[cell repeats an earlier one in this file: 1179 characters]


systematic_name: M18519
exact_source: Table 5S
source_species_code: HS
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Down-regulated genes in pediatric adrenocortical carcinoma (ACC) compared to the adenoma (ACA) tumors.

description_full:
[cell repeats an earlier one in this file: 1050 characters]


systematic_name: M12434
exact_source: Table 1
source_species_code: HS
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes involved in cell cycle regulation which were up-regulated in MCF-7 cells (breast cancer) by tretinoin (retinoic acid) [PubChem=444795].

description_full:
  The anticarcinogenic activities of retinoic acid (RA) are believed to be mediated by the nuclear RA receptor (RAR) and by the RA-binding protein cellular RA-binding protein-II (CRABP-II). In MCF-7 mammary carcinoma cells, growth inhibition by RA entails an early cell cycle arrest followed by induction of apoptosis. Here, we aimed to obtain insights into the initial cell cycle response. We show that a 3- to 5-h RA pulse is sufficient for inducing a robust growth arrest 2 to 4 days later, demonstrating inhibition of the G1-S transition by RA is triggered by immediate-early RAR targets and does not require the continuous presence of the hormone throughout the arrest program. Expression array analyses revealed that RA induces the expression of several genes involved in cell cycle regulation, including the p53-controlled antiproliferative gene B-cell translocation gene, member 2 (Btg2) and the BTG family member Tob1. We show that induction of Btg2 by RA does not require de novo protein synthesis and is augmented by overexpression of CRABP-II. Additionally, we identify a RA response element in the Btg2 promoter and show that the element binds retinoid X receptor/RAR heterodimers in vitro, is occupied by the heterodimers in cells, and can drive RA-induced activation of a reporter gene. Hence, Btg2 is a novel direct target for RA signaling. In concert with the reports that Btg2 inhibits cell cycle progression by down-regulating cyclin D1, induction of Btg2 by RA was accompanied by a marked decrease in cyclin D1 expression. The observations thus show that the antiproliferative activity of RA in MCF-7 cells is mediated, at least in part, by Btg2.


systematic_name: M18550
exact_source: Suppl. Gene List: Red
source_species_code: HS
GEO_id: GSE5665
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Up-regulated genes in MDA-MB-435 cells (breast cancer) undergoing G2/M arrest after treatment with 2-methoxyestradiol (2ME2)[PubChem=1573].

description_full:
  2-methoxyestradiol (2ME2), an estradiol metabolite with antiproliferative and antiangiogenic activities, is in phase I/II clinical trials for breast cancer. 2ME2 inhibits microtubule polymerization and causes cells to arrest in G2-M. The purpose of this study was to further elucidate the molecular mechanism of 2ME2. MDA-MB-435 breast cancer cells were treated with 2ME2 (2 micromol/L) or vehicle alone. RNA was extracted and genomic profiling was done using 22k Agilent microarrays. Expression Analysis Systematic Explorer was used to determine enrichment of Gene Ontology categories. Protein isolates were subjected to Western blot analysis. Protein synthesis was measured with a [35S]methionine pulse assay. An MDA-MB-435 cell line with two beta-tubulin mutations (2ME2R) was used to determine whether novel mechanisms were tubulin-dependent. Gene Ontology categories enriched include genes that regulate the mitotic spindle assembly checkpoint, apoptosis, and the cytosolic ribosome. The target of the mitotic spindle assembly checkpoint is the anaphase-promoting complex (APC). APC inhibition was confirmed by measuring protein levels of its targets securin and cyclin B1, which were increased in 2ME2-treated cells. Because gene expression in the cytosolic ribosome category was decreased, we evaluated whether 2ME2 decreases protein translation. This was confirmed with a pulse assay, which showed decreased isotope incorporation in 2ME2-treated cells, which was maintained in the tubulin-resistant 2ME2R cells. APC inhibition was not maintained in 2ME2R cells. 2ME2 induces tubulin-dependent cell cycle arrest through regulation of genes involved in the mitotic spindle assembly checkpoint, which results in inhibition of the APC and tubulin-independent inhibition of protein translation.


systematic_name: M11825
exact_source: Table 1S
source_species_code: HS
GEO_id: GSE6474
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in A549 cells (lung cancer) expressing MIRLET7A3 [GeneID=406883] microRNA off a plasmid vector.

description_full:
  MicroRNAs (miRNAs) are small noncoding RNAs that repress their target mRNAs by complementary base pairing and induction of the RNA interference pathway. It has been shown that miRNA expression can be regulated by DNA methylation and it has been suggested that altered miRNA gene methylation might contribute to human tumorigenesis. In this study, we show that the human let-7a-3 gene on chromosome 22q13.31 is associated with a CpG island. Let-7a-3 belongs to the archetypal let-7 miRNA gene family and was found to be methylated by the DNA methyltransferases DNMT1 and DNMT3B. The gene was heavily methylated in normal human tissues but hypomethylated in some lung adenocarcinomas. Let-7a-3 hypomethylation facilitated epigenetic reactivation of the gene and elevated expression of let-7a-3 in a human lung cancer cell line resulted in enhanced tumor phenotypes and oncogenic changes in transcription profiles. Our results thus identify let-7a-3 as an epigenetically regulated miRNA gene with oncogenic function and suggest that aberrant miRNA gene methylation might contribute to the human cancer epigenome.


systematic_name: M8876
exact_source: Table 1S
source_species_code: HS
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Down-regulated genes in MM1.S cells (multiple myeloma) treated with adaphostin [PubChem=387042], a tyrosine kinase inhibitor with anticancer properties.

description_full:
  Here we show the antimyeloma cytotoxicity of adaphostin and carried out expression profiling of adaphostin-treated multiple myeloma (MM) cells to identify its molecular targets. Surprisingly, c-Jun was the most up-regulated gene even at the earliest point of analysis (2 h). We also observed adaphostin-induced c-Abl cleavage in immunoblot analysis. Proteasome inhibitor bortezomib, but not melphalan or dexamethasone, induced similar effects, indicating unique agent-dependent mechanisms. Using caspase inhibitors, as well as caspase-resistant mutants of c-Abl (TM-c-Abl and D565A-Abl), we then showed that c-Abl cleavage in MM cells requires caspase activity. Importantly, both overexpression of the c-Abl fragment or c-Jun and knockdown of c-Abl and c-Jun expression by small interfering RNA confirmed that adaphostin-induced c-Jun up-regulation triggers downstream caspase-mediated c-Abl cleavage, inhibition of MM cell growth, and induction of apoptosis. Finally, our data suggest that this mechanism may not only be restricted to MM but may also be important in a broad range of malignancies including erythroleukemia and solid tumors.


systematic_name: M9946
exact_source: Fig. 2C: Fold-Change > 0
source_species_code: HS
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Up-regulated genes of putative pathways stimulated in tumor endothelial cells by papillary serous ovarian epithelial tumor cells.

description_full:
[cell repeats an earlier one in this file: 1214 characters]


systematic_name: M3475
exact_source: Table 2S
source_species_code: HS
GEO_id: GSE2241
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated 6 h after induction of HoxA5 [GeneID=3205] expression in a breast cancer cell line.

description_full:
[cell repeats an earlier one in this file: 1459 characters]


systematic_name: M16369
exact_source: Table 2: S2N score < 0
source_species_code: HS
GEO_id: GSE6569
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes whose expression negatively correlated with resistance of breast cancer cell lines to dasatinib [PubChem=3062316].

description_full:
  Dasatinib is a multitargeted kinase inhibitor that was recently approved for the treatment of chronic myelogenous leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia with resistance or intolerance to prior therapy. It is also in clinical trials for treating patients with solid tumors. The identification of molecular markers predictive of response to dasatinib could assist in clinical development by selecting patients most likely to derive clinical benefit. Using baseline gene expression profiling of a panel of 23 breast cancer cell lines, we identified genomic signatures highly correlated with in vitro sensitivity to dasatinib. The ability of these signatures to predict dasatinib sensitivity was further confirmed and validated in independent test cell lines. A six-gene model was used to correctly predict dasatinib sensitivity in 11 out of 12 (92%) additional breast and 19 out of 23 (83%) lung cancer cell lines. Quantitative real-time PCR and immunohistochemical assays further confirmed the differential expression pattern of selected markers. Finally, these gene signatures were observed in a subset of primary breast, lung, and ovarian tumors suggesting potential utility in patient selection. The subset of breast cancer patients expressing the dasatinib-sensitive signature includes a distinct clinical and molecular subgroup: the so-called triple negative (i.e., estrogen receptor-negative, progesterone receptor-negative, and HER2-negative) or basal breast cancer subtype. This patient population has a poor prognosis and currently has few effective treatment options. Our results implicate that dasatinib may represent a valuable treatment option in this difficult-to-treat population. To test this hypothesis, clinical studies are now under way to determine the activity of dasatinib in these patients.


systematic_name: M15555
exact_source: Table 3S
source_species_code: HS
GEO_id: GSE6477
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Protein biosynthesis, transport or catabolism genes up-regulated in hyperploid multiple myeloma (MM) compared to the non-hyperploid MM samples.

description_full:
  Hyperdiploid multiple myeloma (H-MM) is the most common form of myeloma. In this gene expression profiling study, we show that H-MM is defined by a protein biosynthesis signature that is primarily driven by a gene dosage mechanism as a result of trisomic chromosomes. Within H-MM, four independently validated patient clusters overexpressing nonoverlapping sets of genes that form cognate pathways/networks that have potential biological importance in multiple myeloma were identified. One prominent cluster, cluster 1, is characterized by high expression of cancer testis antigen and proliferation-associated genes. Tumors from these patients were more proliferative than tumors in other clusters (median plasma cell labeling index, 3.8; P < 0.05). Another cluster, cluster 3, is characterized by genes involved in tumor necrosis factor/nuclear factor-kappaB signaling and antiapoptosis. These patients have better response to bortezomib as compared with patients within other clusters (70% versus 29%; P = 0.02). Furthermore, for a group of patients generally thought to have better prognosis, a cluster of patients with short survival (cluster 1; median survival, 27 months) could be identified. This analysis illustrates the heterogeneity within H-MM and the importance of defining specific cytogenetic prognostic factors. Furthermore, the signatures that defined these clusters may provide a basis for tailoring treatment to individual patients.


systematic_name: M1858
exact_source: Table 1: Decreased
source_species_code: HS
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Down-regulated genes in A2780 cells (ovarian cancer) treated with 17AAG [PubChem=6440175], a chemical with anticancer properties.

description_full:
  The promising antitumor activity of 17-allylamino-17-demethoxygeldanamycin (17AAG) results from inhibition of the molecular chaperone heat shock protein 90 (HSP90) and subsequent degradation of multiple oncogenic client proteins. Gene expression microarray and proteomic analysis were used to profile molecular changes in the A2780 human ovarian cancer cell line treated with 17AAG. Comparison of results with an inactive analogue and an alternative HSP90 inhibitor radicicol indicated that increased expression of HSP72, HSC70, HSP27, HSP47, and HSP90beta at the mRNA level were on-target effects of 17AAG. HSP27 protein levels were increased in tumor biopsies following treatment of patients with 17AAG. A group of MYC-regulated mRNAs was decreased by 17AAG. Of particular interest and novelty were changes in expression of chromatin-associated proteins. Expression of the heterochromatin protein 1 was increased, and expression of the histone acetyltransferase 1 and the histone arginine methyltransferase PRMT5 was decreased by 17AAG. PRMT5 was shown to be a novel HSP90-binding partner and potential client protein. Cellular protein acetylation was reduced by 17AAG, which was shown to have an antagonistic interaction on cell proliferation with the histone deacetylase inhibitor trichostatin A. This mRNA and protein expression analysis has provided new insights into the complex molecular pharmacology of 17AAG and suggested new genes and proteins that may be involved in response to the drug or be potential biomarkers of drug action.


systematic_name: M2879
exact_source: Table 3S, 4S: cluster 1
source_species_code: HS
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Selected genes down-regulated in response to the Ras inhibitor salirasib [PubChem=5469318] in a panel of cancer cell lines with constantly active HRAS [GeneID=3265].

description_full:
  Deregulation of Ras pathways results in complex abnormalities of multiple signaling cascades that contribute to human malignancies. Ras is therefore considered an appropriate target for cancer therapy. In light of the complexity of the deregulated Ras pathway, it is important to decipher at the molecular level the response of cancer cells to Ras inhibitors that would reregulate it. In the present study, we used gene expression profiling as a robust method for the global dissection of gene expression alterations that resulted from treatment with the Ras inhibitor S-farnesylthiosalicylic acid (FTS; salirasib). Use of a ranking-based procedure, combined with functional analysis and promoter sequence analysis, enabled us to decipher the common and most prominent patterns of the transcriptional response of five different human cancer cell lines to FTS. Remarkably, the analysis identified a distinctive core transcriptional response to FTS that was common to all cancer cell lines tested. This signature fits well to a recently described deregulated Ras pathway signature that predicted sensitivity to FTS. Taken together, these studies provide strong support for the conclusion that FTS specifically reregulates defective Ras pathways in human tumor cells. Ras pathway reregulation by FTS was manifested by repression of E2F-regulated and NF-Y-regulated genes and of the transcription factor FOS (all of which control cell proliferation), repression of survivin expression (which blocks apoptosis), and induction of activating transcription factor-regulated and Bach2-regulated genes (which participate in translation and stress responses). Our results suggest that cancer patients with deregulated Ras pathway tumors might benefit from FTS treatment.


systematic_name: M178
exact_source: Table 4
source_species_code: HS
GEO_id: GSE2379
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Tumorigenesis markers of head and neck squamous cell carcinoma (HNSCC): up-regulated in the 'early' tumors vs normal samples.

description_full:
[cell repeats an earlier one in this file: 1610 characters]


systematic_name: M123
exact_source: http://stemcellmatrix.scripps.edu/page60/files/PluriNet.xls
source_species_code: HS
GEO_id: GSE11508
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes constituting the PluriNet protein-protein network shared by the pluripotent cells (embryonic stem cells, embryonical carcinomas and induced pluripotent cells).

description_full:
  Stem cells are defined as self-renewing cell populations that can differentiate into multiple distinct cell types. However, hundreds of different human cell lines from embryonic, fetal and adult sources have been called stem cells, even though they range from pluripotent cells-typified by embryonic stem cells, which are capable of virtually unlimited proliferation and differentiation-to adult stem cell lines, which can generate a far more limited repertoire of differentiated cell types. The rapid increase in reports of new sources of stem cells and their anticipated value to regenerative medicine has highlighted the need for a general, reproducible method for classification of these cells. We report here the creation and analysis of a database of global gene expression profiles (which we call the 'stem cell matrix') that enables the classification of cultured human stem cells in the context of a wide variety of pluripotent, multipotent and differentiated cell types. Using an unsupervised clustering method to categorize a collection of approximately 150 cell samples, we discovered that pluripotent stem cell lines group together, whereas other cell types, including brain-derived neural stem cell lines, are very diverse. Using further bioinformatic analysis we uncovered a protein-protein network (PluriNet) that is shared by the pluripotent cells (embryonic stem cells, embryonal carcinomas and induced pluripotent cells). Analysis of published data showed that the PluriNet seems to be a common characteristic of pluripotent cells, including mouse embryonic stem and induced pluripotent cells and human oocytes. Our results offer a new strategy for classifying stem cells and support the idea that pluripotency and self-renewal are under tight control by specific molecular networks.


systematic_name: M7982
exact_source: Fig. 2g
source_species_code: HS
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Primary innate immune response genes induced in 293T cells (embryonic kidney) by overexpression of STING (TMEM173) [GeneID=340061].

description_full:
  The cellular innate immune system is essential for recognizing pathogen infection and for establishing effective host defence. But critical molecular determinants responsible for facilitating an appropriate immune response-following infection with DNA and RNA viruses, for example-remain to be identified. Here we report the identification, following expression cloning, of a molecule (STING; stimulator of interferon genes) that appears essential for effective innate immune signalling processes. It comprises five putative transmembrane regions, predominantly resides in the endoplasmic reticulum and is able to activate both NF-kappaB and IRF3 transcription pathways to induce expression of type I interferon (IFN-alpha and IFN-beta ) and exert a potent anti-viral state following expression. In contrast, loss of STING rendered murine embryonic fibroblasts extremely susceptible to negative-stranded virus infection, including vesicular stomatitis virus. Further, STING ablation abrogated the ability of intracellular B-form DNA, as well as members of the herpesvirus family, to induce IFN-beta, but did not significantly affect the Toll-like receptor (TLR) pathway. Yeast two-hybrid and co-immunoprecipitation studies indicated that STING interacts with RIG-I and with SSR2 (also known as TRAPbeta), which is a member of the translocon-associated protein (TRAP) complex required for protein translocation across the endoplasmic reticulum membrane following translation. Ablation by RNA interference of both TRAPbeta and translocon adaptor SEC61beta was subsequently found to inhibit STING's ability to stimulate expression of IFN-beta. Thus, as well as identifying a regulator of innate immune signalling, our results imply a potential role for the translocon in innate signalling pathways activated by select viruses as well as intracellular DNA.


systematic_name: M1868
exact_source: Fig 2B
source_species_code: HS
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Nuclear receptors whose expression correlated with that of aromatase (CYP19A1) [GeneID=1588] in a panel of breast cancer biopsies.

description_full:
  Aromatase is a key enzyme in intratumoral estrogen production required for the production of estrogens through the conversion of serum androgens in postmenopausal breast cancer patients. There have been, however, controversies regarding the intratumoral localization of aromatase in human breast carcinoma tissues. Therefore, we have first examined the intratumoral localization of aromatase mRNA/protein in 19 breast carcinomas using laser capture microdissection/quantitative reverse transcription-PCR (RT-PCR) and immunohistochemistry. Aromatase mRNA and protein were detected in both intratumoral stromal and parenchymal cells in breast carcinoma tissues. Subsequent microarray expression profiling and clustering analyses, in addition to quantitative RT-PCR studies, showed a significant positive correlation between aromatase and estrogen-related receptor alpha mRNA expression in isolated carcinoma cells. We further examined an interaction between stromal cells isolated from human breast carcinoma tissues and breast carcinoma cell lines using a coculture system to study the biological characteristic of aromatase expression in carcinoma cells. Aromatase mRNA and enzyme activity and 17beta-hydroxysteroid dehydrogenase type 1 mRNA in breast carcinoma cell lines, including MCF-7 and SK-BR-3 cells, were up-regulated in the presence of patient-derived 32N or 74T intratumoral stromal cells. The results from steroid conversion assays were also consistent with the findings above. The results of our study also showed that aromatase inhibitors were more effective in inhibiting aromatization induced by coculture in MCF-7 than that in stromal 32N. The examination of the localization of aromatase and its regulation, including the interactions existing between different cell types in human breast carcinoma tissues, may provide important information as to achieving better clinical response to aromatase inhibitors in breast cancer patients.


systematic_name: M11720
exact_source: Suppl. Data 3: fold regulation < 0.5
source_species_code: HS
GEO_id: GSE7181
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in cancer stem cells derived from glyoblastoma tumors: CD133+ [GeneID=8842]  vs. CD133- cells.

description_full:
  Although glioblastomas show the same histologic phenotype, biological hallmarks such as growth and differentiation properties vary considerably between individual cases. To investigate whether different subtypes of glioblastomas might originate from different cells of origin, we cultured tumor cells from 22 glioblastomas under medium conditions favoring the growth of neural and cancer stem cells (CSC). Secondary glioblastoma (n = 7)-derived cells did not show any growth in the medium used, suggesting the absence of neural stem cell-like tumor cells. In contrast, 11/15 primary glioblastomas contained a significant CD133(+) subpopulation that displayed neurosphere-like, nonadherent growth and asymmetrical cell divisions yielding cells expressing markers characteristic for all three neural lineages. Four of 15 cell lines derived from primary glioblastomas grew adherently in vitro and were driven by CD133(-) tumor cells that fulfilled stem cell criteria. Both subtypes were similarly tumorigenic in nude mice in vivo. Clinically, CD133(-) glioblastomas were characterized by a lower proliferation index, whereas glial fibrillary acidic protein staining was similar. GeneArray analysis revealed 117 genes to be differentially expressed by these two subtypes. Together, our data provide first evidence that CD133(+) CSC maintain only a subset of primary glioblastomas. The remainder stems from previously unknown CD133(-) tumor cells with apparent stem cell-like properties but distinct molecular profiles and growth characteristics in vitro and in vivo.


systematic_name: M12112
exact_source: Table 1S
source_species_code: HS
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Angiogenic markers up-regulated in lymph endothelial cells upon infection with KSHV (Kaposi's sarcoma herpes virus).

description_full:
  Kaposi's sarcoma (KS) is caused by Kaposi's sarcoma-associated herpesvirus (KSHV) and consists of proliferating spindle cells, which are related to lymphatic endothelial cells (LEC). Angiopoietin-2 (Ang2) is a secreted proangiogenic and lymphangiogenic molecule. Here, we show the expression of Ang2 protein in KS and confirm that KSHV infection up-regulates Ang2 in LEC. We show that a paracrine mechanism contributes to this up-regulation. A lentiviral library of individual KSHV-encoding genes, comprising the majority of known latent genes and a selection of lytic viral genes, was constructed to investigate the underlying mechanism of this up-regulation. Two lytic genes, viral interleukin-6 (vIL6) and viral G-protein-coupled receptor (vGPCR), up-regulated Ang2 expression in LEC. Both vIL6 and vGPCR are expressed in KSHV-infected LEC and caused up-regulation of Ang2 in a paracrine manner. KSHV, vIL6, and vGPCR up-regulated Ang2 through the mitogen-activated protein kinase (MAPK) pathway. Gene expression microarray analysis identified several other angiogenic molecules affected by KSHV, including the vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) axis, which is also affected by vIL6 and vGPCR in LEC, and matrix metalloproteinases, which could act in concert with Ang2 to contribute to KS development. These findings support the paracrine and autocrine roles of the lytic KSHV-encoded proteins, vIL6 and vGPCR, in KS pathogenesis and identify Ang2 as a potential therapeutic target for this neoplasm.


systematic_name: M5825
exact_source: Table 1S
source_species_code: HS
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Angiogenic markers down-regulated in lymph endothelial cells upon infection with KSHV (Kaposi's sarcoma herpes virus).

description_full:
  Kaposi's sarcoma (KS) is caused by Kaposi's sarcoma-associated herpesvirus (KSHV) and consists of proliferating spindle cells, which are related to lymphatic endothelial cells (LEC). Angiopoietin-2 (Ang2) is a secreted proangiogenic and lymphangiogenic molecule. Here, we show the expression of Ang2 protein in KS and confirm that KSHV infection up-regulates Ang2 in LEC. We show that a paracrine mechanism contributes to this up-regulation. A lentiviral library of individual KSHV-encoding genes, comprising the majority of known latent genes and a selection of lytic viral genes, was constructed to investigate the underlying mechanism of this up-regulation. Two lytic genes, viral interleukin-6 (vIL6) and viral G-protein-coupled receptor (vGPCR), up-regulated Ang2 expression in LEC. Both vIL6 and vGPCR are expressed in KSHV-infected LEC and caused up-regulation of Ang2 in a paracrine manner. KSHV, vIL6, and vGPCR up-regulated Ang2 through the mitogen-activated protein kinase (MAPK) pathway. Gene expression microarray analysis identified several other angiogenic molecules affected by KSHV, including the vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) axis, which is also affected by vIL6 and vGPCR in LEC, and matrix metalloproteinases, which could act in concert with Ang2 to contribute to KS development. These findings support the paracrine and autocrine roles of the lytic KSHV-encoded proteins, vIL6 and vGPCR, in KS pathogenesis and identify Ang2 as a potential therapeutic target for this neoplasm.


systematic_name: M9433
exact_source: Suppl. file: all_pathways/human_mitoDB_6_2002_HG-U133A_probes
source_species_code: HS
contributor: Vamsi Mootha
contrib_organization: Broad Institute
description_brief:
  Mitochondrial genes; 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: M9788
exact_source: unknown
source_species_code: HS
contributor: Vamsi Mootha
contrib_organization: Broad Institute
description_brief:
  Genes up-regulated in differentiating C2C12 cells (myoblasts) upon expression of PPARGC1A [GeneID=10891] off an adenoviral vector.

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: M18669
exact_source: Suppl. file: all_pathways/TCA_HG-U133A_probes
source_species_code: HS
contributor: Vamsi Mootha
contrib_organization: Broad Institute
description_brief:
  Tricarboxylic acid related genes; based on literature and sequence annotation resources and converted to Affymetrix HG-U133A probe sets.

description_full:
[cell repeats an earlier one in this file: 873 characters]


description_brief: Genes highly expressed in hepatocellular carcinoma with poor survival.
systematic_name: M7987
exact_source: Table 1S
source_species_code: HS
contributor: Yujin Hoshida
contrib_organization: Broad Institute
description_full:
  We analyzed global gene expression patterns of 91 human hepatocellular carcinomas (HCCs) to define the molecular characteristics of the tumors and to test the prognostic value of the expression profiles. Unsupervised classification methods revealed two distinctive subclasses of HCC that are highly associated with patient survival. This association was validated via 5 independent supervised learning methods. We also identified the genes most strongly associated with survival by using the Cox proportional hazards survival analysis. This approach identified a limited number of genes that accurately predicted the length of survival and provides new molecular insight into the pathogenesis of HCC. Tumors from the low survival subclass have strong cell proliferation and antiapoptosis gene expression signatures. In addition, the low survival subclass displayed higher expression of genes involved in ubiquitination and histone modification, suggesting an etiological involvement of these processes in accelerating the progression of HCC. In conclusion, the biological differences identified in the HCC subclasses should provide an attractive source for the development of therapeutic targets (e.g., HIF1a) for selective treatment of HCC patients. Supplementary material for this article can be found on the HEPATOLOGY Web site (http://interscience.wiley.com/jpages/0270-9139/suppmat/index.html)


systematic_name: M2999
exact_source: Suppl. file: all_pathways/ROS_HG-U133A_probes
source_species_code: HS
contributor: Vamsi Mootha
contrib_organization: Broad Institute
description_brief:
  Reactive oxidative species (ROS) genes; based on literature and sequence annotation resources and converted to Affymetrix HG-U133A probe sets.

description_full:
[cell repeats an earlier one in this file: 873 characters]


systematic_name: M19128
exact_source: Table 1
source_species_code: HS
GEO_id: GSE7132
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in  tumor-conditioned vs quiescent endothelial cells and up-regulated upon treatment with decitabine and TSA [PubChem=451668;5562].

description_full:
  Tumor angiogenesis requires intricate regulation of gene expression in endothelial cells. We recently showed that DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibitors directly repress endothelial cell growth and tumor angiogenesis, suggesting that epigenetic modifications mediated by DNMTs and HDAC are involved in regulation of endothelial cell gene expression during tumor angiogenesis. To understand the mechanisms behind the epigenetic regulation of tumor angiogenesis, we used microarray analysis to perform a comprehensive screen to identify genes down-regulated in tumor-conditioned versus quiescent endothelial cells, and reexpressed by 5-aza-2'-deoxycytidine (DAC) and trichostatin A (TSA). Among the 81 genes identified, 77% harbored a promoter CpG island. Validation of mRNA levels of a subset of genes confirmed significant down-regulation in tumor-conditioned endothelial cells and reactivation by treatment with a combination of DAC and TSA, as well as by both compounds separately. Silencing of these genes in tumor-conditioned endothelial cells correlated with promoter histone H3 deacetylation and loss of H3 lysine 4 methylation, but did not involve DNA methylation of promoter CpG islands. For six genes, down-regulation in microdissected human tumor endothelium was confirmed. Functional validation by RNA interference revealed that clusterin, fibrillin 1, and quiescin Q6 are negative regulators of endothelial cell growth and angiogenesis. In summary, our data identify novel angiogenesis-suppressing genes that become silenced in tumor-conditioned endothelial cells in association with promoter histone modifications and reactivated by DNMT and HDAC inhibitors through reversal of these epigenetic modifications, providing a mechanism for epigenetic regulation of tumor angiogenesis.


systematic_name: M679
exact_source: Table 1
source_species_code: HS
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  G1 to S phase regulators significantly changed in DanG cells (pancreatic cancer) treated with Ly294002 [PubChem=3973], a phosphoinositide 3-kinase (PI3K) inhibitor.

description_full:
  The phosphoinositide-3-kinase (PI3K)/AKT signaling pathway controls fundamental processes of cancer cell biology like proliferation and cell survival. The PI3K/AKT pathway is activated in pancreatic ductal adenocarcinoma (PDAC) cells. The molecular mechanisms linking PI3K signaling to the cell cycle machinery in PDAC cells are not investigated in detail. Using the PI3K inhibitor Ly294002 as well as small interfering RNA targeting AKT1 expression, we show that PI3K controls the proliferation and G(1) phase progression of PDAC cells. Gene profiling revealed several important regulators of G(1)-S phase progression controlled by PI3K signaling like p21(Cip1), S-phase kinase-associated protein 2 (SKP2), CDC25a, cyclin A, cyclin D2, CDK2, and cyclin E. We show that the F-box protein SKP2, an oncogene up-regulated in PDAC, is transcriptionally regulated by the PI3K/AKT1 pathway in PDAC cells. At the molecular level, the control of the SKP2 gene by PI3K is due to the regulation of E2F1 binding to the proximal SKP2 gene promoter. The complex and profound connection of PI3K/AKT1 signaling to the cell cycle qualifies this pathway as a suitable target for therapeutic intervention in PDAC.


systematic_name: M3955
exact_source: Table 1S
source_species_code: HS
GEO_id: GSE6576
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Integrin, VEGF, Wnt and TGFbeta signaling pathway genes up-regulated in PC-3 cells (prostate cancer) after knockdown of PDEF [GeneID=25803] by RNAi.

description_full:
  The epithelium-specific Ets transcription factor, PDEF, plays a role in prostate and breast cancer, although its precise function has not been established. In prostate cancer, PDEF is involved in regulating prostate-specific antigen expression via interaction with the androgen receptor and NKX3.1, and down-regulation of PDEF by antiproliferative agents has been associated with reduced PDEF expression. We now report that reduced expression of PDEF leads to a morphologic change, increased migration and invasiveness in prostate cancer cells, reminiscent of transforming growth factor beta (TGFbeta) function and epithelial-to-mesenchymal transition. Indeed, inhibition of PDEF expression triggers a transcriptional program of genes involved in the TGFbeta pathway, migration, invasion, adhesion, and epithelial dedifferentiation. Our results establish PDEF as a critical regulator of genes involved in cell motility, invasion, and adhesion of prostate cancer cells.


systematic_name: M16479
exact_source: Table 1: Genes overexpressed in MRD+
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Up-regulated genes significantly associated with positive minimal residual disease (MRD) on day 46 after chemotherapy treatment of children with acute lymphoblastic leukemia (ALL).

description_full:
  In childhood acute lymphoblastic leukemia (ALL), early response to treatment is a powerful prognostic indicator. To identify genes associated with this response, we analyzed gene expression of diagnostic lymphoblasts from 189 children with ALL and compared the findings with minimal residual disease (MRD) levels on days 19 and 46 of remission induction treatment. After excluding genes associated with genetic subgroups, we identified 17 genes that were significantly associated with MRD. The caspase 8-associated protein 2 (CASP8AP2) gene was studied further because of its reported role in apoptosis and glucocorticoid signaling. In a separate cohort of 99 patients not included in the comparison of gene expression profiles and MRD, low levels of CASP8AP2 expression predicted a lower event-free survival (P = .02) and a higher rate of leukemia relapse (P = .01) and were an independent predictor of outcome. High levels of CASP8AP2 expression were associated with a greater propensity of leukemic lymphoblasts to undergo apoptosis. We conclude that measurement of CASP8AP2 expression at diagnosis offers a means to identify patients whose leukemic cells are highly susceptible to chemotherapy. Therefore, this gene is a strong candidate for inclusion in gene expression arrays specifically designed for leukemia diagnosis.


systematic_name: M4163
exact_source: Fig. 1a: up in sensitive & down in resistant
source_species_code: HS
GEO_id: GSE5682
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Up-regulated genes associated with sensitivity and resistance to gamma-secretase (GSI) in T-cell acute lymphoblastic leukemia (T-ALL) cell lines.

description_full:
  Gain-of-function mutations in NOTCH1 are common in T-cell lymphoblastic leukemias and lymphomas (T-ALL), making this receptor a promising target for drugs such as gamma-secretase inhibitors, which block a proteolytic cleavage required for NOTCH1 activation. However, the enthusiasm for these therapies has been tempered by tumor resistance and the paucity of information on the oncogenic programs regulated by oncogenic NOTCH1. Here we show that NOTCH1 regulates the expression of PTEN (encoding phosphatase and tensin homolog) and the activity of the phosphoinositol-3 kinase (PI3K)-AKT signaling pathway in normal and leukemic T cells. Notch signaling and the PI3K-AKT pathway synergize in vivo in a Drosophila melanogaster model of Notch-induced tumorigenesis, and mutational loss of PTEN is associated with human T-ALL resistance to pharmacological inhibition of NOTCH1. Overall, these findings identify transcriptional control of PTEN and regulation of the PI3K-AKT pathway as key elements of the leukemogenic program activated by NOTCH1 and provide the basis for the design of new therapeutic strategies for T-ALL.


description_brief: A biomarker of plasma signaling proteins that predicts clinical Alzheimer's diagnosis.
systematic_name: M11893
exact_source: Table 1
source_species_code: HS
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_full:
  A molecular test for Alzheimer's disease could lead to better treatment and therapies. We found 18 signaling proteins in blood plasma that can be used to classify blinded samples from Alzheimer's and control subjects with close to 90% accuracy and to identify patients who had mild cognitive impairment that progressed to Alzheimer's disease 2-6 years later. Biological analysis of the 18 proteins points to systemic dysregulation of hematopoiesis, immune responses, apoptosis and neuronal support in presymptomatic Alzheimer's disease.


description_brief: Exercise regulated genes in hyppocampus.
systematic_name: M1878
exact_source: Table 1S
source_species_code: MM
GEO_id: GSE9565
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_full:
  Exercise has many health benefits, including antidepressant actions in depressed human subjects, but the mechanisms underlying these effects have not been elucidated. We used a custom microarray to identify a previously undescribed profile of exercise-regulated genes in the mouse hippocampus, a brain region implicated in mood and antidepressant response. Pathway analysis of the regulated genes shows that exercise upregulates a neurotrophic factor signaling cascade that has been implicated in the actions of antidepressants. One of the most highly regulated target genes of exercise and of the growth factor pathway is the gene encoding the VGF nerve growth factor, a peptide precursor previously shown to influence synaptic plasticity and metabolism. We show that administration of a synthetic VGF-derived peptide produces a robust antidepressant response in mice and, conversely, that mutation of VGF in mice produces the opposite effects. The results suggest a new role for VGF and identify VGF signaling as a potential therapeutic target for antidepressant drug development.


systematic_name: M8108
exact_source: Table 6: up-regulated by SERMs or ICI
source_species_code: HS
GEO_id: GSE848
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in MCF-7 cells (breast cancer) by selective estrogen receptor modulators (SERM) 4-hydroxytamoxifen, raloxifene, or ICI 182780 but not by estradiol [PubChem=44959;5035;3478439;5757].

description_full:
  Selective estrogen receptor modulators (SERMs) such as tamoxifen are effective in the treatment of many estrogen receptor-positive breast cancers and have also proven to be effective in the prevention of breast cancer in women at high risk for the disease. The comparative abilities of tamoxifen versus raloxifene in breast cancer prevention are currently being compared in the Study of Tamoxifen and Raloxifene trial. To better understand the actions of these compounds in breast cancer, we have examined their effects on the expression of approximately 12,000 genes, using Affymetrix GeneChip microarrays, with quantitative PCR verification in many cases, categorizing their actions as agonist, antagonist, or partial agonist/antagonist. Analysis of gene stimulation and inhibition by the SERMs trans-hydroxytamoxifen (TOT) and raloxifene (Ral) or ICI 182,780 (ICI) and by estradiol (E2) in estrogen receptor-containing MCF-7 human breast cancer cells revealed that (a) TOT was the most E2-like of the three compounds, (b) all three compounds either partially or fully antagonized the action of E2 on most genes, with the order of antagonist activity being ICI > Ral > TOT, (c) TOT and Ral, but not ICI, displayed partial agonist/partial antagonist activity on a number of E2-regulated genes, (d) several stimulatory cell cycle-related genes were down-regulated exclusively by ICI, (e) the estrogen-like activity of Ral nearly always overlapped with that of TOT, indicating that Ral has little unique agonist activity different from that of TOT, and (f) some genes were specifically up-regulated by TOT but not Ral, ICI, or E2. Hence, gene expression profiling can discern fundamental differences among SERMs and provides insight into the distinct biologies of TOT, Ral, and ICI in breast cancer.


systematic_name: M11250
exact_source: Table 6: down-regulated by SERMs or ICI
source_species_code: HS
GEO_id: GSE848
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in MCF-7 cells (breast cancer) by selective estrogen receptor modulators (SERM) 4-hydroxytamoxifen, raloxifene, or ICI 182780 but not by estradiol [PubChem=44959;5035;3478439;5757].

description_full:
[cell repeats an earlier one in this file: 1798 characters]


systematic_name: M17033
exact_source: Table 1
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Maturation of monocyte-derived dendritic cells (DC) in response to inflammatory stimuli: genes up-regulated only at 8 hr after the stimulation (cluster A).

description_full:
  Maturation of dendritic cells (DC) serves a deterministic role in the link between innate and adaptive immunity, constituting a checkpoint with regard to whether responses from the lymphocyte compartment shall be raised and what class of response is needed to protect the host against invading pathogens. Since DC have not been shown to possess mechanisms such as gene recombination or somatic mutation for generating a diverse repertoire of antigen-recognition receptors, it is unlikely that these leukocytes can intrinsically respond to all conceivable molecules present in our environment. In the present study, we have therefore determined how mediators of the inflammatory response regulate global gene transcription in DC. The data represent an extensive and time-ordered reprogramming of the DC during their course of maturation, involving genes encoding proteins that regulate responses of both innate cells and lymphocytes. This transcriptional reorganization may reflect the effect of in vivo released inflammatory mediators induced by endogenous or pathogenic stimulation.


systematic_name: M12480
exact_source: Table 2
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Maturation of monocyte-derived dendritic cells (DC) in response to inflammatory stimuli: genes up-regulated both at 8 hr and 48 hr after the stimulation (cluster B).

description_full:
[cell repeats an earlier one in this file: 1083 characters]


systematic_name: M3559
exact_source: Table 1
source_species_code: HS
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Interferon-inducible genes up-regulated in A549 cells (lung cancer) infected with a respiratory syncytial virus (RSV) that had its NS1 [GeneID=1494468] gene knocked down by RNAi.

description_full:
  Respiratory syncytial virus (RSV) infection is one of the major causes of respiratory tract infection for which no vaccine or antiviral treatment is available. The RSV NS1 protein seems to antagonize the host interferon (IFN) response; however, its mechanism is unknown. Here, we used a plasmid-borne small interfering RNA targeting the NS1 gene (siNS1) to examine the role of NS1 in modulating RSV infection. RSV replication was reduced in A549 cells, but not IFN-deficient Vero cells, transfected with siNS1. siNS1 induced upregulated expression of IFN-beta and IFN-inducible genes in A549 cells. siNS1-transfected human dendritic cells, upon RSV infection, produced elevated type-1 IFN and induced differentiation of naive CD4+ T cells to T helper type 1 (TH1) cells. Mice treated intranasally with siNS1 nanoparticles before or after infection with RSV showed substantially decreased virus titers in the lung and decreased inflammation and airway reactivity compared to controls. Thus, siNS1 nanoparticles may provide an effective inhibition of RSV infection in humans.


systematic_name: M12751
exact_source: Table 1S
source_species_code: HS
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in DLD-1 cells (colon cancer) in response to hypoxia; might not be direct targets of HIF1A [GeneID=3091].

description_full:
  Hypoxia inducible factor-1 (HIF-1) is considered a crucial mediator of the cellular response to hypoxia through its regulation of genes that control angiogenesis. It represents an attractive therapeutic target in colon cancer, one of the few tumor types that shows a clinical response to antiangiogenic therapy. But it is unclear whether inhibition of HIF-1 alone is sufficient to block tumor angiogenesis. In HIF-1alpha knockdown DLD-1 colon cancer cells (DLD-1(HIF-kd)), the hypoxic induction of vascular endothelial growth factor (VEGF) was only partially blocked. Xenografts remained highly vascularized with microvessel densities identical to DLD-1 tumors that had wild-type HIF-1alpha (DLD-1(HIF-wt)). In addition to the preserved expression of VEGF, the proangiogenic cytokine interleukin (IL)-8 was induced by hypoxia in DLD-1(HIF-kd) but not DLD-1(HIF-wt) cells. This induction was mediated by the production of hydrogen peroxide and subsequent activation of NF-kappaB. Furthermore, the KRAS oncogene, which is commonly mutated in colon cancer, enhanced the hypoxic induction of IL-8. A neutralizing antibody to IL-8 substantially inhibited angiogenesis and tumor growth in DLD-1(HIF-kd) but not DLD-1(HIF-wt) xenografts, verifying the functional significance of this IL-8 response. Thus, compensatory pathways can be activated to preserve the tumor angiogenic response, and strategies that inhibit HIF-1alpha may be most effective when IL-8 is simultaneously targeted.


systematic_name: M393
exact_source: Table 3S: top 550 with |correlation| > 0.3 & correlation > 0.3
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Up-regulated genes from the optimal set of 550 markers discriminating breast cancer samples by ESR1 [GeneID=2099] expression: ER(+) vs ER(-) tumors.

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


systematic_name: M11951
exact_source: Table 1: black and blue colors
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in primary keratinocytes by expression of p50 (NFKB1) and p65 (RELA) [GeneID=4790;5970] components of NFKB.

description_full:
  NF-kappa B regulates normal and pathological processes, including neoplasia, in a tissue-context-dependent manner. In skin, NF-kappa B is implicated in epidermal homeostasis as well as in the pathogenesis of squamous cell carcinoma; however, its function in the underlying mesenchymal dermis has been unclear. To gain insight into NF-kappa B roles in these two adjacent cutaneous tissue compartments, NF-kappa B effects on expression of 12 435 genes were determined in epidermal keratinocytes and dermal fibroblasts. Although NF-kappa B induced proinflammatory and antiapoptotic genes in both settings, it exhibited divergent effects on growth regulatory genes. In keratinocytes, but not in fibroblasts, NF-kappa B induced p21(CIP1), which was sufficient to inhibit growth of both cell types. Levels of growth inhibitory factor (GIF), in contrast, were increased by NF-kappa B in both settings but inhibited growth only in keratinocytes. These findings indicate that transcription factors such as NF-kappa B can program tissue-selective effects via both differential target gene induction as well as by inducing common targets that exert differing effects depending on cellular lineage.


systematic_name: M4151
exact_source: Table 1: black and red colors
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in primary fibroblast cells by expression of p50 (NFKB1) and p65  (RELA) [GeneID=4790;5970] components of NFKB.

description_full:
  NF-kappa B regulates normal and pathological processes, including neoplasia, in a tissue-context-dependent manner. In skin, NF-kappa B is implicated in epidermal homeostasis as well as in the pathogenesis of squamous cell carcinoma; however, its function in the underlying mesenchymal dermis has been unclear. To gain insight into NF-kappa B roles in these two adjacent cutaneous tissue compartments, NF-kappa B effects on expression of 12 435 genes were determined in epidermal keratinocytes and dermal fibroblasts. Although NF-kappa B induced proinflammatory and antiapoptotic genes in both settings, it exhibited divergent effects on growth regulatory genes. In keratinocytes, but not in fibroblasts, NF-kappa B induced p21(CIP1), which was sufficient to inhibit growth of both cell types. Levels of growth inhibitory factor (GIF), in contrast, were increased by NF-kappa B in both settings but inhibited growth only in keratinocytes. These findings indicate that transcription factors such as NF-kappa B can program tissue-selective effects via both differential target gene induction as well as by inducing common targets that exert differing effects depending on cellular lineage.


systematic_name: M7357
exact_source: Table 3-1S: SOM C1: (ITTP DP) vs (SP4 CB4 AB4)
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated at early stages of progenitor T lymphocyte maturation compared to the late stages.

description_full:
[cell repeats an earlier one in this file: 1531 characters]


systematic_name: M10773
exact_source: Table 1: set C
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  'Wilm's tumor signature': genes highly expressed in Wilm's tumor samples compared to normal fetal kidney and a heterologous tumor, Burkit lymphoma.

description_full:
  Wilms' tumor (WT) has been considered a prototype for arrested cellular differentiation in cancer, but previous studies have relied on selected markers. We have now performed an unbiased survey of gene expression in WTs using oligonucleotide microarrays. Statistical criteria identified 357 genes as differentially expressed between WTs and fetal kidneys. This set contained 124 matches to genes on a microarray used by Stuart and colleagues (Stuart RO, Bush KT, Nigam SK: Changes in global gene expression patterns during development and maturation of the rat kidney. Proc Natl Acad Sci USA 2001, 98:5649-5654) to establish genes with stage-specific expression in the developing rat kidney. Mapping between the two data sets showed that WTs systematically overexpressed genes corresponding to the earliest stage of metanephric development, and underexpressed genes corresponding to later stages. Automated clustering identified a smaller group of 27 genes that were highly expressed in WTs compared to fetal kidney and heterologous tumor and normal tissues. This signature set was enriched in genes encoding transcription factors. Four of these, PAX2, EYA1, HBF2, and HOXA11, are essential for cell survival and proliferation in early metanephric development, whereas others, including SIX1, MOX1, and SALL2, are predicted to act at this stage. SIX1 and SALL2 proteins were expressed in the condensing mesenchyme in normal human fetal kidneys, but were absent (SIX1) or reduced (SALL2) in cells at other developmental stages. These data imply that the blastema in WTs has progressed to the committed stage in the mesenchymal-epithelial transition, where it is partially arrested in differentiation. The WT-signature set also contained the Wnt receptor FZD7, the tumor antigen PRAME, the imprinted gene NNAT and the metastasis-associated transcription factor E1AF.


systematic_name: M8520
exact_source: Cluster 6 of method A
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Cluster 6 of method A: up-regulation of these genes in patients with non-small cell lung cancer (NSCLC) predicts poor survival outcome.

description_full:
[cell repeats an earlier one in this file: 1095 characters]


systematic_name: M18506
exact_source: Suppl. Data 2A: Table 2S: Fold-diff in geom means > 1
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in the ANBL-6 cell line (multiple myeloma, MM) after withdrawal of IL6 [GeneID=3569].

description_full:
[cell repeats an earlier one in this file: 1578 characters]


systematic_name: M5929
exact_source: Suppl. Data 2B: Table 2S: Fold-diff in geom means > 1
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in ANBL-6 cell line (multiple myeloma, MM) co-cultured with bone marrow stromal cells compared to those grown in the presence of IL6 [GeneID=3569].

description_full:
[cell repeats an earlier one in this file: 1578 characters]


systematic_name: M10739
exact_source: Suppl. Data 2C: Table 2S: Fold-diff in geom means < 1
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in ANBL-6 cell line (multiple myeloma, MM)  expressing a constantly active form of NRAS [GeneID=4893] off a plasmid vector compared to those grown in the presence of IL6 [GeneID=3569].

description_full:
[cell repeats an earlier one in this file: 1578 characters]


systematic_name: M4491
exact_source: Suppl. Data 2D: Table 2S: Fold-diff in geom means < 1
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in ANBL-6 cell line (multiple myeloma, MM) expressing an activated form of NRAS [GeneID=4893] off a plasmid vector compared to those co-cultured with bone marrow stromal cells.

description_full:
[cell repeats an earlier one in this file: 1578 characters]


systematic_name: M8696
exact_source: Supplementary Table G1
source_species_code: HS
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Top 40 genes from cluster 7 of acute myeloid leukemia (AML) expression profile; 61% of the samples are FAB M1 or M2 subtype.

description_full:
[cell repeats an earlier one in this file: 1675 characters]


systematic_name: M6241
exact_source: Supplementary Table H1
source_species_code: HS
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Top 40 genes from cluster 8 of aculte myeloid leukemia (AML) expression profile; 69% of the samples are FAB M2 subtype.

description_full:
[cell repeats an earlier one in this file: 1675 characters]


systematic_name: M8467
exact_source: Table 1S: fold change > 1
source_species_code: HS
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in peripheral blood mononuclear cells (PBMC) from sickle cell disease patients compared to those from healthy subjects.

description_full:
  In sickle cell disease, deoxygenation of intra-erythrocytic hemoglobin S leads to hemoglobin polymerization, erythrocyte rigidity, hemolysis, and microvascular occlusion. Ischemia-reperfusion injury, plasma hemoglobin-mediated nitric oxide consumption, and free radical generation activate systemic inflammatory responses. To characterize the role of circulating leukocytes in sickle cell pathogenesis we performed global transcriptional analysis of blood mononuclear cells from 27 patients in steady-state sickle cell disease (10 patients treated and 17 patients untreated with hydroxyurea) compared with 13 control subjects. We used gender-specific gene expression to validate human microarray experiments. Patients with sickle cell disease demonstrated differential gene expression of 112 genes involved in heme metabolism, cell-cycle regulation, antioxidant and stress responses, inflammation, and angiogenesis. Inducible heme oxygenase-1 and downstream proteins biliverdin reductase and p21, a cyclin-dependent kinase, were up-regulated, potentially contributing to phenotypic heterogeneity and absence of atherosclerosis in patients with sickle cell disease despite endothelial dysfunction and vascular inflammation. Hydroxyurea therapy did not significantly affect leukocyte gene expression, suggesting that such therapy has limited direct anti-inflammatory activity beyond leukoreduction. Global transcriptional analysis of circulating leukocytes highlights the intense oxidant and inflammatory nature of steady-state sickle cell disease and provides insight into the broad compensatory responses to vascular injury.


systematic_name: M4911
exact_source: Table 1S: fold change < 1
source_species_code: HS
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in peripheral blood mononuclear cells (PBMC) from sickle cell disease patients compared to those from healthy subjects.

description_full:
  In sickle cell disease, deoxygenation of intra-erythrocytic hemoglobin S leads to hemoglobin polymerization, erythrocyte rigidity, hemolysis, and microvascular occlusion. Ischemia-reperfusion injury, plasma hemoglobin-mediated nitric oxide consumption, and free radical generation activate systemic inflammatory responses. To characterize the role of circulating leukocytes in sickle cell pathogenesis we performed global transcriptional analysis of blood mononuclear cells from 27 patients in steady-state sickle cell disease (10 patients treated and 17 patients untreated with hydroxyurea) compared with 13 control subjects. We used gender-specific gene expression to validate human microarray experiments. Patients with sickle cell disease demonstrated differential gene expression of 112 genes involved in heme metabolism, cell-cycle regulation, antioxidant and stress responses, inflammation, and angiogenesis. Inducible heme oxygenase-1 and downstream proteins biliverdin reductase and p21, a cyclin-dependent kinase, were up-regulated, potentially contributing to phenotypic heterogeneity and absence of atherosclerosis in patients with sickle cell disease despite endothelial dysfunction and vascular inflammation. Hydroxyurea therapy did not significantly affect leukocyte gene expression, suggesting that such therapy has limited direct anti-inflammatory activity beyond leukoreduction. Global transcriptional analysis of circulating leukocytes highlights the intense oxidant and inflammatory nature of steady-state sickle cell disease and provides insight into the broad compensatory responses to vascular injury.


systematic_name: M18436
exact_source: Table 4S: G3_UP
source_species_code: HS
contributor: Yujin Hoshida
contrib_organization: Broad Institute
description_brief:
  Up-regulated genes in hepatocellular carcinoma (HCC) subclass G3, defined by unsupervised clustering.

description_full:
[cell repeats an earlier one in this file: 1740 characters]


systematic_name: M4090
exact_source: Table 4S: G3_DN
source_species_code: HS
contributor: Yujin Hoshida
contrib_organization: Broad Institute
description_brief:
  Down-regulated genes in hepatocellular carcinoma (HCC) subclass G3, defined by unsupervised clustering.

description_full:
[cell repeats an earlier one in this file: 1740 characters]


systematic_name: M4448
exact_source: Table 4S: G23_UP
source_species_code: HS
contributor: Yujin Hoshida
contrib_organization: Broad Institute
description_brief:
  Up-regulated genes in hepatocellular carcinoma (HCC) subclass G23, defined by unsupervised clustering.

description_full:
[cell repeats an earlier one in this file: 1740 characters]


systematic_name: M13831
exact_source: Table 4S: G123_UP
source_species_code: HS
contributor: Yujin Hoshida
contrib_organization: Broad Institute
description_brief:
  Up-regulated genes in hepatocellular  carcinoma (HCC) subclass G123, defined by unsupervised clustering.

description_full:
[cell repeats an earlier one in this file: 1740 characters]


systematic_name: M2218
exact_source: Table 4S: G123_DN
source_species_code: HS
contributor: Yujin Hoshida
contrib_organization: Broad Institute
description_brief:
  Down-regulated genes in hepatocellular  carcinoma (HCC) subclass G123, defined by unsupervised clustering.

description_full:
[cell repeats an earlier one in this file: 1740 characters]


systematic_name: M3268
exact_source: Table 7S: Overexpressed in Proliferation class
source_species_code: HS
GEO_id: GSE9843
contributor: Yujin Hoshida
contrib_organization: Broad Institute
description_brief:
  Top 200 marker genes up-regulated in the 'proliferation' subclass of hepatocellular carcinoma (HCC); characterized by increased proliferation, high levels of serum AFP [GeneID=174], and chromosomal instability.

description_full:
[cell repeats an earlier one in this file: 1805 characters]


systematic_name: M16932
exact_source: Table 7S: Underexpressed in Proliferation class
source_species_code: HS
GEO_id: GSE9843
contributor: Yujin Hoshida
contrib_organization: Broad Institute
description_brief:
  Top 200 marker genes down-regulated in the 'proliferation' subclass of hepatocellular carcinoma (HCC); characterized by increased proliferation, high levels of serum AFP [GeneID=174], and chromosomal instability.

description_full:
[cell repeats an earlier one in this file: 1805 characters]


systematic_name: M10986
exact_source: Table 6-10S: Underexpressed in unannotated class
source_species_code: HS
GEO_id: GSE9843
contributor: Yujin Hoshida
contrib_organization: Broad Institute
description_brief:
  Marker genes down-regulated in the 'unannotated' subclass of hepatocellular carcinoma (HCC) samples.

description_full:
[cell repeats an earlier one in this file: 1805 characters]


systematic_name: M19245
exact_source: Table 2S
source_species_code: HS
GEO_id: GSE1898,GSE4024
contributor: Yujin Hoshida
contrib_organization: Broad Institute
description_brief:
  'Early-TGFB1 signature': genes overexpressed in primary hepatocytes at an early phase of TGFB1 [GeneID=7040] treatment; is associated with a less invasive phenotype.

description_full:
  Hepatocellular carcinoma (HCC) is one of the most common cancers in the world. The clinical heterogeneity of HCC, and the lack of good diagnostic markers and treatment strategies, has rendered the disease a major challenge. Patients with HCC have a highly variable clinical course, indicating that HCC comprises several biologically distinctive subgroups reflecting a molecular heterogeneity of the tumors. Transforming growth factor beta (TGF-beta) is known to exhibit tumor stage dependent suppressive (that is, growth inhibition) and oncogenic (that is, invasiveness) properties. Here, we asked if a TGF-beta specific gene expression signature could refine the classification and prognostic predictions for HCC patients. Applying a comparative functional genomics approach we demonstrated that a temporal TGF-beta gene expression signature established in mouse primary hepatocytes successfully discriminated distinct subgroups of HCC. The TGF-beta positive cluster included two novel homogeneous groups of HCC associated with early and late TGF-beta signatures. Kaplan-Meier plots and log-rank statistics indicated that the patients with a late TGF-beta signature showed significantly (P < 0.005) shortened mean survival time (16.2 +/- 5.3 months) compared to the patients with an early (60.7 +/- 16.1 months) TGF-beta signature. Also, tumors expressing late TGF-beta-responsive genes displayed invasive phenotype and increased tumor recurrence. We also showed that the late TGF-beta signature accurately predicted liver metastasis and discriminated HCC cell lines by degree of invasiveness. Finally, we established that the TGF-beta gene expression signature possessed a predictive value for tumors other than HCC. CONCLUSION: These data demonstrate the clinical significance of the genes embedded in TGF-beta expression signature for the molecular classification of HCC.


systematic_name: M13658
exact_source: Fig. 3D
source_species_code: HS
GEO_id: GSE10143
contributor: Yujin Hoshida
contrib_organization: Broad Institute
description_brief:
  Genes whose expression correlated with lower risk of late recurrence of hepatocellular carcinoma (HCC).

description_full:
  BACKGROUND: It is a challenge to identify patients who, after undergoing potentially curative treatment for hepatocellular carcinoma, are at greatest risk for recurrence. Such high-risk patients could receive novel interventional measures. An obstacle to the development of genome-based predictors of outcome in patients with hepatocellular carcinoma has been the lack of a means to carry out genomewide expression profiling of fixed, as opposed to frozen, tissue. METHODS: We aimed to demonstrate the feasibility of gene-expression profiling of more than 6000 human genes in formalin-fixed, paraffin-embedded tissues. We applied the method to tissues from 307 patients with hepatocellular carcinoma, from four series of patients, to discover and validate a gene-expression signature associated with survival. RESULTS: The expression-profiling method for formalin-fixed, paraffin-embedded tissue was highly effective: samples from 90% of the patients yielded data of high quality, including samples that had been archived for more than 24 years. Gene-expression profiles of tumor tissue failed to yield a significant association with survival. In contrast, profiles of the surrounding nontumoral liver tissue were highly correlated with survival in a training set of tissue samples from 82 Japanese patients, and the signature was validated in tissues from an independent group of 225 patients from the United States and Europe (P=0.04). CONCLUSIONS: We have demonstrated the feasibility of genomewide expression profiling of formalin-fixed, paraffin-embedded tissues and have shown that a reproducible gene-expression signature correlated with survival is present in liver tissue adjacent to the tumor in patients with hepatocellular carcinoma.


systematic_name: M5451
exact_source: Table 2S: good survival
source_species_code: HS
contributor: Yujin Hoshida
contrib_organization: Broad Institute
description_brief:
  Survival signature genes defined in adjacent liver tissue: genes correlated with good survival of hepatocellular carcinoma (HCC) patients.

description_full:
[cell repeats an earlier one in this file: 1745 characters]


systematic_name: M2184
exact_source: Table 4
source_species_code: HS
contributor: Yujin Hoshida
contrib_organization: Broad Institute
description_brief:
  Selected down-regulated MET [GeneID=4233] target genes from a classifier of hepatocellular carcinoma (HCC) cases; associated with poor survival.

description_full:
  Identification of specific gene expression signatures characteristic of oncogenic pathways is an important step toward molecular classification of human malignancies. Aberrant activation of the Met signaling pathway is frequently associated with tumor progression and metastasis. In this study, we defined the Met-dependent gene expression signature using global gene expression profiling of WT and Met-deficient primary mouse hepatocytes. Newly identified transcriptional targets of the Met pathway included genes involved in the regulation of oxidative stress responses as well as cell motility, cytoskeletal organization, and angiogenesis. To assess the importance of a Met-regulated gene expression signature, a comparative functional genomic approach was applied to 242 human hepatocellular carcinomas (HCCs) and 7 metastatic liver lesions. Cluster analysis revealed that a subset of human HCCs and all liver metastases shared the Met-induced expression signature. Furthermore, the presence of the Met signature showed significant correlation with increased vascular invasion rate and microvessel density as well as with decreased mean survival time of HCC patients. We conclude that the genetically defined gene expression signatures in combination with comparative functional genomics constitute an attractive paradigm for defining both the function of oncogenic pathways and the clinically relevant subgroups of human cancers.


systematic_name: M16542
exact_source: Fig.1A
source_species_code: HS
GEO_id: GSE364,GSE5975
contributor: Yujin Hoshida
contrib_organization: Broad Institute
description_brief:
  Up-regulated genes distinguishing hepatocellular carcinoma (HCC) samples positive for EPCAM [GeneID=4072] from the negative ones.

description_full:
  The heterogeneous nature of hepatocellular carcinoma (HCC) and the lack of appropriate biomarkers have hampered patient prognosis and treatment stratification. Recently, we have identified that a hepatic stem cell marker, epithelial cell adhesion molecule (EpCAM), may serve as an early biomarker of HCC because its expression is highly elevated in premalignant hepatic tissues and in a subset of HCC. In this study, we aimed to identify novel HCC subtypes that resemble certain stages of liver lineages by searching for EpCAM-coexpressed genes. A unique signature of EpCAM-positive HCCs was identified by cDNA microarray analysis of 40 HCC cases and validated by oligonucleotide microarray analysis of 238 independent HCC cases, which was further confirmed by immunohistochemical analysis of an additional 101 HCC cases. EpCAM-positive HCC displayed a distinct molecular signature with features of hepatic progenitor cells including the presence of known stem/progenitor markers such as cytokeratin 19, c-Kit, EpCAM, and activated Wnt-beta-catenin signaling, whereas EpCAM-negative HCC displayed genes with features of mature hepatocytes. Moreover, EpCAM-positive and EpCAM-negative HCC could be further subclassified into four groups with prognostic implication by determining the level of alpha-fetoprotein (AFP). These four subtypes displayed distinct gene expression patterns with features resembling certain stages of hepatic lineages. Taken together, we proposed an easy classification system defined by EpCAM and AFP to reveal HCC subtypes similar to hepatic cell maturation lineages, which may enable prognostic stratification and assessment of HCC patients with adjuvant therapy and provide new insights into the potential cellular origin of HCC and its activated molecular pathways.


systematic_name: M9914
exact_source: Fig.1A
source_species_code: HS
GEO_id: GSE364,GSE5975
contributor: Yujin Hoshida
contrib_organization: Broad Institute
description_brief:
  Down-regulated genes distinguishing hepatocellular carcinoma (HCC) samples positive for EPCAM [GeneID=4072] from the negative ones.

description_full:
  The heterogeneous nature of hepatocellular carcinoma (HCC) and the lack of appropriate biomarkers have hampered patient prognosis and treatment stratification. Recently, we have identified that a hepatic stem cell marker, epithelial cell adhesion molecule (EpCAM), may serve as an early biomarker of HCC because its expression is highly elevated in premalignant hepatic tissues and in a subset of HCC. In this study, we aimed to identify novel HCC subtypes that resemble certain stages of liver lineages by searching for EpCAM-coexpressed genes. A unique signature of EpCAM-positive HCCs was identified by cDNA microarray analysis of 40 HCC cases and validated by oligonucleotide microarray analysis of 238 independent HCC cases, which was further confirmed by immunohistochemical analysis of an additional 101 HCC cases. EpCAM-positive HCC displayed a distinct molecular signature with features of hepatic progenitor cells including the presence of known stem/progenitor markers such as cytokeratin 19, c-Kit, EpCAM, and activated Wnt-beta-catenin signaling, whereas EpCAM-negative HCC displayed genes with features of mature hepatocytes. Moreover, EpCAM-positive and EpCAM-negative HCC could be further subclassified into four groups with prognostic implication by determining the level of alpha-fetoprotein (AFP). These four subtypes displayed distinct gene expression patterns with features resembling certain stages of hepatic lineages. Taken together, we proposed an easy classification system defined by EpCAM and AFP to reveal HCC subtypes similar to hepatic cell maturation lineages, which may enable prognostic stratification and assessment of HCC patients with adjuvant therapy and provide new insights into the potential cellular origin of HCC and its activated molecular pathways.


description_brief: Genes up-regulated in hepatocellular carcinoma (HCC) cells with hepatic stem cell properties.
systematic_name: M16956
exact_source: Table 3S, 4S: Up
source_species_code: HS
GEO_id: GSE5975
contributor: Yujin Hoshida
contrib_organization: Broad Institute
description_full:
  BACKGROUND & AIMS: Cancer progression/metastases and embryonic development share many properties including cellular plasticity, dynamic cell motility, and integral interaction with the microenvironment. We hypothesized that the heterogeneous nature of hepatocellular carcinoma (HCC), in part, may be owing to the presence of hepatic cancer cells with stem/progenitor features. METHODS: Gene expression profiling and immunohistochemistry analyses were used to analyze 235 tumor specimens derived from 2 recently identified HCC subtypes (EpCAM(+) alpha-fetoprotein [AFP(+)] HCC and EpCAM(-) AFP(-) HCC). These subtypes differed in their expression of AFP, a molecule produced in the developing embryo, and EpCAM, a cell surface hepatic stem cell marker. Fluorescence-activated cell sorting was used to isolate EpCAM(+) HCC cells, which were tested for hepatic stem/progenitor cell properties. RESULTS: Gene expression and pathway analyses revealed that the EpCAM(+) AFP(+) HCC subtype had features of hepatic stem/progenitor cells. Indeed, the fluorescence-activated cell sorting-isolated EpCAM(+) HCC cells displayed hepatic cancer stem cell-like traits including the abilities to self-renew and differentiate. Moreover, these cells were capable of initiating highly invasive HCC in nonobese diabetic, severe combined immunodeficient mice. Activation of Wnt/beta-catenin signaling enriched the EpCAM(+) cell population, whereas RNA interference-based blockage of EpCAM, a Wnt/beta-catenin signaling target, attenuated the activities of these cells. CONCLUSIONS: Taken together, our results suggest that HCC growth and invasiveness is dictated by a subset of EpCAM(+) cells, opening a new avenue for HCC cancer cell eradication by targeting Wnt/beta-catenin signaling components such as EpCAM.


systematic_name: M12602
exact_source: Table 2S
source_species_code: HS
contributor: Yujin Hoshida
contrib_organization: Broad Institute
description_brief:
  Genes positively correlated with recurrence free survival in patients with hepatitis B-related (HBV) hepatocellular carcinoma (HCC).

description_full:
  PURPOSE: The poor prognosis of hepatocellular carcinoma (HCC) is, in part, due to the high rate of recurrence even after curative resection of tumors. Therefore, it is axiomatic that the development of an effective prognostic prediction model for HCC recurrence after surgery would, at minimum, help to identify in advance those who would most benefit from the treatment, and at best, provide new therapeutic strategies for patients with a high risk of early recurrence. EXPERIMENTAL DESIGN: For the prediction of the recurrence time in patients with HCC, gene expression profiles were generated in 65 HCC patients with hepatitis B infections. RESULT: Recurrence-associated gene expression signatures successfully discriminated between patients at high-risk and low-risk of early recurrence (P=1.9 x 10(-6), log-rank test). To test the consistency and robustness of the recurrence signature, we validated its prognostic power in an independent HCC microarray data set. CD24 was identified as a putative biomarker for the prediction of early recurrence. Genetic network analysis suggested that SP1 and peroxisome proliferator-activated receptor-alpha might have regulatory roles for the early recurrence of HCC. CONCLUSION: We have identified a gene expression signature that effectively predicted early recurrence of HCC independent of microarray platforms and cohorts, and provided novel biological insights into the mechanisms of tumor recurrence.


systematic_name: M9911
exact_source: Table 2S
source_species_code: HS
contributor: Yujin Hoshida
contrib_organization: Broad Institute
description_brief:
  Genes negatively correlated with recurrence free survival in patients with hepatitis B-related (HBV) hepatocellular carcinoma (HCC).

description_full:
  PURPOSE: The poor prognosis of hepatocellular carcinoma (HCC) is, in part, due to the high rate of recurrence even after curative resection of tumors. Therefore, it is axiomatic that the development of an effective prognostic prediction model for HCC recurrence after surgery would, at minimum, help to identify in advance those who would most benefit from the treatment, and at best, provide new therapeutic strategies for patients with a high risk of early recurrence. EXPERIMENTAL DESIGN: For the prediction of the recurrence time in patients with HCC, gene expression profiles were generated in 65 HCC patients with hepatitis B infections. RESULT: Recurrence-associated gene expression signatures successfully discriminated between patients at high-risk and low-risk of early recurrence (P=1.9 x 10(-6), log-rank test). To test the consistency and robustness of the recurrence signature, we validated its prognostic power in an independent HCC microarray data set. CD24 was identified as a putative biomarker for the prediction of early recurrence. Genetic network analysis suggested that SP1 and peroxisome proliferator-activated receptor-alpha might have regulatory roles for the early recurrence of HCC. CONCLUSION: We have identified a gene expression signature that effectively predicted early recurrence of HCC independent of microarray platforms and cohorts, and provided novel biological insights into the mechanisms of tumor recurrence.


systematic_name: M1983
exact_source: Fig. 2A
source_species_code: HS
GEO_id: GSE8772
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in A375 cells (melanoma) treated with KINK-1, a small molecule inhibitor of NFKB.

description_full:
  BACKGROUND: Increasing the efficacy of chemotherapeutics by reducing chemoresistance may be a useful strategy in cancer therapy. Constitutive activation of nuclear factor-kappa B (NF-kappaB) is a hallmark of various cancers, including melanoma, which is almost universally resistant to chemotherapy. NF-kappaB is regulated by inhibitory kappaB (IkappaB) proteins, which are in turn phosphorylated by the IkappaB kinase (IKK) complex. METHODS: The effect on NF-kappaB activity of a novel small-molecule inhibitor of the beta subunit of IKK (KINK-1; kinase inhibitor of nuclear factor-kappaB-1) was assessed by measuring phosphorylation of the alpha subunit of IkappaB by immunoblotting, DNA binding by electrophoretic mobility shift assays, and nuclear translocation of NF-kappaB using immunofluorescence. Regulation of NF-kappaB-dependent gene expression was determined by microarray analysis, real-time and semiquantitative reverse transcription polymerase chain reaction (RT-PCR), and Western blot analyses. The effects of KINK-1 (alone and in combination with cytostatic agents) on melanoma cells were characterized by assessing proliferation, soft agar colony formation, and markers of apoptosis. The antitumoral efficacy of KINK-1 in combination with the cytostatic agents doxorubicin or camptothecin (all injected intraperitoneally) was tested in vivo by measuring lung weight and counting metastases in C57BL6 mice (groups of six) bearing metastases of melanoma cells. All statistical tests were two-sided. Results KINK-1 strongly suppressed both constitutive and induced NF-kappaB activity in melanoma cells. It reduced the expression of NF-kappaB-dependent gene products that regulate proliferation, cytokine production, and antiapoptotic responses but exhibited little antiproliferative or proapoptotic activity at the cellular level. However, KINK-1 markedly increased the activities of some cytostatic agents in vitro and abrogated doxorubicin-induced NF-kappaB activation. Combined treatment of C57BL6 mice that had been injected with melanoma cells with KINK-1 and doxorubicin or camptothecin reduced metastases and pulmonary tumor mass compared with either treatment alone (mean lung weight 19 days after injection of melanoma cells of mice treated with 3 mg/kg KINK-1 alone, 1 mg/kg doxorubicin alone, and 1 mg/kg doxorubicin plus 3 mg/kg KINK-1 = 260 mg, 95% confidence interval (CI) = 216 to 305 mg; 268 mg, 95% CI = 224 to 313 mg; and 181 mg, 95% CI = 171 to 192 mg, respectively, P < .001 from t tests comparing mean lung weight of double-treated mice to that in mice treated with either compound alone). CONCLUSION: Inhibition of constitutive and induced IKKbeta-activity through treatment with KINK-1 might increase tumor susceptibility to chemotherapy.


systematic_name: M19965
exact_source: Table 1
source_species_code: HS
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Proteins with reduced expression in mulignant glioma cell line (A172) which bears loss of heterozygosity (LOH) in the 1p region.

description_full:
  BACKGROUND: Malignant gliomas are generally resistant to all conventional therapies. Notable exceptions are anaplastic oligodendrogliomas with loss of heterozygosity on chromosome 1p (1p+/-). Patients with 1p+/- anaplastic oligodendroglioma frequently respond to procarbazine, 1-(2-chloroethyl)-3-cyclohexyl-l-nitrosourea, and vincristine. Because the underlying biologic basis for this clinical finding is unclear, we evaluated differentially expressed 1p-encoded proteins in 1p+/- and 1p+/+ malignant glioma cell lines and then examined whether their expression was associated with outcome of patients with anaplastic oligodendroglioma. METHODS: We used a comparative proteomic screen of A172 (1p+/-) and U251 (1p+/+) malignant glioma cell lines to identify differentially expressed 1p-encoded proteins, including stathmin, a microtubule-associated protein. 1p+/- and 1p+/+ anaplastic oligodendroglioma specimens from 24 patients were assessed for stathmin expression by immunohistochemistry. The relationship between stathmin expression and clinical outcome was assessed with Kaplan-Meier analyses. RNA inhibition and cDNA transfection experiments tested effects of stathmin under- and overexpression, respectively, on the in vitro and in vivo resistance of malignant glioma cells to treatment with nitrosourea. For in vivo resistance studies, 36 mice with intracranial and 16 mice with subcutaneous xenograft tumor implants were used (one tumor per mouse). Flow cytometry was used for cell cycle analysis. Immunoblotting was used to assess protein expression. All statistical tests were two-sided. RESULTS: Decreased stathmin expression in tumors was statistically significantly associated with loss of heterozygosity in 1p (P<.001) and increased recurrence-free survival (P<.001). The median recurrence-free survival times for patients with tumors expressing low, intermediate, or high stathmin levels were 45 months (95% confidence interval [CI] = 0 to 90 months), 17 months (95% CI = 10.6 to 23.4 months), and 6 months (95% CI = 1.7 to 10.3 months), respectively. Expression of stathmin was inversely associated with overall survival of nitrosourea-treated mice carrying xenograft tumors. Median survival of mice with stathmin+/- tumors was 95 days (95% CI = 68.7 to 121.3 days) and that of mice with stathmin+/+ tumors was 64 days (95% CI = 58.2 to 69.8 days) (difference = 31 days, 95% CI = 4.1 to 57.9 days; P<.001, log-rank test). Nitrosoureas induced mitotic arrest in malignant glioma cells, and this effect was greater in cells with decreased stathmin expression. CONCLUSIONS: Loss of heterozygosity for the stathmin gene may be associated with improved outcomes of patients with 1p+/- anaplastic oligodendroglioma tumors.


systematic_name: M13669
exact_source: Table 1: Stimulated genes
source_species_code: HS
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in CL1-5 cells (lung cancer) overexpressing DNAJB4 [GeneID=11080] off a plasmid vector.

description_full:
  BACKGROUND: We previously identified DnaJ-like heat shock protein (HLJ1) as a gene associated with tumor invasion. Here, we investigated the clinical significance of HLJ1 expression in non-small-cell lung cancer (NSCLC) patients and its role in cancer progression. METHODS: We induced HLJ1 overexpression or knockdown in human lung adenocarcinoma CL1-5 cells and analyzed cell proliferation, anchorage-independent growth, in vivo tumorigenesis, cell motility, invasion, and cell cycle progression. Expression of genes that act downstream of HLJ1 was examined by DNA microarray analysis, pathway analysis, and western blotting. We measured HLJ1 expression in tumors and adjacent normal tissues of 71 NSCLC patients by quantitative reverse transcription-polymerase chain reaction. Associations between HLJ1 expression and disease-free and overall survival were determined using the log-rank test and multivariable Cox proportional hazards regression analysis. Validation was performed in an independent cohort of 56 NSCLC patients. Loss of heterozygosity (LOH) mapping of the HLJ1 locus was analyzed in 48 paired microdissected NSCLC tumors. All statistical tests were two-sided. RESULTS: HLJ1 expression inhibited lung cancer cell proliferation, anchorage-independent growth, tumorigenesis, cell motility, and invasion, and slowed cell cycle progression through a novel STAT1/P21(WAF1) pathway that is independent of P53 and interferon. HLJ1 expression was lower in tumors than in adjacent normal tissue in 55 of 71 patients studied. NSCLC patients with high HLJI expressing tumors had reduced cancer recurrence (hazard ratio [HR] = 0.47; 95% confidence interval [CI] = 0.23 to 0.93; P = .03) and longer overall survival (HR = 0.38; 95% CI = 0.16 to 0.89; P = .03) than those with low-expressing tumors. Validation in the independent patient cohort confirmed the association between HLJ1 expression and patient outcome. LOH mapping revealed high frequencies (66.7% and 70.8%) of allelic loss and microsatellite instability (87.5% and 95.2%) of the HLJ1 locus at chromosome 1p31.1. CONCLUSIONS: HLJ1 is a novel tumor suppressor in NSCLC, and high HLJ1 expression is associated with reduced cancer recurrence and prolonged survival of NSCLC patients.


description_brief: Interferon cluster genes up-regulated in skin tumors treated with imiquimod [PubChem=57469].
systematic_name: M4857
exact_source: Fig. 1A
source_species_code: HS
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_full:
  BACKGROUND: Imiquimod, an immune response modifier that is used topically to treat different types of skin cancer, induces the production of proinflammatory cytokines that stimulate an antitumor immune response. We assessed characteristics of the imiquimod-induced immune activation in epithelial and lymphoproliferative neoplasias of human skin. We focused on plasmacytoid predendritic cells (PDCs), the primary producer of interferon alpha (IFN-alpha) after imiquimod activation in vitro. METHODS: We used Affymetrix oligonucleotide arrays to compare gene expression profiles from tumors from 16 patients, 10 with superficial basal cell carcinomas (sBCCs), five with cutaneous T-cell lymphomas (CTCLs), and one with Bowen's disease, before and after topical imiquimod treatment. We used quantitative immunohistochemistry with PDC-specific antibodies against BDCA-2 and CD123 to characterize the PDC population before and after imiquimod treatment in these specimens. Activation status of PDCs from four sBCC patients was assessed by intracellular IFN-alpha staining and flow cytometry. RESULTS: Expression of various IFN-alpha-inducible genes (e.g., CIG5, G1P2, OASL, IFIT1, STAT1, IFI35, OAS1, ISG20, MxA, and IRF7), the so-called IFN-alpha signature, was increased similarly in both sBCC and CTCL lesions after imiquimod treatment. PDCs were recruited and activated in both lesion types, and they produced IFN-alpha after imiquimod treatment in vivo (mean percentage of PDCs producing IFN-alpha = 14.5%, 95% confidence interval [CI] = 4.9% to 24%; range = 3.3%-27%, n = 4 lesions). Imiquimod induced similar immune activation patterns in all three diseases, and these patterns were associated with the number of PDCs recruited to the treatment site. Two imiquimod-treated sBCC patients who did not mount an inflammatory response to imiquimod and whose lesions lacked the IFN-alpha signature after treatment had fewer PDCs in treated lesions compared with other treated patients with such a response. CONCLUSIONS: Imiquimod induces immune activation patterns that relate to the number of the PDCs recruited to the treatment site, thus supporting the role of PDC in responsiveness to imiquimod in humans.


systematic_name: M1985
exact_source: Table 1S
source_species_code: RN
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Inflammatory cytokines and their receptors modulated in brain tumors after treatment with an oncocytic virus, a potential anticancer therapy.

description_full:
  BACKGROUND: The tumor microenvironment is being increasingly recognized as an important determinant of tumor progression as well as of therapeutic response. We investigated oncolytic virus (OV) therapy-induced changes in tumor blood vessels and the impact of modulating tumor vasculature on the efficacy of oncolytic virus therapy. METHODS: Rat glioma cells (D74/HveC) were implanted intracranially in immune-competent rats. Seven days later, the rats (groups of 3-7 rats) were treated with oncolytic virus (hrR3), and, 3 days later, brains were harvested for evaluation. Some rats were treated with angiostatic cRGD peptide 4 days before oncolytic virus treatment. Some rats were treated with cyclophosphamide (CPA), an immunosuppressant, 2 days before oncolytic virus treatment. Changes in tumor vascular perfusion were evaluated by magnetic resonance imaging of live rats and by fluorescence microscopy of tumor sections from rats perfused with Texas red-conjugated lectin immediately before euthanasia. Leukocyte infiltration in tumors was evaluated by anti-CD45 immunohistochemistry, and the presence of oncolytic virus in tumors was evaluated by viral titration. Changes in cytokine gene expression in tumors were measured by quantitative real-time polymerase chain reaction-based microarrays. Survival was analyzed by the Kaplan-Meier method. All statistical tests were two-sided. RESULTS: Oncolytic virus treatment of experimental rat gliomas increased tumor vascular permeability, host leukocyte infiltration into tumors, and intratumoral expression of inflammatory cytokine genes, including interferon gamma (IFN-gamma). The increase in vascular permeability was suppressed in rats pretreated with cyclophosphamide. Compared with rats treated with hrR3 alone, rats pretreated with a single dose of cRGD peptide before hrR3 treatment had reduced tumor vascular permeability, leukocyte infiltration, and IFN-gamma protein levels (mean IFN-gamma level for hrR3 versus hrR3 + cRGD = 203 versus 65.6 microg/mg, difference = 137 microg/mg, 95% confidence interval = 72.7 to 202.9 microg/mg, P = .006); increased viral titers in tumor tissue; and longer median survival (21 days versus 17 days, P<.001). CONCLUSIONS: A single dose of angiostatic cRGD peptide treatment before oncolytic virus treatment enhanced the antitumor efficacy of oncolytic virus.


systematic_name: M1986
exact_source: Table 2S
source_species_code: RN
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Inflammatory cytokines and their receptors moduated in brain tumors in response to treatment with cyclic RGD peptide prior to the oncocytic virus therapy.

description_full:
  BACKGROUND: The tumor microenvironment is being increasingly recognized as an important determinant of tumor progression as well as of therapeutic response. We investigated oncolytic virus (OV) therapy-induced changes in tumor blood vessels and the impact of modulating tumor vasculature on the efficacy of oncolytic virus therapy. METHODS: Rat glioma cells (D74/HveC) were implanted intracranially in immune-competent rats. Seven days later, the rats (groups of 3-7 rats) were treated with oncolytic virus (hrR3), and, 3 days later, brains were harvested for evaluation. Some rats were treated with angiostatic cRGD peptide 4 days before oncolytic virus treatment. Some rats were treated with cyclophosphamide (CPA), an immunosuppressant, 2 days before oncolytic virus treatment. Changes in tumor vascular perfusion were evaluated by magnetic resonance imaging of live rats and by fluorescence microscopy of tumor sections from rats perfused with Texas red-conjugated lectin immediately before euthanasia. Leukocyte infiltration in tumors was evaluated by anti-CD45 immunohistochemistry, and the presence of oncolytic virus in tumors was evaluated by viral titration. Changes in cytokine gene expression in tumors were measured by quantitative real-time polymerase chain reaction-based microarrays. Survival was analyzed by the Kaplan-Meier method. All statistical tests were two-sided. RESULTS: Oncolytic virus treatment of experimental rat gliomas increased tumor vascular permeability, host leukocyte infiltration into tumors, and intratumoral expression of inflammatory cytokine genes, including interferon gamma (IFN-gamma). The increase in vascular permeability was suppressed in rats pretreated with cyclophosphamide. Compared with rats treated with hrR3 alone, rats pretreated with a single dose of cRGD peptide before hrR3 treatment had reduced tumor vascular permeability, leukocyte infiltration, and IFN-gamma protein levels (mean IFN-gamma level for hrR3 versus hrR3 + cRGD = 203 versus 65.6 microg/mg, difference = 137 microg/mg, 95% confidence interval = 72.7 to 202.9 microg/mg, P = .006); increased viral titers in tumor tissue; and longer median survival (21 days versus 17 days, P<.001). CONCLUSIONS: A single dose of angiostatic cRGD peptide treatment before oncolytic virus treatment enhanced the antitumor efficacy of oncolytic virus.


systematic_name: M731
exact_source: Table 1S: ICP, 5mC (log2) in fibroblasts > 0
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Germline-specific genes with intermediate-CpG-density promoters (ICP) that are methylated in primary fibroblasts.

description_full:
[cell repeats an earlier one in this file: 1138 characters]


systematic_name: M2180
exact_source: Table 4S: Difference > 0
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  The XPRSS-Int network genes up-regulated in breast tumors from patients with germline mutations in BRCA1 [GeneID=672] compared to those with the wild type allele.

description_full:
[cell repeats an earlier one in this file: 1255 characters]


systematic_name: M8583
exact_source: Table 2S: Class 4 = CLASS 4
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated by estradiol [PubChem=5757] and not modulated by ESRRA [GeneID=2101] in MCF-7 cells (breast cancer).

description_full:
[cell repeats an earlier one in this file: 1714 characters]


systematic_name: M9224
exact_source: Table 3
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Selected genes up-regulated in peripheral blood monocytes (PBMC) of patients with hepatocellular carcinoma (HCC) compared to those with chronic hepatitis.

description_full:
[cell repeats an earlier one in this file: 1739 characters]


systematic_name: M16010
exact_source: Table 2S
source_species_code: HS
contributor: Arthur Liberzon
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 24h.

description_full:
[cell repeats an earlier one in this file: 1694 characters]


systematic_name: M4077
exact_source: Table 6S
source_species_code: HS
GEO_id: GSE8096
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes identified by method 2 as coordinately down-regulated late in HMEC cells (mammary epithelium) during acinar development in vitro.

description_full:
[cell repeats an earlier one in this file: 1261 characters]


systematic_name: M4772
exact_source: Table 7S: Fold change rC2/rC1 >= 1.3
source_species_code: HS
GEO_id: E-MEXP-1853,E-MEXP-1851,E-MEXP-1852
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in robust Cluster 2 (rC2) of hepatoblastoma samples compared to those in the robust Cluster 1 (rC1).

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


systematic_name: M12176
exact_source: Table 7S: Fold change rC2/rC1 <= 0.8
source_species_code: HS
GEO_id: E-MEXP-1853,E-MEXP-1852,E-MEXP-1851
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in robust Cluster 2 (rC2) of hepatoblastoma samples compared to those in the robust Cluster 1 (rC1).

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


systematic_name: M6387
exact_source: Table 3S: direction=upregulated in M+
source_species_code: HS
GEO_id: E-TABM-2,E-TABM-1,E-TABM-4
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes from the 254-gene classifier which were up-regulated in melanoma patients with a reported distant metastasis within 4 years.

description_full:
  BACKGROUND: Gene expression profiling data for human primary cutaneous melanomas are scarce because of the lack of retrospective collections of frozen tumors. To identify differentially expressed genes that may be involved in melanoma progression and prognosis, we investigated the relationship between gene expression profiles and clinical outcome in a cohort of patients with primary melanoma. METHODS: Labeled complementary RNA (cRNA) from each tissue sample was hybridized to a pangenomic 44K 60-mer oligonucleotide microarray. Class comparison and class prediction analyses were performed to identify genes whose expression in primary melanomas was associated with 4-year distant metastasis-free survival among 58 patients with at least 4 years of follow-up, distant metastasis, or death. Results were validated immunohistochemically at the protein level in 176 independent primary melanomas from patients with a median clinical follow-up of 8.5 years. Survival was analyzed with a Cox multivariable model and stratified log-rank test. All statistical tests were two-sided. RESULTS: We identified 254 genes that were associated with distant metastasis-free survival of patients with primary melanoma. These 254 genes include genes involved in activating DNA replication origins, such as minichromosome maintenance genes and geminin. Twenty-three of these genes were studied at the protein level; expression of five (MCM4, P = .002; MCM3, P = .030; MCM6, P = .004; KPNA2, P = .021; and geminin, P = .004) was statistically significantly associated with overall survival in the validation set. In a multivariable Cox model adjusted for tumor thickness, ulceration, age, and sex, expression of MCM4 (hazard ratio [HR] of death = 4.04, 95% confidence interval [CI] = 1.39 to 11.76; P = .010) and MCM6 (HR of death = 7.42, 95% CI = 1.99 to 27.64; P = .003) proteins was still statistically significantly associated with overall survival. CONCLUSION: We identified 254 genes whose expression was associated with metastatic dissemination of cutaneous melanomas. These genes may shed light on the molecular mechanisms underlying poor prognosis in melanoma patients.


systematic_name: M9162
exact_source: Table 1S
source_species_code: HS
GEO_id: GSE3589
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in HUVEC cells (primary endothelium) after stimulation with leukotriene LTD4 [PubChem=3908] or thrombin (F2) [GeneID=2147] for 1 h.

description_full:
  Cysteinyl leukotrienes (cysLT), i.e., LTC4, LTD4, and LTE4, are lipid mediators derived from the 5-lipoxygenase pathway, and the cysLT receptors cysLT1-R/cysLT2-R mediate inflammatory tissue reactions. Although endothelial cells (ECs) predominantly express cysLT2-Rs, their role in vascular biology remains to be fully understood. To delineate cysLT2-R actions, we stimulated human umbilical vein EC with LTD4 and determined early induced genes. We also compared LTD4 effects with those induced by thrombin that binds to protease-activated receptor (PAR)-1. Stringent filters yielded 37 cysLT2-R- and 34 PAR-1-up-regulated genes (>2.5-fold stimulation). Most LTD4-regulated genes were also induced by thrombin. Moreover, LTD4 plus thrombin augmented gene expression when compared with each agonist alone. Strongly induced genes were studied in detail: Early growth response (EGR) and nuclear receptor subfamily 4 group A transcription factors; E-selectin; CXC ligand 2; IL-8; a disintegrin-like and metalloprotease (reprolysin type) with thrombospondin type 1 motif 1 (ADAMTS1); Down syndrome critical region gene 1 (DSCR1); tissue factor (TF); and cyclooxygenase 2. Transcripts peaked at approximately 60 min, were unaffected by a cysLT1-R antagonist, and were superinduced by cycloheximide. The EC phenotype was markedly altered: LTD4 induced de novo synthesis of EGR1 protein and EGR1 localized in the nucleus; LTD4 up-regulated IL-8 formation and secretion; and LTD4 raised TF protein and TF-dependent EC procoagulant activity. These data show that cysLT2-R activation results in a proinflammatory EC phenotype. Because LTD4 and thrombin are likely to be formed concomitantly in vivo, cysLT2-R and PAR-1 may cooperate to augment vascular injury.


systematic_name: M14693
exact_source: Table 2S: top 70 with |correlation| > 0.3
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  The optimal set of 70 prognostic markers predicting poor breast cancer clinical outcome (defined as developing metastases with 5 years).

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


systematic_name: M17204
exact_source: Fig. 3
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes whose expression predicted relapse in less than 2 years after chemotherapy for adult patients with T-ALL (T cell lymphoblastic leukemia).

description_full:
  Gene expression profiles were examined in 33 adult patients with T-cell acute lymphocytic leukemia (T-ALL). Nonspecific filtering criteria identified 313 genes differentially expressed in the leukemic cells. Hierarchical clustering of samples identified 2 groups that reflected the degree of T-cell differentiation but was not associated with clinical outcome. Comparison between refractory patients and those who responded to induction chemotherapy identified a single gene, interleukin 8 (IL-8), that was highly expressed in refractory T-ALL cells and a set of 30 genes that was highly expressed in leukemic cells from patients who achieved complete remission. We next identified 19 genes that were differentially expressed in T-ALL cells from patients who either had a relapse or remained in continuous complete remission. A model based on the expression of 3 of these genes was predictive of duration of remission. The 3-gene model was validated on a further set of T-ALL samples from 18 additional patients treated on the same clinical protocol. This study demonstrates that gene expression profiling can identify a limited number of genes that are predictive of response to induction therapy and remission duration in adult patients with T-ALL.


systematic_name: M13569
exact_source: Table 3S: Subgroup = LB
source_species_code: HS
GEO_id: GSE2658
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Top 50 down-regulated genes in cluster LB of multiple myeloma samples belonging to the low bone disease group.

description_full:
[cell repeats an earlier one in this file: 1481 characters]


systematic_name: M6506
exact_source: http://www.myccancergene.org/site/mycTargetDB.asp
source_species_code: HS
contributor: Chi Dang
contrib_organization: Johns Hopkins University
description_brief:
  Genes up-regulated by MYC [GeneID=4609] and whose promoters are bound by MYC, according to MYC Target Gene Database.

description_full:
[cell repeats an earlier one in this file: 548 characters]


systematic_name: M17557
exact_source: http://www.myccancergene.org/site/mycTargetDB.asp
source_species_code: HS
contributor: Chi Dang
contrib_organization: Johns Hopkins University
description_brief:
  Genes down-regulated by MYC [GeneID=4609] and whose promoters are bound by MYC, according to MYC Target Gene Database.

description_full:
[cell repeats an earlier one in this file: 548 characters]


description_brief: Genes up-regulated in HeLa cells (cervical carcinoma) 12 h after infection with adenovirus Ad12.
systematic_name: M10668
exact_source: Table 1: 12 h p.i. >= 1
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_full:
  The infection of human cells by adenoviruses leads to a gradual reduction in the activity of host cell functions while viral gene expression progresses in a regulated way. We used the DNA microarray technique to determine the transcriptional activity profiles of cellular genes upon infection with adenovirus type 12 (Ad12). The microarray data were validated by quantitative real-time PCR for genes which showed significant alterations after Ad12 infection. At 12 h postinfection, there is a striking up-regulation between 10- and 30-fold in the expression of the G1P2, IFIT1, and IFIT2 cellular immune response genes compared to mock-infected cells. At later stages of infection, when the majority of regulated cellular genes has been turned down, a limited number of cellular genes exhibit increased activities by factors of 3 or less. These genes belong to the signal transduction or transcriptional regulator classes or are active in protein degradation, like ANPEP, an aminopeptidase. The SCD and CYP2S1 genes function in lipid metabolism. The eucaryotic translation initiation factor 4 is up-regulated, and one of the major histocompatibility complex genes is diminished in activity. For two of the genes, one up-regulated (CTSF gene) and one down-regulated (CYR61 gene), alterations in gene activity were confirmed at the protein level by Western blotting experiments. Increased genetic activity of cellular genes late in adenovirus infection has not been reported previously and demonstrates that Ad12 has a sustained control of host cell gene expression well into the late phase of infection.


description_brief: Genes modulated in HeLa cells (cervical carcinoma) by TNF [GeneID=7124] via NFKB pathway.
systematic_name: M14435
exact_source: Table 4
source_species_code: HS
GEO_id: GSE2624
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_full:
  Tumor necrosis factor (TNF) is a pro-inflammatory cytokine that controls expression of inflammatory genetic networks. Although the nuclear factor-kappaB (NF-kappaB) pathway is crucial for mediating cellular TNF responses, the complete spectrum of NF-kappaB-dependent genes is unknown. In this study, we used a tetracycline-regulated cell line expressing an NF-kappaB inhibitor to systematically identify NF-kappaB-dependent genes. A microarray data set generated from a time course of TNF stimulation in the presence or absence of NF-kappaB signaling was analyzed. We identified 50 unique genes that were regulated by TNF (Pr(F)<0.001) and demonstrated a change in signal intensity of+/-3-fold relative to control. Of these, 28 were NF-kappaB-dependent, encoding proteins involved in diverse cellular activities. Quantitative real-time PCR assays of eight characterized NF-kappaB-dependent genes and five genes not previously known to be NF-kappaB-dependent (Gro-beta and-gamma, IkappaBepsilon, interleukin (IL)-7R, and Naf-1) were used to determine whether they were directly or indirectly NF-kappaB regulated. Expression of constitutively active enhanced green fluorescent.NF-kappaB/Rel A fusion protein transactivated all but IL-6 and IL-7R in the absence of TNF stimulation. Moreover, TNF strongly induced all 12 genes in the absence of new protein synthesis. High probability NF-kappaB sites in novel genes were predicted by binding site analysis and confirmed by electrophoretic mobility shift assay. Chromatin immunoprecipitation assays show the endogenous IkappaBalpha/epsilon, Gro-beta/gamma, and Naf-1 promoters directly bound NF-kappaB/Rel A in TNF-stimulated cells. Together, these studies systematically identify the direct NF-kappaB-dependent gene network downstream of TNF signaling, extending our knowledge of biological processes regulated by this pathway.


systematic_name: M7079
exact_source: Table 6S: Human Entrez Gene ID
source_species_code: HS
GEO_id: GSE10423
contributor: Nikolaos Papanikolaou
contrib_organization: Aristoteles University of Thessaloniki
description_brief:
  The 'core ESC-like gene module': genes coordinately up-regulated in a compendium of mouse embryonic stem cells (ESC) which are shared with the human ESC-like module.

description_full:
  Self-renewal is a hallmark of stem cells and cancer, but existence of a shared stemness program remains controversial. Here, we construct a gene module map to systematically relate transcriptional programs in embryonic stem cells (ESCs), adult tissue stem cells, and human cancers. This map reveals two predominant gene modules that distinguish ESCs and adult tissue stem cells. The ESC-like transcriptional program is activated in diverse human epithelial cancers and strongly predicts metastasis and death. c-Myc, but not other oncogenes, is sufficient to reactivate the ESC-like program in normal and cancer cells. In primary human keratinocytes transformed by Ras and I kappa B alpha, c-Myc increases the fraction of tumor-initiating cells by 150-fold, enabling tumor formation and serial propagation with as few as 500 cells. c-Myc-enhanced tumor initiation is cell-autonomous and independent of genomic instability. Thus, activation of an ESC-like transcriptional program in differentiated adult cells may induce pathologic self-renewal characteristic of cancer stem cells.


systematic_name: M2761
exact_source: Table 3: 2nd PCA genes (+)
source_species_code: HS
GEO_id: GSE6481
contributor: Nikolaos Papanikolaou
contrib_organization: Aristoteles University of Thessaloniki
description_brief:
  Top 100 probe sets contrubuting to the positive side of the 2nd principal component; associated with adipocytic differentiation.

description_full:
  In soft tissue sarcomas, the diagnosis of malignant fibrous histiocytoma (MFH) has been a very controversial issue, and MFH is now considered to be reclassified into pleomorphic subtypes of other sarcomas. To characterize MFH genetically, we used an oligonucleotide microarray to analyze gene expression in 105 samples from 10 types of soft tissue tumors. Spindle cell and pleomorphic sarcomas, such as dedifferentiated liposarcoma, myxofibrosarcoma, leiomyosarcoma, malignant peripheral nerve sheath tumor (MPNST), fibrosarcoma and MFH, showed similar gene expression patterns compared to other tumors. Samples from those five sarcoma types could be classified into respective clusters based on gene expression by excluding MFH samples. We calculated distances between MFH samples and other five sarcoma types (dedifferentiated liposarcoma, myxofibrosarcoma, leiomyosarcoma, MPNST and fibrosarcoma) based on differentially expressed genes and evaluated similarities. Three of the 21 MFH samples showed marked similarities to one of the five sarcoma types, which were supported by histological findings. Although most of the remaining 18 MFH samples showed little or no histological resemblance to one of the five sarcoma types, 12 of them showed moderate similarities in terms of gene expression. These results explain the heterogeneity of MFH and show that the majority of MFHs could be reclassified into pleomorphic subtypes of other sarcomas. Taken together, gene expression profiling could be a useful tool to unveil the difference in the underlying molecular backgrounds, which leads to a rational taxonomy and diagnosis of a diverse group of soft tissue sarcomas.


systematic_name: M1451
exact_source: Table 3: 2nd PCA genes (-)
source_species_code: HS
GEO_id: GSE6481
contributor: Nikolaos Papanikolaou
contrib_organization: Aristoteles University of Thessaloniki
description_brief:
  Top 100 probe sets contrubuting to the negative side of the 2nd principal component; associated with adipocytic differentiation.

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


systematic_name: M5871
exact_source: Suppl. file: all_pathways/PYR_HG-U133A_probes
source_species_code: HS
contributor: Vamsi Mootha
contrib_organization: Broad Institute
description_brief:
  Genes involved in pyruvate metabolism; based on literature and sequence annotation resources and converted to Affymetrix HG-U133A probe sets.

description_full:
[cell repeats an earlier one in this file: 873 characters]


systematic_name: M15531
exact_source: Suppl. file: all_pathways/FA_HG-U133A_probes
source_species_code: HS
contributor: Vamsi Mootha
contrib_organization: Broad Institute
description_brief:
  Genes involved in free fatty acid oxidation; based on literature and sequence annotation resources and coverted to Affymetrix HG-U133A probe sets.

description_full:
[cell repeats an earlier one in this file: 873 characters]


systematic_name: M13448
exact_source: Suppl. file: all_pathways/GLUCO_HG-U133A_probes
source_species_code: HS
contributor: Vamsi Mootha
contrib_organization: Broad Institute
description_brief:
  Genes involved in gluconeogenesis; based on literature and sequence annotation resources and converted to Affymetrix HG-U133A probe sets.

description_full:
[cell repeats an earlier one in this file: 873 characters]


systematic_name: M10376
exact_source: Suppl. file: all_pathways/GLYCOGEN_HG-U133A_probes
source_species_code: HS
contributor: Vamsi Mootha
contrib_organization: Broad Institute
description_brief:
  Genes involved in glycogen metabolism; based on literature and sequence annotation resources and converted to Affymetrix HG-U133A probe sets.

description_full:
[cell repeats an earlier one in this file: 873 characters]


systematic_name: M16111
exact_source: Suppl. file: all_pathways/GLYCOL_HG-U133A_probes
source_species_code: HS
contributor: Vamsi Mootha
contrib_organization: Broad Institute
description_brief:
  Genes involved in glycolysis; based on literature and sequence annotation resources and converted to Affymetrix HG-U133A probe sets.

description_full:
[cell repeats an earlier one in this file: 873 characters]


systematic_name: M2025
exact_source: Fig. 2: % of change <-80% at days 1,3 or 5
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in mesenchymal stem cells during early phase of adipogenesis, defined as days 1 to 5 of culturing with adipogenic hormones.

description_full:
  Human bone marrow mesenchymal stem cells (hMSCs) give rise to adipocytes in response to adipogenic hormones. An in-house cDNA microarray representing 3400 genes was employed to characterize the modulation of genes involved in this process. A total of 197 genes showed temporal gene expression changes during adipogenesis, including genes encoding transcriptional regulators and signaling molecules. Semi-quantitative RT-PCR analyses confirmed differential expression at the transcriptional level of several genes identified by cDNA microarray screening. Cluster analysis of the genes regulated during the late phase (from day 7 to day 14) of hMSC adipogenesis indicated that these changes are well correlated with data previously reported for murine preadipocytes. However, during the early phase (day 1-day 5), the modulations of genes differed from those reported for the preadipocytes. These data provide novel information on the molecular mechanisms required for lineage commitment and maturation accompanying adipogenesis of hMSC.


systematic_name: M2030
exact_source: Fig.2: % of changed <-80% at days 7,9 or 14
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in mesenchymal stem cells during late phase of adipogenesis, defined as days 7 to 14 of culturing with adipogenic hormones.

description_full:
[cell repeats an earlier one in this file: 1035 characters]


systematic_name: M15114
exact_source: Table 2S: Cluster#=5
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Cluster G5: genes up-regulated in NHEK cells (normal keratinocyte) at 3 h and 24 h time points after UV-B irradiation.

description_full:
[cell repeats an earlier one in this file: 2087 characters]


systematic_name: M2055
exact_source: Fig 6c
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Cluster G28: genes differentially up-regulated in NHEK (normal keratinocyte) compared to SCC12B2 cells (squamous cell carcinoma) by UV-B radiation.

description_full:
[cell repeats an earlier one in this file: 2087 characters]


systematic_name: M5407
exact_source: Table 2: 24 h Down-regulated
source_species_code: HS
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Genes down-regulated in A172 cells (glioma, does not express MGMT [GeneID=4255]) by carmustine [PubChem=2578] at 24 h.

description_full:
[cell repeats an earlier one in this file: 1725 characters]


systematic_name: M2063
exact_source: Table 2: Fold change > 0
source_species_code: HS
GEO_id: GSE17766
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in MCF7 cells (breast cancer) upon knockdown of CLOCK [GeneID=9575] by RNAi that also belong to the highest confidence network (according to Ingenuity Pathway Analysis).

description_full:
  The transcription factors responsible for maintaining circadian rhythm influence a variety of biological processes. Recently, it has been suggested that the core circadian genes may play a role in breast tumorigenesis, possibly by influencing hormone regulation or other pathways relevant to cancer. To evaluate this hypothesis, we conducted a genetic and epigenetic association study, as well as a transcriptional profiling array and a pathway-based network analysis. We report significant correlations between single nucleotide polymorphisms associated with the central circadian regulator CLOCK and breast cancer risk, with apparent effect modification by estrogen receptor/progesterone receptor status. We also found that hypermethylation in the CLOCK promoter reduced the risk of breast cancer, and lower levels of CLOCK expression were documented in healthy controls relative to normal or tumor tissue from patients with breast cancer. Finally, we silenced CLOCK in vitro and performed a whole-genome expression microarray and pathway analysis, which identified a cancer-relevant network of transcripts with altered expression following CLOCK gene knockdown. Our findings support the hypothesis that circadian genes influence tumorigenesis, and identify a set of circadian gene variants as candidate breast cancer susceptibility biomarkers.


description_brief: A list of known cell cycle regulated genes that was compiled from the literature by the authors.
systematic_name: M2066
exact_source: Table 2
source_species_code: HS
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_full:
  The genome-wide program of gene expression during the cell division cycle in a human cancer cell line (HeLa) was characterized using cDNA microarrays. Transcripts of >850 genes showed periodic variation during the cell cycle. Hierarchical clustering of the expression patterns revealed coexpressed groups of previously well-characterized genes involved in essential cell cycle processes such as DNA replication, chromosome segregation, and cell adhesion along with genes of uncharacterized function. Most of the genes whose expression had previously been reported to correlate with the proliferative state of tumors were found herein also to be periodically expressed during the HeLa cell cycle. However, some of the genes periodically expressed in the HeLa cell cycle do not have a consistent correlation with tumor proliferation. Cell cycle-regulated transcripts of genes involved in fundamental processes such as DNA replication and chromosome segregation seem to be more highly expressed in proliferative tumors simply because they contain more cycling cells. The data in this report provide a comprehensive catalog of cell cycle regulated genes that can serve as a starting point for functional discovery. The full dataset is available at http://genome-www.stanford.edu/Human-CellCycle/HeLa/.


description_brief: Genes downstream of both CDKN1A and TP53 [GeneID=1026;7157] in 2774qw1 cells (ovarian cancer).
systematic_name: M10169
exact_source: Table 4: 1
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_full:
  In this study we used adenovirus vector-mediated transduction of either the p53 gene (rAd-p53) or the p21(WAF1/CIP1) gene (rAd-p21) to mimic both p53-dependent and -independent up-regulation of p21(WAF1/CIP1) within a human ovarian cancer cell line, 2774, and the derivative cell lines, 2774qw1 and 2774qw2. We observed that rAd-p53 can induce apoptosis in both 2774 and 2774qw1 cells but not in 2774qw2 cells. Surprisingly, overexpression of p21(WAF1/CIP1) also triggered apoptosis within these two cell lines. Quantitative reverse transcription-PCR analysis revealed that the differential expression of BAX, BCL2, and caspase 3 genes, specific in rAd-p53-induced apoptotic cells, was not altered in rAd-p21-induced apoptotic cells, suggesting p21(WAF1/CIP1)-induced apoptosis through a pathway distinguishable from p53-induced apoptosis. Expression analysis of 2774qw1 cells infected with rAd-p21 on 60,000 cDNA microarrays identified 159 genes in response to p21(WAF1/CIP1) expression in at least one time point with 2.5-fold change as a cutoff. Integration of the data with the parallel microarray experiments with rAd-p53 infection allowed us to extract 66 genes downstream of both p53 and p21(WAF1/CIP1) and 93 genes in response to p21(WAF1/CIP1) expression in a p53-independent pathway. The genes in the former set may play a dual role in both p53-dependent and p53-independent pathways, and the genes in the latter set gave a mechanistic molecular explanation for p53-independent p21(WAF1/CIP1)-induced apoptosis. Furthermore, promoter sequence analysis suggested that transcription factor E2F family is partially responsible for the differential expression of genes following p21(WAF1/CIP1). This study has profound significance toward understanding the role of p21(WAF1/CIP1) in p53-independent apoptosis.


systematic_name: M6312
exact_source: Table 4: 2
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes downstream of CDKN1A [GeneID=1026] in a TP53 [GeneID=7157] independent pathway in 2774qw1 cells (ovarian cancer).

description_full:
  In this study we used adenovirus vector-mediated transduction of either the p53 gene (rAd-p53) or the p21(WAF1/CIP1) gene (rAd-p21) to mimic both p53-dependent and -independent up-regulation of p21(WAF1/CIP1) within a human ovarian cancer cell line, 2774, and the derivative cell lines, 2774qw1 and 2774qw2. We observed that rAd-p53 can induce apoptosis in both 2774 and 2774qw1 cells but not in 2774qw2 cells. Surprisingly, overexpression of p21(WAF1/CIP1) also triggered apoptosis within these two cell lines. Quantitative reverse transcription-PCR analysis revealed that the differential expression of BAX, BCL2, and caspase 3 genes, specific in rAd-p53-induced apoptotic cells, was not altered in rAd-p21-induced apoptotic cells, suggesting p21(WAF1/CIP1)-induced apoptosis through a pathway distinguishable from p53-induced apoptosis. Expression analysis of 2774qw1 cells infected with rAd-p21 on 60,000 cDNA microarrays identified 159 genes in response to p21(WAF1/CIP1) expression in at least one time point with 2.5-fold change as a cutoff. Integration of the data with the parallel microarray experiments with rAd-p53 infection allowed us to extract 66 genes downstream of both p53 and p21(WAF1/CIP1) and 93 genes in response to p21(WAF1/CIP1) expression in a p53-independent pathway. The genes in the former set may play a dual role in both p53-dependent and p53-independent pathways, and the genes in the latter set gave a mechanistic molecular explanation for p53-independent p21(WAF1/CIP1)-induced apoptosis. Furthermore, promoter sequence analysis suggested that transcription factor E2F family is partially responsible for the differential expression of genes following p21(WAF1/CIP1). This study has profound significance toward understanding the role of p21(WAF1/CIP1) in p53-independent apoptosis.


systematic_name: M6977
exact_source: Table 1S: 30min >= 3 & Diff Call [30 min] = I, MI
source_species_code: HS
GEO_id: GSE675
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in primary fibroblast cell culture at 30 min time point after infection with HCMV (AD169 strain).

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


systematic_name: M0
exact_source: Table 1S: 30min =< -3 & Diff Call [30 min] = D, MD
source_species_code: HS
GEO_id: GSE675
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in primary fibroblast cell culture at 30 min time point after infection with HCMV (AD169 strain).

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


systematic_name: M5823
exact_source: Table 1S: 60min >= 3 & Diff Call [60 min] = I, MI
source_species_code: HS
GEO_id: GSE675
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in primary fibroblast cell culture after infection with HCMV (AD169 strain) at 1 h time point that were not up-regulated at the previous time point, 30 min.

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


systematic_name: M9802
exact_source: Table 1S: 60min =< -3 & Diff Call [60 min] = D, MD
source_species_code: HS
GEO_id: GSE675
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in primary fibroblast cell culture after infection with HCMV (AD169 strain) at 1 h time point that were not down-regulated at the previous time point, 30 min.

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


systematic_name: M3649
exact_source: Table 1S: 2hpi >= 3 & Diff Call [2hpi] = I, MI
source_species_code: HS
GEO_id: GSE675
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in primary fibroblast cell culture point after infection with HCMV (AD169 strain) at 2 h time point that were not up-regulated at the previous time point, 1 h.

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


systematic_name: M521
exact_source: Table 1S: 2hpi =< -3 & Diff Call [2hpi] = D, MD
source_species_code: HS
GEO_id: GSE675
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in primary fibroblast cell culture point after infection with HCMV (AD169 strain) at 2 h time point that were not down-regulated at the previous time point, 1 h.

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


systematic_name: M10161
exact_source: Table 1S: 4hpi >= 3 & Diff Call [4hpi] = I, MI
source_species_code: HS
GEO_id: GSE675
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in primary fibroblast cell culture point after infection with HCMV (AD169 strain) at 4 h time point that were not up-regulated at the previous time point, 2 h.

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


systematic_name: M789
exact_source: Table 1S: 4hpi =< -3 & Diff Call [4hpi] = D, MD
source_species_code: HS
GEO_id: GSE675
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in primary fibroblast cell culture point after infection with HCMV (AD169 strain) at 4 h time point that were not down-regulated at the previous time point, 2 h.

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


systematic_name: M2074
exact_source: Suppl. File CellCycleGeneList_1134.txt, Annotation=G1/S
source_species_code: HS
GEO_id: GSE3497
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes periodically expressed in synchronized HeLa cells (cervical carcinoma), with peak during the G1/S phase of cell cycle.

description_full:
  The genome-wide program of gene expression during the cell division cycle in a human cancer cell line (HeLa) was characterized using cDNA microarrays. Transcripts of >850 genes showed periodic variation during the cell cycle. Hierarchical clustering of the expression patterns revealed coexpressed groups of previously well-characterized genes involved in essential cell cycle processes such as DNA replication, chromosome segregation, and cell adhesion along with genes of uncharacterized function. Most of the genes whose expression had previously been reported to correlate with the proliferative state of tumors were found herein also to be periodically expressed during the HeLa cell cycle. However, some of the genes periodically expressed in the HeLa cell cycle do not have a consistent correlation with tumor proliferation. Cell cycle-regulated transcripts of genes involved in fundamental processes such as DNA replication and chromosome segregation seem to be more highly expressed in proliferative tumors simply because they contain more cycling cells. The data in this report provide a comprehensive catalog of cell cycle regulated genes that can serve as a starting point for functional discovery. The full dataset is available at http://genome-www.stanford.edu/Human-CellCycle/HeLa/.


systematic_name: M2075
exact_source: Suppl. File CellCycleGeneList_1134.txt, Annotation=S
source_species_code: HS
GEO_id: GSE3497
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes periodically expressed in synchronized HeLa cells (cervical carcinoma), with peak during the S phase of cell cycle.

description_full:
  The genome-wide program of gene expression during the cell division cycle in a human cancer cell line (HeLa) was characterized using cDNA microarrays. Transcripts of >850 genes showed periodic variation during the cell cycle. Hierarchical clustering of the expression patterns revealed coexpressed groups of previously well-characterized genes involved in essential cell cycle processes such as DNA replication, chromosome segregation, and cell adhesion along with genes of uncharacterized function. Most of the genes whose expression had previously been reported to correlate with the proliferative state of tumors were found herein also to be periodically expressed during the HeLa cell cycle. However, some of the genes periodically expressed in the HeLa cell cycle do not have a consistent correlation with tumor proliferation. Cell cycle-regulated transcripts of genes involved in fundamental processes such as DNA replication and chromosome segregation seem to be more highly expressed in proliferative tumors simply because they contain more cycling cells. The data in this report provide a comprehensive catalog of cell cycle regulated genes that can serve as a starting point for functional discovery. The full dataset is available at http://genome-www.stanford.edu/Human-CellCycle/HeLa/.


systematic_name: M2076
exact_source: Suppl. File CellCycleGeneList_1134.txt, Annotation=G2
source_species_code: HS
GEO_id: GSE3497
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes periodically expressed in synchronized HeLa cells (cervical carcinoma), with peak during the G2 phase of cell cycle.

description_full:
[cell repeats an earlier one in this file: 1297 characters]


systematic_name: M2077
exact_source: Suppl. File CellCycleGeneList_1134.txt, Annotation=G2/M
source_species_code: HS
GEO_id: GSE3497
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes periodically expressed in synchronized HeLa cells (cervical carcinoma), with peak during the G2/M phase of cell cycle.

description_full:
[cell repeats an earlier one in this file: 1297 characters]


systematic_name: M2078
exact_source: Suppl. File CellCycleGeneList_1134.txt, Annotation=M/G1
source_species_code: HS
GEO_id: GSE3497
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes periodically expressed in synchronized HeLa cells (cervical carcinoma), with peak during the M/G1 phase of cell cycle.

description_full:
[cell repeats an earlier one in this file: 1297 characters]


systematic_name: M2082
exact_source: Table 2: ER-positive group, Cox > 0
source_species_code: HS
GEO_id: GSE2034
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes whose expression in primary ER(+) [GeneID=2099] breast cancer tumors positively correlates with developing distant metastases.

description_full:
  BACKGROUND: Genome-wide measures of gene expression can identify patterns of gene activity that subclassify tumours and might provide a better means than is currently available for individual risk assessment in patients with lymph-node-negative breast cancer. METHODS: We analysed, with Affymetrix Human U133a GeneChips, the expression of 22000 transcripts from total RNA of frozen tumour samples from 286 lymph-node-negative patients who had not received adjuvant systemic treatment. FINDINGS: In a training set of 115 tumours, we identified a 76-gene signature consisting of 60 genes for patients positive for oestrogen receptors (ER) and 16 genes for ER-negative patients. This signature showed 93% sensitivity and 48% specificity in a subsequent independent testing set of 171 lymph-node-negative patients. The gene profile was highly informative in identifying patients who developed distant metastases within 5 years (hazard ratio 5.67 [95% CI 2.59-12.4]), even when corrected for traditional prognostic factors in multivariate analysis (5.55 [2.46-12.5]). The 76-gene profile also represented a strong prognostic factor for the development of metastasis in the subgroups of 84 premenopausal patients (9.60 [2.28-40.5]), 87 postmenopausal patients (4.04 [1.57-10.4]), and 79 patients with tumours of 10-20 mm (14.1 [3.34-59.2]), a group of patients for whom prediction of prognosis is especially difficult. INTERPRETATION: The identified signature provides a powerful tool for identification of patients at high risk of distant recurrence. The ability to identify patients who have a favourable prognosis could, after independent confirmation, allow clinicians to avoid adjuvant systemic therapy or to choose less aggressive therapeutic options.


systematic_name: M2132
exact_source: Table 2S: Downregulated genes
source_species_code: HS
GEO_id: GSE19736
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in RS4;11 cells (MLL, mixed lineage leukemia) in response to SB216763 [PubChem=176158], an inhibitor of GSK3B [GeneID=2932].

description_full:
  Acute leukemias induced by MLL chimeric oncoproteins are among the subset of cancers distinguished by a paradoxical dependence on GSK-3 kinase activity for sustained proliferation. We demonstrate here that GSK-3 maintains the MLL leukemia stem cell transcriptional program by promoting the conditional association of CREB and its coactivators TORC and CBP with homedomain protein MEIS1, a critical component of the MLL-subordinate program, which in turn facilitates HOX-mediated transcription and transformation. This mechanism also applies to hematopoietic cells transformed by other HOX genes, including CDX2, which is highly expressed in a majority of acute myeloid leukemias, thus providing a molecular approach based on GSK-3 inhibitory strategies to target HOX-associated transcription in a broad spectrum of leukemias.


systematic_name: M2137
exact_source: Table 1S
source_species_code: HS
GEO_id: GSE21499
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes identified as synthetic lethal with imatinib [PubChem=5291] in RNAi screen in K562 cells (CML, chronic myelogenous leukemia).

description_full:
  Although Bcr-Abl kinase inhibitors have proven effective in the treatment of chronic myeloid leukemia (CML), they generally fail to eradicate Bcr-Abl(+) leukemia cells. To identify genes whose inhibition sensitizes Bcr-Abl(+) leukemias to killing by Bcr-Abl inhibitors, we performed an RNAi-based synthetic lethal screen with imatinib mesylate in CML cells. This screen identified numerous components of a Wnt/Ca(2+)/NFAT signaling pathway. Antagonism of this pathway led to impaired NFAT activity, decreased cytokine production, and enhanced sensitivity to Bcr-Abl inhibition. Furthermore, NFAT inhibition with cyclosporin A facilitated leukemia cell elimination by the Bcr-Abl inhibitor dasatinib and markedly improved survival in a mouse model of Bcr-Abl(+) acute lymphoblastic leukemia (ALL). Targeting this pathway in combination with Bcr-Abl inhibition could improve treatment of Bcr-Abl(+) leukemias.


systematic_name: M2210
exact_source: Table 2S: Fold change STAT3A(1*6)-ER > 1
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in CD34+ [GeneID=947] cells by intermediate activity levels of STAT5A [GeneID=6776]; predominant long-term growth and self-renewal phenotype.

description_full:
  The level of transcription factor activity critically regulates cell fate decisions, such as hematopoietic stem cell (HSC) self-renewal and differentiation. We introduced STAT5A transcriptional activity into human HSCs/progenitor cells in a dose-dependent manner by overexpression of a tamoxifen-inducible STAT5A(1*6)-estrogen receptor fusion protein. Induction of STAT5A activity in CD34(+) cells resulted in impaired myelopoiesis and induction of erythropoiesis, which was most pronounced at the highest STAT5A transactivation levels. In contrast, intermediate STAT5A activity levels resulted in the most pronounced proliferative advantage of CD34(+) cells. This coincided with increased cobblestone area-forming cell and long-term-culture-initiating cell frequencies, which were predominantly elevated at intermediate STAT5A activity levels but not at high STAT5A levels. Self-renewal of progenitors was addressed by serial replating of CFU, and only progenitors containing intermediate STAT5A activity levels contained self-renewal capacity. By extensive gene expression profiling we could identify gene expression patterns of STAT5 target genes that predominantly associated with a self-renewal and long-term expansion phenotype versus those that identified a predominant differentiation phenotype.


systematic_name: M2215
exact_source: Table 3S
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated to their maximal levels in CD34+ [GeneID=947] cells by intermediate activity levels of STAT5A [GeneID=6776]; predominant long-term growth and self-renewal phenotype.

description_full:
  The level of transcription factor activity critically regulates cell fate decisions, such as hematopoietic stem cell (HSC) self-renewal and differentiation. We introduced STAT5A transcriptional activity into human HSCs/progenitor cells in a dose-dependent manner by overexpression of a tamoxifen-inducible STAT5A(1*6)-estrogen receptor fusion protein. Induction of STAT5A activity in CD34(+) cells resulted in impaired myelopoiesis and induction of erythropoiesis, which was most pronounced at the highest STAT5A transactivation levels. In contrast, intermediate STAT5A activity levels resulted in the most pronounced proliferative advantage of CD34(+) cells. This coincided with increased cobblestone area-forming cell and long-term-culture-initiating cell frequencies, which were predominantly elevated at intermediate STAT5A activity levels but not at high STAT5A levels. Self-renewal of progenitors was addressed by serial replating of CFU, and only progenitors containing intermediate STAT5A activity levels contained self-renewal capacity. By extensive gene expression profiling we could identify gene expression patterns of STAT5 target genes that predominantly associated with a self-renewal and long-term expansion phenotype versus those that identified a predominant differentiation phenotype.


systematic_name: M2216
exact_source: Table 4S
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in a linear fashion in CD34+ [GeneID=947] cells upon increasing activity levels of STAT5A [GeneID=6776]; predominant long-term growth and self-renewal phenotype.

description_full:
[cell repeats an earlier one in this file: 1303 characters]


systematic_name: M2222
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 down-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: M2230
exact_source: Table 3S: # 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 up-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: M2234
exact_source: Table 4S: # 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 up-regulated by estradiol [PubChem=5757] in MCF-7 cells (breast cancer) expressing constitutevly active form of AKT1 [GeneID=207].

description_full:
[cell repeats an earlier one in this file: 1513 characters]


systematic_name: M2238
exact_source: Table 2S: Inc. in 2 x 3D exps
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 collagen I and 3D Matrigel only.

description_full:
[cell repeats an earlier one in this file: 1061 characters]


description_brief: Genes up-regulated in HCT116 cells (colorectal carcinoma) upon knockout of PTEN [GeneID=5728].
systematic_name: M2276
exact_source: Table 1
source_species_code: HS
GEO_id: GSE6263
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_full:
  In an effort to identify genes whose expression is regulated by activated phosphatidylinositol 3-kinase (PI3K) signaling, we performed microarray analysis and subsequent quantitative reverse transcription-PCR on an isogenic set of PTEN gene-targeted human cancer cells. Numerous p53 effectors were upregulated following PTEN deletion, including p21, GDF15, PIG3, NOXA, and PLK2. Stable depletion of p53 led to reversion of the gene expression program. Western blots revealed that p53 was stabilized in HCT116 PTEN(-/-) cells via an Akt1-dependent and p14(ARF)-independent mechanism. Stable depletion of PTEN in untransformed human fibroblasts and epithelial cells also led to upregulation of p53 and senescence-like growth arrest. Simultaneous depletion of p53 rescued this phenotype, enabling PTEN-depleted cells to continue proliferating. Next, we tested whether oncogenic PIK3CA, like inactivated PTEN, could activate p53. Retroviral expression of oncogenic human PIK3CA in MCF10A cells led to activation of p53 and upregulation of p53-regulated genes. Stable depletion of p53 reversed these PIK3CA-induced expression changes and synergized with oncogenic PIK3CA in inducing anchorage-independent growth. Finally, targeted deletion of an endogenous allele of oncogenic, but not wild-type, PIK3CA in a human cancer cell line led to a reduction in p53 levels and a decrease in the expression of p53-regulated genes. These studies demonstrate that activation of PI3K signaling by mutations in PTEN or PIK3CA can lead to activation of p53-mediated growth suppression in human cells, indicating that p53 can function as a brake on phosphatidylinositol (3,4,5)-triphosphate-induced mitogenesis during human cancer pathogenesis.


systematic_name: M2308
exact_source: Table 2
source_species_code: MM
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Representative genes up-regulated in MEF cells (embryonic fibroblast) in response to TNF [GeneID=7124].

description_full:
  NF-kappaB signaling is implicated as an important regulator of skeletal muscle homeostasis, but the mechanisms by which this transcription factor contributes to muscle maturation and turnover remain unclear. To gain insight into these mechanisms, gene expression profiling was examined in C2C12 myoblasts devoid of NF-kappaB activity. Interestingly, even in proliferating myoblasts, the absence of NF-kappaB caused the pronounced induction of several myofibrillar genes, suggesting that NF-kappaB functions as a negative regulator of late-stage muscle differentiation. Although several myofibrillar promoters contain predicted NF-kappaB binding sites, functional analysis using the troponin-I2 gene as a model revealed that NF-kappaB-mediated repression does not occur through direct DNA binding. In the search for an indirect mediator, the transcriptional repressor YinYang1 (YY1) was identified. While inducers of NF-kappaB stimulated YY1 expression in multiple cell types, genetic ablation of the RelA/p65 subunit of NF-kappaB in both cultured cells and adult skeletal muscle correlated with reduced YY1 transcripts and protein. NF-kappaB regulation of YY1 occurred at the transcriptional level, mediated by direct binding of the p50/p65 heterodimer complex to the YY1 promoter. Furthermore, YY1 was found associated with multiple myofibrillar promoters in C2C12 myoblasts containing NF-kappaB activity. Based on these results, we propose that NF-kappaB regulation of YY1 and transcriptional silencing of myofibrillar genes represent a new mechanism by which NF-kappaB functions in myoblasts to modulate skeletal muscle differentiation.


systematic_name: M2314
exact_source: Table 1: DLD23 24 hours; green
source_species_code: HS
GEO_id: E-MEXP-721
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-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: M2316
exact_source: Table 4S: Upregulated genes in Bmi-1+ Mel-18 shRNA-expressing DAOY cells
source_species_code: HS
GEO_id: GSE7578
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in DAOY cells (medulloblastoma) upon knockdown of both BMI1 and PCGF2 [GeneID=648, 7703] by RNAi.

description_full:
  Bmi-1 and Mel-18 are structural homologues that belong to the Polycomb group of transcriptional regulators and are believed to stably maintain repression of gene expression by altering the state of chromatin at specific promoters. While a number of clinical and experimental observations have implicated Bmi-1 in human tumorigenesis, the role of Mel-18 in cancer cell growth has not been investigated. We report here that short hairpin RNA-mediated knockdown of either Bmi-1 or Mel-18 in human medulloblastoma DAOY cells results in the inhibition of proliferation, loss of clonogenic survival, anchorage-independent growth, and suppression of tumor formation in nude mice. Furthermore, overexpression of both Bmi-1 and Mel-18 significantly increases the clonogenic survival of Rat1 fibroblasts. In contrast, stable downregulation of Bmi-1 or Mel-18 alone does not affect the growth of normal human WI38 fibroblasts. Proteomics-based characterization of Bmi-1 and Mel-18 protein complexes isolated from cancer cells revealed substantial similarities in their respective compositions. Finally, gene expression analysis identified a number of cancer-relevant pathways that may be controlled by Bmi-1 and Mel-18 and also showed that these Polycomb proteins regulate a set of common gene targets. Taken together, these results suggest that Bmi-1 and Mel-18 may have overlapping functions in cancer cell growth.


description_brief: Genes down-regulated in HeLa cells upon knockdown of ELAVL1 [GeneID=1994] by RNAi.
systematic_name: M2323
exact_source: Fig. 3A
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_full:
  A high expression level of the beta-actin protein is required for important biological mechanisms, such as maintaining cell shape, growth, and motility. Although the elevated cellular level of the beta-actin protein is directly linked to the long half-life of its mRNA, the molecular mechanisms responsible for this effect are unknown. Here we show that the RNA-binding protein HuR stabilizes the beta-actin mRNA by associating with a uridine-rich element within its 3' untranslated region. Using RNA interference to knock down the expression of HuR in HeLa cells, we demonstrate that HuR plays an important role in the stabilization but not in the nuclear/cytoplasmic distribution of the beta-actin mRNA. HuR depletion in HeLa cells alters key beta-actin-based cytoskeleton functions, such as cell adhesion, migration, and invasion, and these defects correlate with a loss of the actin stress fiber network. Together our data establish that the posttranscriptional event involving HuR-mediated beta-actin mRNA stabilization could be a part of the regulatory mechanisms responsible for maintaining cell integrity, which is a prerequisite for avoiding transformation and tumor formation.


systematic_name: M2344
exact_source: Table 2
source_species_code: HS
GEO_id: GSE15583
contributor: Paolo Fardin
contrib_organization: Giannina Gaslini Institute
description_brief:
  Genes in the hypoxia signature, based on analysis of nine neuroblastoma cell lines in hypoxia and normal oxygen conditions.

description_full:
  Gene expression signatures are clusters of genes discriminating different statuses of the cells and their definition is critical for understanding the molecular bases of diseases. The identification of a gene signature is complicated by the high dimensional nature of the data and by the genetic heterogeneity of the responding cells. The l1-l2 regularization is an embedded feature selection technique that fulfills all the desirable properties of a variable selection algorithm and has the potential to generate a specific signature even in biologically complex settings. We studied the application of this algorithm to detect the signature characterizing the transcriptional response of neuroblastoma tumor cell lines to hypoxia, a condition of low oxygen tension that occurs in the tumor microenvironment.


systematic_name: M2345
exact_source: Fig. 2
source_species_code: HS
GEO_id: GSE17714
contributor: Paolo Fardin
contrib_organization: Giannina Gaslini Institute
description_brief:
  Genes in the hypoxia signature, based on analysis of 11 neuroblastoma cell lines in hypoxia and normal oxygen conditions.

description_full:
  Hypoxia is a condition of low oxygen tension occurring in the tumor microenvironment and it is related to poor prognosis in human cancer. To examine the relationship between hypoxia and neuroblastoma, we generated and tested an in vitro derived hypoxia gene signature for its ability to predict patients' outcome.


description_brief: Transcripts (mRNA molecules) rapidly degraded upon interaction with KHSRP [GeneID=8570].
systematic_name: M2352
exact_source: Table 1
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_full:
  mRNA stability is a major determinant of inflammatory gene expression. Rapid degradation of interleukin-8 (IL-8) mRNA is imposed by a bipartite AU-rich element (ARE) in the 3' untranslated region (R. Winzen et al., Mol. Cell. Biol. 24:4835-4847, 2004). Small interfering RNA-mediated knockdown of the ARE-binding protein KSRP resulted in stabilization of IL-8 mRNA or of a beta-globin reporter mRNA containing the IL-8 ARE. Rapid deadenylation was impaired, indicating a crucial role for KSRP in this step of mRNA degradation. The two IL-8 ARE domains both contribute to interaction with KSRP, corresponding to the importance of both domains for rapid degradation. Exposure to the inflammatory cytokine IL-1 has been shown to stabilize IL-8 mRNA through p38 mitogen-activated protein (MAP) kinase and MK2. IL-1 treatment impaired the interaction of KSRP with the IL-8 ARE in a manner dependent on p38 MAP kinase but apparently independent of MK2. Instead, evidence that TTP, a target of MK2, can also destabilize the IL-8 ARE reporter mRNA is presented. In a comprehensive approach to identify mRNAs controlled by KSRP, two criteria were evaluated by microarray analysis of (i) association of mRNAs with KSRP in pulldown assays and (ii) increased amounts in KSRP knockdown cells. According to both criteria, a group of 100 mRNAs is controlled by KSRP, many of which are unstable and encode proteins involved in inflammation. These results indicate that KSRP functions as a limiting factor in inflammatory gene expression.


systematic_name: M2371
exact_source: Table 1S
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated by VHL [GeneID=7428] and re-expressed under hypoxia conditions in renal carcinoma cells.

description_full:
  The von Hippel-Lindau tumor suppressor gene (VHL) is mutated in clear cell renal cell carcinomas (RCC), leading to the activation of hypoxia-inducible factor (HIF)-mediated gene transcription. Several VHL/HIF targets, such as glycolysis, angiogenesis, cell growth, and chemotaxis of tumor cells, have been implicated in the transformed phenotype of RCC-regulating properties. Here, we show that VHL suppresses key features of cell transformation through downregulation of the HIF-dependent expression of activin B, a member of the transforming growth factor beta superfamily. Activin B expression is repressed by restoration of VHL in VHL-deficient RCC cells and upregulated by hypoxia. RCC tumor samples show increased expression of activin B compared to that in the normal kidney. VHL increases cell adhesion to the extracellular matrix, promotes cell flattening, and reduces invasiveness. These effects are completely phenocopied by RNA interference-mediated knockdown of activin B and reverted by treatment with recombinant activin B. Finally, knockdown of activin B reduces tumor growth of RCC cells in nude mice. Our data indicate that activin B is a key mediator of VHL/HIF-induced transformation in RCC.


description_brief: Genes up-regulated in U2OS cells (osteosarcoma) upon knockdown of TOPBP1 [GeneID=11073].
systematic_name: M2382
exact_source: Table 1S
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_full:
  Proper control of the G(1)/S checkpoint is essential for normal proliferation. The activity of p53 must be kept at a very low level under unstressed conditions to allow growth. Here we provide evidence supporting a crucial role for TopBP1 in actively repressing p53. Depletion of TopBP1 upregulates p53 target genes involved in cell cycle arrest and apoptosis and enhances DNA damage-induced apoptosis. The regulation is mediated by an interaction between the seventh and eighth BRCT domains of TopBP1 and the DNA-binding domain of p53, leading to inhibition of p53 promoter binding activity. Importantly, TopBP1 overexpression is found in 46 of 79 primary breast cancer tissues and is associated with high tumor grade and shorter patient survival time. Overexpression of TopBP1 to a level comparable to that seen in breast tumors leads to inhibition of p53 target gene expression and DNA damage-induced apoptosis and G(1) arrest. Thus, a physiological level of TopBP1 is essential for normal G(1)/S transition, but a pathological level of TopBP1 in cancer may perturb p53 function and contribute to an aggressive tumor behavior.


systematic_name: M2407
exact_source: Table 1S: Probeset average sheet: 611- 15h, 60h and HER2-60h regulated
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes regulated in MCF7 cells (breast cancer) by expression of full-length and truncated (611-CTF) forms of ERBB2 [GeneID=2064] at both 15 h and 60 h time points.

description_full:
[cell repeats an earlier one in this file: 1380 characters]


systematic_name: M2441
exact_source: Table 2S: Expression=Down
source_species_code: HS
GEO_id: GSE14787
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated during neuronal differentiation of SH-SY5Y cells (neuroblastoma) in response to stimulation by tretinoin (all-trans retinoic acid, ATRA) [PubChem=444795] and BDNF [GeneID=627].

description_full:
  MicroRNAs (miRNAs) are a class of small noncoding RNAs that regulate gene expression at the posttranscriptional level. Research on miRNAs has highlighted their importance in neural development, but the specific functions of neurally enriched miRNAs remain poorly understood. We report here the expression profile of miRNAs during neuronal differentiation in the human neuroblastoma cell line SH-SY5Y. Six miRNAs were significantly upregulated during differentiation induced by all-trans-retinoic acid and brain-derived neurotrophic factor. We demonstrated that the ectopic expression of either miR-124a or miR-125b increases the percentage of differentiated SH-SY5Y cells with neurite outgrowth. Subsequently, we focused our functional analysis on miR-125b and demonstrated the important role of this miRNA in both the spontaneous and induced differentiations of SH-SH5Y cells. miR-125b is also upregulated during the differentiation of human neural progenitor ReNcell VM cells, and miR-125b ectopic expression significantly promotes the neurite outgrowth of these cells. To identify the targets of miR-125b regulation, we profiled the global changes in gene expression following miR-125b ectopic expression in SH-SY5Y cells. miR-125b represses 164 genes that contain the seed match sequence of the miRNA and/or that are predicted to be direct targets of miR-125b by conventional methods. Pathway analysis suggests that a subset of miR-125b-repressed targets antagonizes neuronal genes in several neurogenic pathways, thereby mediating the positive effect of miR-125b on neuronal differentiation. We have further validated the binding of miR-125b to the miRNA response elements of 10 selected mRNA targets. Together, we report here for the first time the important role of miR-125b in human neuronal differentiation.


description_brief: Major erythrocyte membrane genes.
systematic_name: M2442
exact_source: Table 1
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_full:
  Erythrocyte membrane protein genes serve as excellent models of complex gene locus structure and function, but their study has been complicated by both their large size and their complexity. To begin to understand the intricate interplay of transcription, dynamic chromatin architecture, transcription factor binding, and genomic organization in regulation of erythrocyte membrane protein genes, we performed chromatin immunoprecipitation (ChIP) coupled with microarray analysis and ChIP coupled with massively parallel DNA sequencing in both erythroid and nonerythroid cells. Unexpectedly, most regions of GATA-1 and NF-E2 binding were remote from gene promoters and transcriptional start sites, located primarily in introns. Cooccupancy with FOG-1, SCL, and MTA-2 was found at all regions of GATA-1 binding, with cooccupancy of SCL and MTA-2 also found at regions of NF-E2 binding. Cooccupancy of GATA-1 and NF-E2 was found frequently. A common signature of histone H3 trimethylation at lysine 4, GATA-1, NF-E2, FOG-1, SCL, and MTA-2 binding and consensus GATA-1-E-box binding motifs located 34 to 90 bp away from NF-E2 binding motifs was found frequently in erythroid cell-expressed genes. These results provide insights into our understanding of membrane protein gene regulation in erythropoiesis and the regulation of complex genetic loci in erythroid and nonerythroid cells and identify numerous candidate regions for mutations associated with membrane-linked hemolytic anemia.


systematic_name: M2467
exact_source: Table 2S: list 1
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes dependent on KDM3A [GeneID=55818] for hypoxic induction 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.


systematic_name: M2468
exact_source: Table 2S: list 2
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes not induced under hypoxia, but dependent on KDM3A [GeneID=55818] for hypoxic expression 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.


systematic_name: M2476
exact_source: Table 2: Genes upregulated in the primingmodel
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in BEAS-2B cells (bronchial epithelium) stimulated with IL13 [GeneID=3596] on days 1 to 3, rested on days 4 and 5, and then restimulated on day 6 for 1 h before lysis (priming model).

description_full:
  Our objective was to establish an experimental model of a self-sustained and bistable extracellular signal-regulated kinase 1/2 (ERK1/2) signaling process. A single stimulation of cells with cytokines causes rapid ERK1/2 activation, which returns to baseline in 4 h. Repeated stimulation leads to sustained activation of ERK1/2 but not Jun N-terminal protein kinase (JNK), p38, or STAT6. The ERK1/2 activation lasts for 3 to 7 days and depends upon a positive-feedback mechanism involving Sprouty 2. Overexpression of Sprouty 2 induces, and its genetic deletion abrogates, ERK1/2 bistability. Sprouty 2 directly activates Fyn kinase, which then induces ERK1/2 activation. A genome-wide microarray analysis shows that the bistable phospho-ERK1/2 (pERK1/2) does not induce a high level of gene transcription. This is due to its nuclear exclusion and compartmentalization to Rab5+ endosomes. Cells with sustained endosomal pERK1/2 manifest resistance against growth factor withdrawal-induced cell death. They are primed for heightened cytokine production. Epithelial cells from cases of human asthma and from a mouse model of chronic asthma manifest increased pERK1/2, which is associated with Rab5+ endosomes. The increase in pERK1/2 was associated with a simultaneous increase in Sprouty 2 expression in these tissues. Thus, we have developed a cellular model of sustained ERK1/2 activation, which may provide a mechanistic understanding of self-sustained biological processes in chronic illnesses such as asthma.


systematic_name: M2496
exact_source: Table 1S: Fold changes > 0
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in Calu-6 cells (lung cancer) at 1 h time point after TNF [GeneID=7124] treatment.

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: M2502
exact_source: Table 2S: p38i LY79754 response=partial
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 partially by p38 inhibitor LY479754.

description_full:
[cell repeats an earlier one in this file: 1444 characters]


systematic_name: M2504
exact_source: Table 2S: p38i LY79754 response=no response
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 not affected by p38 inhibitor LY479754.

description_full:
[cell repeats an earlier one in this file: 1444 characters]


systematic_name: M2509
exact_source: Fig. 6A
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Major ELAVL4 [GeneID=1996] associated mRNAs encoding proteins with functions in neuronal physiology.

description_full:
  Neuronal development and plasticity are maintained by tightly regulated gene expression programs. Here, we report that the developmentally regulated microRNA miR-375 affects dendrite formation and maintenance. miR-375 overexpression in mouse hippocampus potently reduced dendrite density. We identified the predominantly neuronal RNA-binding protein HuD as a key effector of miR-375 influence on dendrite maintenance. Heterologous reporter analysis verified that miR-375 repressed HuD expression through a specific, evolutionarily conserved site on the HuD 3' untranslated region. miR-375 overexpression lowered both HuD mRNA stability and translation and recapitulated the effects of HuD silencing, which reduced the levels of target proteins with key functions in neuronal signaling and cytoskeleton organization (N-cadherin, PSD-95, RhoA, NCAM1, and integrin alpha1). Moreover, the increase in neurite outgrowth after brain-derived neurotrophic factor (BDNF) treatment was diminished by miR-375 overexpression; this effect was rescued by reexpression of miR-375-refractory HuD. Our findings indicate that miR-375 modulates neuronal HuD expression and function, in turn affecting dendrite abundance.


description_brief: Genes deregulated in U2OS cells (osteosarcoma) upon knockdown of BAP1 [GeneID=8314] by RNAi.
systematic_name: M2515
exact_source: Table 1
source_species_code: HS
GEO_id: GSE23035
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_full:
  The candidate tumor suppressor BAP1 is a deubiquitinating enzyme (DUB) involved in the regulation of cell proliferation, although the molecular mechanisms governing its function remain poorly defined. BAP1 was recently shown to interact with and deubiquitinate the transcriptional regulator host cell factor 1 (HCF-1). Here we show that BAP1 assembles multiprotein complexes containing numerous transcription factors and cofactors, including HCF-1 and the transcription factor Yin Yang 1 (YY1). Through its coiled-coil motif, BAP1 directly interacts with the zinc fingers of YY1. Moreover, HCF-1 interacts with the middle region of YY1 encompassing the glycine-lysine-rich domain and is essential for the formation of a ternary complex with YY1 and BAP1 in vivo. BAP1 activates transcription in an enzymatic-activity-dependent manner and regulates the expression of a variety of genes involved in numerous cellular processes. We further show that BAP1 and HCF-1 are recruited by YY1 to the promoter of the cox7c gene, which encodes a mitochondrial protein used here as a model of BAP1-activated gene expression. Our findings (i) establish a direct link between BAP1 and the transcriptional control of genes regulating cell growth and proliferation and (ii) shed light on a novel mechanism of transcription regulation involving ubiquitin signaling.


systematic_name: M2525
exact_source: Table 1S
source_species_code: MM
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Transcripts bound to IGF2BP2 [GeneID=10644] complexes and differentially regulated in myoblasts with IGF2BP2 [GeneID=10644] knockdown by RNAi.

description_full:
  Insulin-like growth factor 2 (IGF-2) mRNA-binding proteins (IMPs) are a family of posttranscriptional regulatory factors with well-understood roles in embryonic development and cancer but with poorly characterized functions in normal adult cells and tissues. We now show that IMP-2, the most ubiquitously expressed member of the family, is abundant in human and mouse adult skeletal myoblasts, where it is indispensable for cell motility and for stabilization of microtubules. To explore the functions of IMP-2, we analyzed the transcripts that were differentially regulated in IMP-2-depleted myoblasts and bound to IMP-2 in normal myoblasts. Among them were the mRNAs of PINCH-2, an important mediator of cell adhesion and motility, and MURF-3, a microtubule-stabilizing protein. By gain- and loss-of-function assays and gel shift experiments, we show that IMP-2 regulates the expression of PINCH-2 and MURF-3 proteins via direct binding to their mRNAs. Upregulation of PINCH-2 in IMP-2-depleted myoblasts is the key event responsible for their decreased motility. Our data reveal how the posttranscriptional regulation of gene expression by IMP-2 contributes to the control of adhesion structures and stable microtubules and demonstrate an important function for IMP-2 in cellular motility.


description_brief: Genes representing a co-expression network in atopic CD4 [GeneID=920] T lymphocyte responses.
systematic_name: M2526
exact_source: Tables 1, 2S
source_species_code: HS
GEO_id: GSE14908
contributor: Antony Bosco
contrib_organization: Telethon Kids Institute
description_full:
  Complex cellular functions within immunoinflammatory cascades are conducted by networks of interacting genes. In this study, we employed a network modeling approach to dissect and interpret global gene expression patterns in allergen-induced Th cell responses that underpin human atopic disease. We demonstrate that a subnet of interconnected genes enriched for Th2 and regulatory T cell-associated signatures plus many novel genes is hardwired into the atopic response and is a hallmark of atopy at the systems level. We show that activation of this subnet is stabilized via hyperconnected hub genes, the selective disruption of which can collapse the entire network in a comprehensive fashion. Finally, we investigated gene expression in different Th cell subsets and show that regulatory T cell- and Th2-associated signatures partition at different stages of Th memory cell differentiation. Moreover, we demonstrate the parallel presence of a core element of the Th2-associated gene signature in bystander naive cells, which can be reproduced by rIL-4. These findings indicate that network analysis provides significant additional insight into atopic mechanisms beyond that achievable with conventional microarray analyses, predicting functional interactions between novel genes and previously recognized members of the allergic cascade. This approach provides novel opportunities for design of therapeutic strategies that target entire networks of genes rather than individual effector molecules.


systematic_name: M2534
exact_source: Table 1S: sheet=hNMSC-signature; I 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 up-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: M2536
exact_source: Fig. 1B
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Proteins interacting with AIRE [GeneID=326], based on massspectroscopy analysis of co-immunoprecipitates in 293T cells (embryonic kidney).

description_full:
  Aire induces the expression of a battery of peripheral-tissue self-antigens (PTAs) in thymic stromal cells, promoting the clonal deletion of differentiating T cells that recognize them. Just how Aire targets and induces PTA transcripts remains largely undefined. Screening via Aire-targeted coimmunoprecipitation followed by mass spectrometry, and validating by multiple RNAi-mediated knockdown approaches, we identified a large set of proteins that associate with Aire. They fall into four major functional classes: nuclear transport, chromatin binding/structure, transcription and pre-mRNA processing. One set of Aire interactions centered on DNA protein kinase and a group of proteins it partners with to resolve DNA double-stranded breaks or promote transcriptional elongation. Another set of interactions was focused on the pre-mRNA splicing and maturation machinery, potentially explaining the markedly more effective processing of PTA transcripts in the presence of Aire. These findings suggest a model to explain Aire's widespread targeting and induction of weakly transcribed chromatin regions.


systematic_name: M2553
exact_source: Fig. 7S: R/S ratio > 1
source_species_code: HS
GEO_id: GSE635
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes distinguishing asparaginase resistant and sensitive B-lineage ALL; here - genes up-regulated in the drug resistant samples.

description_full:
[cell repeats an earlier one in this file: 214 characters]


systematic_name: M2565
exact_source: Fig. 11S: R/S > 1
source_species_code: HS
GEO_id: GSE635
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes distinguishing asparaginase resistant and sensitive ALL (B- and T-lineage ALL); here - genes up-regulated in the drug resistant samples.

description_full:
[cell repeats an earlier one in this file: 214 characters]


systematic_name: M2568
exact_source: Table 1S
source_species_code: MM
GEO_id: GSE2411
contributor: Jernej Godec
contrib_organization: Dana-Farber Cancer Institute
description_brief:
  Genes up-regulated in lung tissue upon LPS aspiration with mechanical ventilation (MV) compared to control (PBS aspiration without MV).

description_full:
  Mechanical ventilation (MV) with tidal volumes of 10-12 ml/kg is considered safe in the absence of acute lung injury (ALI). However, recent studies show that, when lung injury is already present, tidal volumes of this magnitude increase inflammation and injury in the lungs. We hypothesized that MV with tidal volumes of 10-ml/kg can also function as a cofactor in the initiation of ALI by modulating the transcriptional response to bacterial products. To test this hypothesis, we developed a mouse model in which MV did not independently cause inflammation or injury but augmented the inflammatory response to low-dose aspirated LPS and promoted development of ALI. We analyzed gene expression in lungs from 24 mice assigned to four different groups: control, MV only, intratracheal LPS only, and MV + LPS. There were twice as many differentially regulated genes in the MV + LPS group compared with the LPS-only group and 10 times as many differentially regulated genes compared with the MV-only group. For genes up-regulated by LPS treatment alone, the addition of MV further augmented expression. Cytokine concentrations in bronchoalveolar lavage fluid and tissue distribution of an intracellular protein, GADD45-gamma, correlated with mRNA levels. We conclude that MV with conventional tidal volumes enhanced the transcriptional response to LPS and promoted development of ALI.


description_brief: Invasiveness signature resulting from cancer cell/microenvironment interaction.
systematic_name: M2572
exact_source: Table 1
source_species_code: HS
GEO_id: GSE34481
contributor: Dimitris Anastassiou
contrib_organization: Columbia University
description_full:
  BACKGROUND: The biological mechanisms underlying cancer cell motility and invasiveness remain unclear, although it has been hypothesized that they involve some type of epithelial-mesenchymal transition (EMT).  METHODS: We used xenograft models of human cancer cells in immunocompromised mice, profiling the harvested tumors separately with species-specific probes and computationally analyzing the results.  RESULTS: Here we show that human cancer cells express in vivo a precise multi-cancer invasion-associated gene expression signature that prominently includes many EMT markers, among them the transcription factor Slug, fibronectin, and alpha-SMA. We found that human, but not mouse, cells express the signature and Slug is the only upregulated EMT-inducing transcription factor. The signature is also present in samples from many publicly available cancer gene expression datasets, suggesting that it is produced by the cancer cells themselves in multiple cancer types, including nonepithelial cancers such as neuroblastoma. Furthermore, we found that the presence of the signature in human xenografted cells was associated with a downregulation of adipocyte markers in the mouse tissue adjacent to the invasive tumor, suggesting that the signature is triggered by contextual microenvironmental interactions when the cancer cells encounter adipocytes, as previously reported.  CONCLUSIONS: The known, precise and consistent gene composition of this cancer mesenchymal transition signature, particularly when combined with simultaneous analysis of the adjacent microenvironment, provides unique opportunities for shedding light on the underlying mechanisms of cancer invasiveness as well as identifying potential diagnostic markers and targets for metastasis-inhibiting therapeutics.


description_brief: Genes up-regulated in B lymphocytes at 2 h after exprosure to 10 Gy dose of ionizing radiation.
systematic_name: M2585
exact_source: Table 1S: Current Study 2hr avg log2 fold change >= 0.58
source_species_code: HS
GEO_id: GSE26835
contributor: Itai Pashtan
contrib_organization: Dana-Farber Cancer Institute
description_full:
  Radiation exposure through environmental, medical, and occupational settings is increasingly common. While radiation has harmful effects, it has utility in many applications such as radiotherapy for cancer. To increase the efficacy of radiation treatment and minimize its risks, a better understanding of the individual differences in radiosensitivity and the molecular basis of radiation response is needed. Here, we integrated human genetic and functional genomic approaches to study the response of human cells to radiation. We measured radiation-induced changes in gene expression and cell death in B cells from normal individuals. We found extensive individual variation in gene expression and cellular responses. To understand the genetic basis of this variation, we mapped the DNA sequence variants that influence expression response to radiation. We also identified radiation-responsive genes that regulate cell death; silencing of these genes by small interfering RNA led to an increase in radiation-induced cell death in human B cells, colorectal and prostate cancer cells. Together these results uncovered DNA variants that contribute to radiosensitivity and identified genes that can be targeted to increase the sensitivity of tumors to radiation.


systematic_name: M2591
exact_source: Table 1S: FDR < 0.1 & mean > 1
source_species_code: HS
GEO_id: GSE12435
contributor: Itai Pashtan
contrib_organization: Dana-Farber Cancer Institute
description_brief:
  Genes significantly (FDR < 10%) up-regulated in IMR-90 cells (fibroblast) in response to direct irradiation.

description_full:
  Background: The existence of a radiation bystander effect, in which non-irradiated cells respond to signals from irradiated cells, is now well established. It raises concerns for the interpretation of risks arising from exposure to low doses of ionizing radiation. However, the regulatory mechanisms involved in the bystander response have not been well elucidated. To provide insight into the signaling pathways responding in bystanders, we have measured global gene expression four hours after bystander and direct alpha particle exposure of primary human lung fibroblasts. Results: Although common p53-regulated radiation response genes like CDKN1A were expressed at elevated levels in the directly exposed cultures, they showed little or no change in the bystanders. In contrast, genes regulated by NF_B, such as PTGS2 (cyclooxygenase-2), IL8 and BCL2A1, responded nearly identically in bystander and irradiated cells. This trend was substantiated by gene ontology and pathway analyses of the microarray data, which suggest that bystander cells mount a full NF_B response, but a muted or partial p53 response. In time-course analyses, quantitative real-time PCR measurements of CDKN1A showed the expected 4-hour peak of expression in irradiated but not bystander cells. In contrast, PTGS2, IL8 and BCL2A1 responded with two waves of expression in both bystander and directly irradiated cells, one peaking at half an hour and the other between four and six hours after irradiation. Conclusion: Two major transcriptional hubs that regulate the direct response to ionizing radiation are also implicated in regulation of the bystander response, but to dramatically different degrees. While activation of the p53 response pathway is minimal in bystander cells, the NF_B response is virtually identical in irradiated and bystander cells. This alteration in the balance of signaling is likely to lead to different outcomes in irradiated cells and their bystanders, perhaps leading to greater survival of bystanders and increased risk from any long-term damage they have sustained.


systematic_name: M2597
exact_source: Table 2S: FDR < 0.1
source_species_code: HS
GEO_id: GSE12435
contributor: Itai Pashtan
contrib_organization: Dana-Farber Cancer Institute
description_brief:
  Genes significantly (FDR < 10%) up-regulated in IMR-90 cells (fibroblast) in response to bystander irradiation.

description_full:
[cell repeats an earlier one in this file: 2077 characters]


description_brief: Genes displaying an ionizing radiation response in the human skin cell samples.
systematic_name: M2600
exact_source: Suppl. Data File: sheet 'SAM identified genes'
source_species_code: HS
GEO_id: GSE14466
contributor: Itai Pashtan
contrib_organization: Dana-Farber Cancer Institute
description_full:
  Although skin is usually exposed during human exposures to ionizing radiation, there have been no thorough examinations of the transcriptional response of skin fibroblasts and keratinocytes to radiation. The transcriptional response of quiescent primary fibroblasts and keratinocytes exposed to from 10 cGy to 5 Gy and collected 4 h after treatment was examined. RNA was isolated and examined by microarray analysis for changes in the levels of gene expression. Exposure to ionizing radiation altered the expression of 279 genes across both cell types. Changes in RNA expression could be arranged into three main categories: (1) changes in keratinocytes but not in fibroblasts, (2) changes in fibroblasts but not in keratinocytes, and (3) changes in both. All of these changes were primarily of p53 target genes. Similar radiation-induced changes were induced in immortalized fibroblasts or keratinocytes. In separate experiments, protein was collected and analyzed by Western blotting for expression of proteins observed in microarray experiments to be overexpressed at the mRNA level. Both Q-PCR and Western blot analysis experiments validated these transcription changes. Our results are consistent with changes in the expression of p53 target genes as indicating the magnitude of cell responses to ionizing radiation.


systematic_name: M2601
exact_source: Suppl. Data File: sheet 'SAM identified genes'
source_species_code: HS
GEO_id: GSE14466
contributor: Itai Pashtan
contrib_organization: Dana-Farber Cancer Institute
description_brief:
  Genes up-regulated in the human skin cells at 4 h after exprosure to 5 Gy dose of ionizing radiation.

description_full:
  Although skin is usually exposed during human exposures to ionizing radiation, there have been no thorough examinations of the transcriptional response of skin fibroblasts and keratinocytes to radiation. The transcriptional response of quiescent primary fibroblasts and keratinocytes exposed to from 10 cGy to 5 Gy and collected 4 h after treatment was examined. RNA was isolated and examined by microarray analysis for changes in the levels of gene expression. Exposure to ionizing radiation altered the expression of 279 genes across both cell types. Changes in RNA expression could be arranged into three main categories: (1) changes in keratinocytes but not in fibroblasts, (2) changes in fibroblasts but not in keratinocytes, and (3) changes in both. All of these changes were primarily of p53 target genes. Similar radiation-induced changes were induced in immortalized fibroblasts or keratinocytes. In separate experiments, protein was collected and analyzed by Western blotting for expression of proteins observed in microarray experiments to be overexpressed at the mRNA level. Both Q-PCR and Western blot analysis experiments validated these transcription changes. Our results are consistent with changes in the expression of p53 target genes as indicating the magnitude of cell responses to ionizing radiation.


systematic_name: M2604
exact_source: Table 9S: 'Target' sheet: P_2h =< 0.05
source_species_code: HS
GEO_id: GSE7469, GSE7075
contributor: Itai Pashtan
contrib_organization: Dana-Farber Cancer Institute
description_brief:
  Cell cycle genes significantly (p =< 0.05) changed in fibroblast cells at 2 h after exposure to ionizing radiation.

description_full:
  The changes in global gene expression in response to DNA damage may derive from either direct induction or repression by transcriptional regulation or indirectly by synchronization of cells to specific cell cycle phases, such as G1 or G2. We developed a model that successfully estimated the expression levels of >400 cell cycle-regulated genes in normal human fibroblasts based on the proportions of cells in each phase of the cell cycle. By isolating effects on the gene expression associated with the cell cycle phase redistribution after genotoxin treatment, the direct transcriptional target genes were distinguished from genes for which expression changed secondary to cell synchronization. Application of this model to ionizing radiation (IR)-treated normal human fibroblasts identified 150 of 406 cycle-regulated genes as putative direct transcriptional targets of IR-induced DNA damage. Changes in expression of these genes after IR treatment derived from both direct transcriptional regulation and cell cycle synchronization.


systematic_name: M2606
exact_source: Table 9S: 'Target' sheet: P_6h =< 0.05
source_species_code: HS
GEO_id: GSE7469, GSE7075
contributor: Itai Pashtan
contrib_organization: Dana-Farber Cancer Institute
description_brief:
  Cell cycle genes significantly (p =< 0.05) changed in fibroblast cells at 6 h after exposure to ionizing radiation.

description_full:
  The changes in global gene expression in response to DNA damage may derive from either direct induction or repression by transcriptional regulation or indirectly by synchronization of cells to specific cell cycle phases, such as G1 or G2. We developed a model that successfully estimated the expression levels of >400 cell cycle-regulated genes in normal human fibroblasts based on the proportions of cells in each phase of the cell cycle. By isolating effects on the gene expression associated with the cell cycle phase redistribution after genotoxin treatment, the direct transcriptional target genes were distinguished from genes for which expression changed secondary to cell synchronization. Application of this model to ionizing radiation (IR)-treated normal human fibroblasts identified 150 of 406 cycle-regulated genes as putative direct transcriptional targets of IR-induced DNA damage. Changes in expression of these genes after IR treatment derived from both direct transcriptional regulation and cell cycle synchronization.


systematic_name: M2608
exact_source: Table 9S: 'Target' sheet: P_24h =< 0.05
source_species_code: HS
GEO_id: GSE7469, GSE7075
contributor: Itai Pashtan
contrib_organization: Dana-Farber Cancer Institute
description_brief:
  Cell cycle genes significantly (p =< 0.05) changed in fibroblast cells at 24 h after exposure to ionizing radiation.

description_full:
  The changes in global gene expression in response to DNA damage may derive from either direct induction or repression by transcriptional regulation or indirectly by synchronization of cells to specific cell cycle phases, such as G1 or G2. We developed a model that successfully estimated the expression levels of >400 cell cycle-regulated genes in normal human fibroblasts based on the proportions of cells in each phase of the cell cycle. By isolating effects on the gene expression associated with the cell cycle phase redistribution after genotoxin treatment, the direct transcriptional target genes were distinguished from genes for which expression changed secondary to cell synchronization. Application of this model to ionizing radiation (IR)-treated normal human fibroblasts identified 150 of 406 cycle-regulated genes as putative direct transcriptional targets of IR-induced DNA damage. Changes in expression of these genes after IR treatment derived from both direct transcriptional regulation and cell cycle synchronization.


systematic_name: M2620
exact_source: Table 2S: Interval repressed
source_species_code: HS
GEO_id: GSE27629
contributor: Yaara Zwang
contrib_organization: Broad Institute
description_brief:
  Genes repressed in the time interval between two pulses of EGF [GeneID =1950] in 184A1 cells (mammary epithelium).

description_full:
[cell repeats an earlier one in this file: 1034 characters]


description_brief: Genes up-regulated in type 1 (soleus) vs type 2B (EDL) myofibers.
systematic_name: M3001
exact_source: Dataset 1S: Fig4: MyHC1 > MyHC 2B
source_species_code: MM
GEO_id: GSE23244
contributor: Emmanuelle Fouilloux-Meugnier
contrib_organization: CarMeN Laboratory
description_full:
  BACKGROUND: Skeletal muscle is a complex, versatile tissue composed of a variety of functionally diverse fiber types. Although the biochemical, structural and functional properties of myofibers have been the subject of intense investigation for the last decades, understanding molecular processes regulating fiber type diversity is still complicated by the heterogeneity of cell types present in the whole muscle organ. METHODOLOGY/PRINCIPAL FINDINGS: We have produced a first catalogue of genes expressed in mouse slow-oxidative (type 1) and fast-glycolytic (type 2B) fibers through transcriptome analysis at the single fiber level (microgenomics). Individual fibers were obtained from murine soleus and EDL muscles and initially classified by myosin heavy chain isoform content. Gene expression profiling on high density DNA oligonucleotide microarrays showed that both qualitative and quantitative improvements were achieved, compared to results with standard muscle homogenate. First, myofiber profiles were virtually free from non-muscle transcriptional activity. Second, thousands of muscle-specific genes were identified, leading to a better definition of gene signatures in the two fiber types as well as the detection of metabolic and signaling pathways that are differentially activated in specific fiber types. Several regulatory proteins showed preferential expression in slow myofibers. Discriminant analysis revealed novel genes that could be useful for fiber type functional classification. CONCLUSIONS/SIGNIFICANCE: As gene expression analyses at the single fiber level significantly increased the resolution power, this innovative approach would allow a better understanding of the adaptive transcriptomic transitions occurring in myofibers under physiological and pathological conditions.


systematic_name: M3010
exact_source: Table 1S
source_species_code: HS
GEO_id: GSE33464
contributor: Michael Hecker
contrib_organization: Steinbeis Foundation
description_brief:
  Genes transcriptionally modulated in the blood of multiple sclerosis patients in response to subcutaneous treatment with recombinant IFNB1 [GeneID = 3456].

description_full:
  Therapy with interferon-beta (IFN-beta) is a mainstay in the management of relapsing-remitting multiple sclerosis (MS), with proven long-term effectiveness and safety. Much has been learned about the molecular mechanisms of action of IFN-beta in the past years. Previous studies described more than a hundred genes to be modulated in expression in blood cells in response to the therapy. However, for many of these genes, the precise temporal expression pattern and the therapeutic relevance are unclear. We used Affymetrix microarrays to investigate in more detail the gene expression changes in peripheral blood mononuclear cells from MS patients receiving subcutaneous IFN-beta-1a. The blood samples were obtained longitudinally at five different time points up to 2 years after the start of therapy, and the patients were clinically followed up for 5 years. We examined the functions of the genes that were upregulated or downregulated at the transcript level after short-term or long-term treatment. Moreover, we analyzed their mutual interactions and their regulation by transcription factors. Compared to pretreatment levels, 96 genes were identified as highly differentially expressed, many of them already after the first IFN-beta injection. The interactions between these genes form a large network with multiple feedback loops, indicating the complex crosstalk between innate and adaptive immune responses during therapy. We discuss the genes and biological processes that might be important to reduce disease activity by attenuating the proliferation of autoreactive immune cells and their migration into the central nervous system. In summary, we present novel insights that extend the current knowledge on the early and late pharmacodynamic effects of IFN-beta therapy and describe gene expression differences between the individual patients that reflect clinical heterogeneity.


systematic_name: M3015
exact_source: Table 2: S2N Score > 0
source_species_code: HS
GEO_id: GSE6569
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes whose expression positively correlated with sensitivity of breast cancer cell lines to dasatinib [PubChem=3062316].

description_full:
  Dasatinib is a multitargeted kinase inhibitor that was recently approved for the treatment of chronic myelogenous leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia with resistance or intolerance to prior therapy. It is also in clinical trials for treating patients with solid tumors. The identification of molecular markers predictive of response to dasatinib could assist in clinical development by selecting patients most likely to derive clinical benefit. Using baseline gene expression profiling of a panel of 23 breast cancer cell lines, we identified genomic signatures highly correlated with in vitro sensitivity to dasatinib. The ability of these signatures to predict dasatinib sensitivity was further confirmed and validated in independent test cell lines. A six-gene model was used to correctly predict dasatinib sensitivity in 11 out of 12 (92%) additional breast and 19 out of 23 (83%) lung cancer cell lines. Quantitative real-time PCR and immunohistochemical assays further confirmed the differential expression pattern of selected markers. Finally, these gene signatures were observed in a subset of primary breast, lung, and ovarian tumors suggesting potential utility in patient selection. The subset of breast cancer patients expressing the dasatinib-sensitive signature includes a distinct clinical and molecular subgroup: the so-called triple negative (i.e., estrogen receptor-negative, progesterone receptor-negative, and HER2-negative) or basal breast cancer subtype. This patient population has a poor prognosis and currently has few effective treatment options. Our results implicate that dasatinib may represent a valuable treatment option in this difficult-to-treat population. To test this hypothesis, clinical studies are now under way to determine the activity of dasatinib in these patients.


description_brief: Feeder Pathways for Glycolysis
systematic_name: M3061
external_details_URL: http://cgap.nci.nih.gov/Pathways/BioCarta/feederPathway
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  The glycolytic pathway begins with the simple sugar glucose and leads to pyruvate and eventually the Kreb's cycle. Dietary carbohydrates include a variety of sugars that are funneled into glycolysis to supply energy, including other monosaccharides, disaccharides, and polysaccharides like starch. Fructose is an abundant monosaccharide in fruit, and is also found along with glucose in the common disaccharide sucrose. Fructose enters glycolysis by different pathways in the liver and muscle. In muscle, fructose is a substrate of hexokinase, like glucose, and enters the pathway directly as fructose 6-phosphate. In liver, hexokinase is present in very low levels and fructose passes through a more complex pathway. Fructose is first phosphorylated to form fructose 1-phosphate, which is then split into glyceraldehyde and dihydroxyacetone phosphate to enter glycolysis as glyceraldehyde 3-phosphate. The sugar mannose also enters glycolysis at this point, first being converted to mannose 6-phosphate that is then isomerized to produce fructose 6-phosphate. Lactose is a disaccharide found in milk, and is composed of glucose and galactose. Galactose only differs from glucose in its stereochemistry at one position, but must be converted to glucose to enter glycolysis. The first step is phosphorylation to produce galactose 1-phosphate. Then, a UDP nucleotide group is exchanged between galactose 1-phosphate and UDP-glucose. The result of this reaction is the production of glucose 1-phosphate and UDP-galactose. UDP-galactose is enzymatically converted to UDP-glucose, which is then converted to glucose 1-phosphate in the next round of this loop. Glucose 1-phosphate is isomerized to produce glucose 6-phosphate, part of the glycolytic pathway. The complex polysaccharides starch and glycogen differ in their source and in their structure (they have different bonds between each individual sugar unit) but they are both composed entirely of glucose subunits polymerized together. Starch is found in plants and is digested to release individual glucose molecules in the digestive tract that are absorbed and transported to the tissues. Glycogen is the main storage carbohydrate in animals, and is mobilized by liver and muscle to release glucose when hormones like adrenalin indicate that a burst of energy is required. When glucose is mobilized from glycogen, it is released as glucose 1-phosphate. In muscle, there is no enzyme present that converts glucose 1-phosphate to glucose, so the only fate of this glucose 1-phosphate is to enter glycolysis after being converted glucose 6-phosphate. Deficiencies in the enzymes that direct sugars into glycolysis have distinct clinical effects in some cases. Lactose intolerance is very common in many parts of the world, and is caused in adults by a reduction in the enzyme that breaks lactose down into galactose and glucose in the intestine. Some individuals suffer from the genetic condition galactosemia, in which they lack the enzymes to convert galactose to glucose. The accumulation of galactose leads to mental retardation, liver damage and cataracts unless dietary intake of galactose is controlled.


description_brief: Proteasome Complex
systematic_name: M194
external_details_URL: http://cgap.nci.nih.gov/Pathways/BioCarta/proteasomePathway
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Attachment of the ubiquitin peptide to proteins targets them for proteolytic degradation by a complex cellular structure, the proteasome. The regulated proteolysis of proteins by proteasomes removes denatured, damaged or improperly translated proteins from cells and regulates the level of proteins like cyclins or some transcription factors. E1 and E2 enzymes prepare ubiquitin chains that are then attached to proteins by the E3 enzyme. The sequence of ubiquitin and the basic structure and function of the proteasome are highly conserved. The core proteasome in man (20S proteasome) consists of four rings each with 14 subunits stacked on top of each other that are responsible for the proteolytic activity of the proteasome. The PA700 regulatory complex is stacked on the ends of the cylindrical core to form a 26S proteasome. Proteins that are tagged with ubiquitin are recognized and bound by the regulatory subunits, then unfolded in an ATP-dependent manner, and inserted into the core particle, where proteases degrade the protein, releasing small peptides and releasing the ubiquitin intact. The PA28 regulatory complex is alternative regulatory complex that appears to play a role in antigen processing for presentation of peptides to immune cells in the MHC I complex.


description_brief: The Citric Acid Cycle
systematic_name: M6831
external_details_URL: http://cgap.nci.nih.gov/Pathways/BioCarta/krebPathway
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  The Krebs cycle, also called the citric acid cycle, is a fundamental metabolic pathway involving eight enzymes essential for energy production through aerobic respiration, and, like glycolysis, arose early in evolution. This pathway is also an important source of biosynthetic building blocks used in gluconeogenesis, amino acid biosynthesis, and fatty acid biosynthesis. The Krebs cycle takes place in mitochondria where it oxidizes acetyl-CoA, releasing carbon dioxide and extracting energy primarily as the reduced high-energy electron carriers NADH and FADH2. NADH and FADH2 transfer chemical energy from metabolic intermediates to the electron transport chain to create a different form of energy, a gradient of protons across the inner mitochondrial membrane. The energy of the proton gradient in turn drives synthesis of the high-energy phosphate bonds in ATP, the common energy currency of the cell used to drive a huge variety of reactions and processes. An acetyl-CoA molecule (2 carbons) enters the cycle when citrate synthase condenses it with oxaloacetate (4 carbons) to create citrate (6 carbons). One source of the acetyl-CoA that enters the Krebs cycle is the conversion of pyruvate from glycolysis to acetyl-CoA by pyruvate dehydrogenase. Acetyl-CoA is a key metabolic junction, derived not only from glycolysis but also from the oxidation of fatty acids. As the cycle proceeds, the Krebs cycle intermediates are oxidized, transferring their energy to create reduced NADH and FADH2. The oxidation of the metabolic intermediates of the pathway also releases two carbon dioxide molecules for each acetyl-CoA that enters the cycle, leaving the net carbons the same with each turn of the cycle. This carbon dioxide, along with more released by pyruvate dehydrogenase, is the source of CO2 released into the atmosphere when you breathe. The Krebs cycle, like other metabolic pathways, is tightly regulated to efficiently meet the needs of the cell and the organis. The irreversible synthesis of acetyl-CoA from pyruvate by pyruvate dehydrogenase is one important regulatory step, and is inhibited by high concentrations of ATP that indicate abundant energy. Citrate synthase, alpha-ketoglutarate dehydrogenase and isocitrate dehydrogenase are all key regulatory steps in the cycle and are each inhibited by abundant energy in the cell, indicated through high concentrations of ATP or NADH. The activity of the Krebs cycle is closely linked to the availability of oxygen, although none of the steps in the pathway directly use oxygen. Oxygen is required for the electron transport chain to function, which recycles NADH back to NAD+ and FADH2 back to FADH, providing NAD+ and ADH required by enzymes in the Krebs cycle. If the oxygen supply to a muscle cell or a yeast cell is low, NAD+ and FADH levels fall, the Krebs cycle cannot proceed forward, and the cell must resort to fermentation to continue making ATP. Some Krebs cycle enzymes require non-protein cofactors for activity, such as thiamine, vitamin B1. Insufficient quantities of this vitamin in the diet leads to decreased activity of pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase, and a decrease in the ability of the Krebs cycle to meet metabolic demands, causing the disease beriberi. Although the elucidation of the Krebs cycle remains one of the landmarks of biochemistry, aspects of the Krebs cycle and its enzymes are still actively researched in the modern proteomic era.


description_brief: Actions of Nitric Oxide in the Heart
systematic_name: M4383
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_no1Pathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Nitric oxide (NO) has a number of important physiological actions in the cardiovascular system. In the heart, NO plays role in keeping the vessels patent via vasodilation and prevention of platelet aggregation. It also plays an important role in regulating the force and rate of contraction. In vivo NO is released by shear stress of ligands that increase intracellular Ca2+ in endothelial cells. The increase intracellular Ca2+ activates nitric oxide synthase III (NOSIII) by promoting the binding of Ca/Calmodulin to the enzyme. NOSIII, which is resident in the Golgi complex, is transported together with caveolin-1 to the caveolae at the plasma membrane via vesicles. Shear stress signals via a potassium channel and the cytoskeleton, which results in tyrosine phosphorylation of specific proteins, activation of phosphatidylinositol 3-kinase, and subsequently in activation of Akt kinase. Akt activation by shear stress but also by VEGF activates NOSIII by serine phosphorylation, which increases the affinity of NOSIII for calmodulin. After agonist binding at the plasma membrane, NOSIII-activating receptors translocate to caveolae. VEGF receptor signals via its tyrosine kinase domain. Furthermore, agonist receptors activate calcium channels of the endoplasmic reticulum (ER) via phospholipase C and inositol 1,4,5-trisphosphate. This calcium flux induces binding of calmodulin to NOSIII, whereas the NOSIII-caveolin-1 interaction is disrupted. At the same time, NOSIII is translocated into the cytosol. On binding of calmodulin, NOSIII generates NO, is enhanced by the interaction with Hsp90. Once activated, NOSIII catabolizes L-arginine to NO, which diffuses out of the cell. NO stimulates guanylate (G-) cyclase and increases cGMP levels. cGMP activates cGMP-dependent protein kinase (PKG), cGMP-inhibited phosphodiesterase (PDEIII), and cGMP-stimulated phosphodiesterase (PDEII). PKG may reduce the force and rate of contraction, possibly by phosphorylating troponin I or by phosphorylating phospholamban. PDEIII is inhibited by the increases in cGMP brought about by NO. This may result in an increase in cAMP and cAMP-dependent protein kinase (PKA). PKA in turn activates Ca2+ channels, countering the effects of PKG. In contrast, cGMP may stimulate PDEII, reduce cAMP levels and PKA activity, and thereby reduce Ca2+ channel activity. Ach, acetylcholine. CAT-1, cationic amino acid transporter.


description_brief: Activation of Csk by cAMP-dependent Protein Kinase Inhibits Signaling through the T Cell Receptor
systematic_name: M6327
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_cskPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Interaction of T cell receptor with specific antigen in the context of MHC II activates a signal transduction pathway that leads to T cell activation. In the T cell receptor signaling pathway, the src family kinases Lck and Fyn are activated to phosphorylate proteins in the T cell receptor complex which recruit and activate the ZAP70 kinase. The activation of ZAP70 phosphorylates downstream targets that activate MAP kinase pathways and cause T cell activation. The CD45 phosphorylase also plays a role in T cell receptor signaling, dephosphorylated Lck and Fyn to activate them. Other factors modulate T cell receptor activation. Csk (COOH-terminal Srk kinase) phosphorylates Lck and deactivates it, opposing the action of CD45. The phosphorylation of Lck by Csk inhibits T cell receptor signaling and inhibits T cell activation. Csk activity is regulated in T cells by PKA, the cAMP-dependent protein kinase activated by the second messenger cAMP. The activity of Csk also appears to depend on other factors such as CBP, which recruits Csk to the plasma membrane in lipid rafts where other signaling factors such the T cell receptor complex are localized. CBP also directly activates Csk.


description_brief: Activation of Src by Protein-tyrosine phosphatase alpha
systematic_name: M10994
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_srcRPTPPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Progression through the cell cycle is accompanied by activation of the proto-oncogene c-Src, a protein tyrosine kinase. Overexpression of Src leads to tyrosine phosphorylation of multiple protein substrates and cellular transformation. During interphase the Src protein folds back upon itself to stay in the inactive state, with a phophotyrosine residue in one domain at Tyrosine 529 bound by an SH2 domain in the same protein. Activation of c-Src involves protein-tyrosine phosphatase alpha (PTP-alpha, or RPTP-alpha), a transmembrane protein with a cytoplasmic phosphatase domain. A variety of evidence has indicated that PTP-alpha dephosphorylates c-Src at Tyr529, allowing Src to open up and become activated, and that this activation occurs in association with mitosis. To activate Src, PTP-alpha must first open up the folded Src through binding itself to the phosphorylated Src domain, a process blocked by binding of Grb-2 to PTP-alpha at phosphorylated Tyr789. PTP-alpha phosphorylated at Tyr789 also binds to the Src SH2 domain, causing the Src structure to open at Src Tyr529 to become available for dephosphorylation. During mitosis the mitotic kinase Cdc-2 phosphorylates Src, along with other cellular substrates, and in so doing makes Src more prone PTP-alpha dephosphorylation and activation. The activity of PTP-alpha toward Src is also regulated by phosphorylation of PTP-alpha by protein kinase C at serines 180 and 204, releasing the inhibition of PTP-alpha by Grb-2. In the normal cell cycle, Src activity is down-regulated after cell division through dephosphorylation by protein phosphatases and phosphorylation by Csk (C-terminal src kinase) and PTP-alpha dephoshorylation returns the cycle to its interphase condition. The regulation of Src activity during mitosis demonstrates how protein phosphorylation can shifts the delicate equilibrium of molecular interactions and cellular responses.


description_brief: Acute Myocardial Infarction
systematic_name: M15394
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_amiPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Myocardial infraction (MI)is the condition of irreversible necrosis of the heart muscle that results from prolonged ischemia. Nearly 1.5 million people in US sustain an MI each year, and this event proves fatal in approximately one third of patients. Approximately 90% of MI result from formation of an acute thrombus that obstructs an atherosclerotic coronary artery. The thrombus transforms a region of plaque narrowing to one of complete vessel occlusion (top right in pink). The responsible thrombus appears to be generated by interactions between the atherosclerotic plaque, the coronary endothelium, circulating platelets, and dynamic vasomotor tone of the vessel wall, all of which overwhelm natural protective mechanisms. The endogenous protective mechanisms against thrombosis include: 1. Inactivation of thrombin by antithrombin III (ATIII), the effectiveness of which is enhanced by binding of ATIII to heparin sulafate. The antithrombin binding region of commercial heparin consists of sulfated disaccharide units (bottom panel). 2. Inactivation of clotting factors Va and VIIIa by activated protein C (protein C*), an action that is enhanced by protein S. Protein C is activated by the thrombomodulin (TM)-thrombin complex. 3. Inactivation of factor VII/tissue factor complex by tissue factor pathway inhibitor (TFPI). Coumarin drugs (Warfarin) blocks the g-carboxylation of Glu residues in prothrombin and factors VII, IX and X which results in incomplete molecules that are biologically inactive in coagulation (left panel). 4. Lysis of fibrin clots by tissue plasminogen activator (tPA). 5. Inhibition of platelet activation by prostacyclin and EDRF-NO. Platelets adhere to exposed collagen and are activated at the site of endothelial damage in the blood vessel. Activated platelets release adenosine diphosphate (ADP), serotonin (5-HT), and thromboxane A2 (TXA2), which activate additional platelets. Binding of thrombin further activates the platelets. Three adjoining platelets are shown in the process of viscous metamorphosis (top right). Increased cellular Ca2+ facilitates binding of fibrinogen. If the intraluminal thrombus at the site of plaque disruption totally occludes the vessel, blood flow beyond the obstruction will cease, prolonged ischemia will occur and MI (usually Q-wave MI) will likely result.


description_brief: ADP-Ribosylation Factor
systematic_name: M2482
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_arapPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  ADP-ribosylation factors (ARFs) are 20-kDa guanine nucleotide-binding proteins, members of the Ras GTPase superfamily that were initially recognized and purified because of their ability to stimulate the ADP-ribosyltransferase activity of the cholera toxin A subunit. We now know that they are critical components of several different vesicular trafficking pathways in all eukaryotic cells and activators of specific phospholipase Ds (PLDs) (reviewed in Refs. 13). ARF interacts with many proteins and other molecules that regulate its state of activation or are involved in its intracellular function. Arf proteins cycle between GDP-bound, inactive and GTP-bound, active forms, and the cycling is regulated by specific GEPs and GAPs. Members of the Arf GEP family can be grouped into two major subfamilies on the basis of their sequence similarities and functional differences. The high-molecular-weight Arf GEP subfamily includes yeast Sec7, Gea1, and Gea2, and mammalian BIG1/p200, BIG2, and GBF1, which all consist of 1,400 2,000 amino acid residues. Many Arf GAPs are multidomain proteins and have been found to interact with multiple signaling molecules. For instance, ASAP1 has a PH domain, ankyrin (ANK) repeats, proline-rich and Src-homology (SH) 3 domains and has been shown to bind PI(4,5)P2, Src, and Crk. PAPa/PAG3, with a similar domain structure, binds phosphoinositides, Src, Pyk, and paxillin. The GITs bind bARK, paxillin and the Rac/Cdc42 exchange factor PIX (also known as Cool). ASAP-related proteins, ARAP1, 2 and 3 have Arf GAP, Rho GAP,Ankyrin repeat, Ras-associating (RA), and five PH domains, and therefore have the potential of integrating four signaling pathways.


description_brief: Agrin in Postsynaptic Differentiation
systematic_name: M6220
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_agrPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  The heparan sulphate proteoglycan agrin is well known as the key assembly factor of postsynaptic differentiation at the neuromuscular junction (NMJ), but recent data suggest it also plays a direct role in the organization of the cytoskeleton in the skeletal muscle. Signaling through muscle-specific proteins such as muscle specific kinase (MuSK) and or acetylcholine receptor (AchRs)/rapsyn, agrin can activate ubiquitously expressed Rac, Cdc42, and p21-activated kinase (PAK) that are involved in actin polymerization. Agrin also engages signaling pathways of several potent oncogenes (i.e., SFK, ErbB receptors, and cortactin).


description_brief: AKAP95 role in mitosis and chromosome dynamics
systematic_name: M5731
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_akap95Pathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  The chromatin packaging of the genome is dynamic, changing with the cell cycle and with transcriptional regulation. During mitosis, chromatin is condensed for segregation of chromosomes, while for transcription chromatin is more open. The nuclear matrix, or scaffold, is a protein network in the nucleus providing structure and regulating chromatin condensation. Regulated interactions of matrix proteins with each other, DNA and other factors in different phases of the cell cycle alter the structure and function of chromatin. AKAP95 (A-kinase anchoring protein) is a nuclear matrix associated protein that also binds DNA and different proteins during different phases of the cell cycle. The interaction of AKAP95 with DNA and proteins alters the condensation and transcription of chromatin. A specific domain of AKAP95 regulates its interaction with the nuclear matrix and another regulates its association with DNA. One key protein that AKAP95 interacts with is the cAMP-dependent protein kinase, PKA. AKAP95 binds to PKA through a PKA RII regulatory subunit, an interaction that requires PKA phosphorylation by Cdk1. PKA activity and cAMP are reduced during entry into mitosis, but PKA recruited by AKAP95 to condensed chromosomes is essential to maintain the condensed state. Another protein recruited by AKAP95 is Eg7, a 150 kD protein recruited during mitotic chromatin condensation. Eg7 is a part of a multiprotein condensin complex, recruiting another key component of mitotic chromatin condensation. Modification of the core histones through phosphorylation regulates chromatin condensation. Histone H3 interacts with the condensin complex, and is phosphorylated during mitosis. Histone H3 phosphorylation by Aurora-2 induces chromatin condensation, and dephosphorylation by PP1 promotes chromatin decondensation for reentry into interphase. AKAP95 may play a role during the regulation of chromatin structure for transcription during interphase as well. The interaction of AKAP95 with the p68 RNA helicase recruits this enzyme to the nuclear matrix during interphase. Other nuclear RNA helicases interact with transcription factors and cofactors, suggesting that the p68 RNA helicase also may regulate interactions of transcription complexes.


description_brief: AKT Signaling Pathway
systematic_name: M15258
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_aktPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Many cell-surface receptors induce production of second messengers like PIP3, phosphatidylinositol 3,4,5-trisphosphate, that convey signals to the cytoplasm from the cell surface. PIP3 signals activates the kinase PDK1, 3-phosphoinositide-dependent protein kinase-1, which in turn activates the kinase AKT, also known as protein kinase B. Proteins phosphorylated by activated AKT promote cell survival. Phosphorylation of Ikappa-B kinase leads to activation of the transcription factor NF-kB to oppose apoptosis. Bad is a protein in the Bcl-2 gene family that opposes Bcl-2 to induce apoptosis. Phosphorylation of Bad by AKT blocks anti-apoptotic activity to promote cell survival. Similarly, phosphorylation of the protease caspase 9 or forkhead transcription factors by AKT block the induction of apoptosis by these factors. AKT promotes cell survival and opposes apoptosis by a variety of routes.


description_brief: ALK in cardiac myocytes
systematic_name: M17400
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_alkPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Heart formation is cued by a combination of positive and negative signals from surrounding tissues. Inhibitory signals that block heart formation in anterior paraxial mesoderm include Wnt family members expressed in dorsal neural tube and anti-BMPs expressed in the axial tissues (i.e., noggin in the notochord). Wnt signalling pathway, which is essential for setting up the entire body pattern during embryonic development involves glycogen synthase kinase-3 (GSK3). In the absence of Wnt signaling, GSK3 is active and phosphorylates b-catenin resulting in its degradation by ubiquitin-mediated proteolysis. Activation of Wnt signaling inhibits GSK3, thereby preventing phosphorylation of b-catenin, which is then able to move to the nucleus. There it associates with members of the LEF-1/TCF family of transcription factors, which activate the transcription of genes like cyclin-D1, myc, and MMPs. The Wnt signaling pathway is blocked by a family of secreted proteins such as crescent and Dkk-1 sufficient for induction of heart formation in posterior mesoderm. BMP signaling can also be blocked by the BMP antagonists noggin and chordin, which are secreted from the notochord and cooperate with Wnts to prevent cardiogenesis. Receptors for BMPs, members of the transforming growth factor-beta (TGFb) superfamily, are persistently expressed during cardiac development, yet mice lacking type II or type IA BMP receptors die at gastrulation and cannot be used to assess potential later roles in creation of the heart. Activin receptor-like kinase 3 (ALK3) is specifically required at mid-gestation for normal development of the trabeculae, compact myocardium, interventricular septum, and endocardial cushion. Cardiac muscle lacking ALK3 is specifically deficient in expressing TGFb2, an established paracrine mediator of cushion morphogenesis. In humans, congenital heart defects occur with a prevalence of at least 1% in newborns, and are even more common in death before term. Most frequent are defects in septation and the cardiac valves, and few single gene etiologies are known. The invariable defects in myocardium and AV cushion resulting from congenital deletion of ALK3 provide strong support for its assessment as a candidate gene in human congenital heart disease.


description_brief: Angiotensin II mediated activation of JNK Pathway via Pyk2 dependent signaling
systematic_name: M14899
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_at1rPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Ang II binding to AT1-R triggers the activation of Ca2+ signaling and PKC. The signal is then transmitted to the Pyk2 and further to the small G protein Rac1 but not Cdc42, although the direct activation of Rac1 by Pyk2 is not proved in this study. In turn, Rac1 activates a small G protein-activated kinase whose identity is still controversial, but one of which has been suggested to be PAK1. Finally, the JNK cascade, including MEKK1, SEK1, and JNK, is activated, causing induction of c-Jun gene via binding of ATF2 and c-Jun heterodimer to the junTRE2 site. Ang II is closely involved in the cardiac remodeling by stimulating synthesis of extracellular matrix proteins. It was recently found that expression of fibronectin by Ang II is transcriptionally regulated by AP-1 complex in cardiac fibroblasts. Collagenase gene containg AP-1 sites is also regulated by AP-1 components including c-Jun. AP-1 activity is also enhanced in Ang II-induced cardiac hypertrophy. Expression of ANF is regulated by AP-1 components.


description_brief: Angiotensin-converting enzyme 2 regulates heart function
systematic_name: M12950
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_ace2Pathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Cardiovascular diseases are predicted to be the most common cause of death worldwide by 2020. The major regulator of blood pressure homeostasis is the renin-angiotensis system. Angiotensinogen is digested by renin to produce angiotensin I (AGT I). AGT I is an inactive 10 amino-acid peptide that is further degraded to produce angiotensin II by the agiotensin-converting enzyme (ACE). Angiotensis II is the master regulator of blood pressure increase acting on the heart, kidneys and blood vessels. Angiotensin II causes direct constriction of the resistance vessels and stimulation of the adrenal cortex to increase blood volume and sodium absorption. In 2000, Tipnis et al., discovered ACE 2 a second carboxypeptidase that digests angiotensin. ACE is a di-peptidase, cleaving off 2 peptides from the c-terminal end of angiotensin. ACE 2 only cleaves 1 amino acid to produce angiotensin 1-9 (AGT 1-9) which has no identified function at this time. AGT 1-9 is not converted to angiotensin II but further degraded by ACE to AGT 1-7, a vasodilator. It would appear that ACE 2 inhibits the formation of angiotensin and reduces blood pressure increases. Crackower et al determined that ace2 -/- mice suffered significant heart defects at 6 months. Further deletion of ACE resulted in restored cardiac functions.


description_brief: Antigen Dependent B Cell Activation
systematic_name: M7298
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_asbcellPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  A key part of the immune system is the production of immunoglobulins (antibodies) by B cells to bind and inactivate specific foreign antigens. The body produces B cells with a wide range of antigen specificities in the immunoglobulin B cell receptor, one antigen specificity per cell. When the B cell receptor immunoglobulin binds antigen, that cell is activated to proliferate and create plasma cells secreting immunoglobulins to bind that specific antigen. B cell activation also creates memory cells with the same antigen specificity that do not actively secrete immunoglobulin but provide for rapid future immune responses to the same antigen. B cells are not activated by antigen on their own, but require interaction with helper CD4+ T cells to become activated and proliferate. The B cell first expresses immunoglobulin on the cell surface as the B cell receptor. If the B cell receptor immunoglobulin binds specific antigen, then the cell internalizes the antigen and presents it to T cells in MHC II, where it is recognized by the T cell receptor. In addition to the interaction between the T cell receptor and the B cell MHC-antigen, T cell interaction with the B cell involves additional positive and negative regulatory signals. CD40 interaction with CD40L and CD28 interaction with CD80 provide positive costimulatory signals that stimulate B cell activation and proliferation. T cell receptor activation induces expression of molecules like the CD40 ligand that modulate the B cell-T cell interaction. The CD40-CD40L interaction induces cytokine production and expression of other genes and alters the fate of the B cell involved in the interaction. If the interaction between CD40 and CD40L is prolonged, the B cell can be induced to become a memory cell rather than a plasma cell. Fas ligand binding to Fas between B and T cells may negatively modulate B cell activation, inducing apoptosis that limits B cell proliferation and activation. Cytokines like IL-2, IL-4 and IL-10 also play an important role in B cell activation.


description_brief: Apoptotic DNA fragmentation and tissue homeostasis
systematic_name: M7239
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_DNAfragmentPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Apoptotic cell death can be triggered by many different cellular stimuli, resulting in activation of apoptotic signaling pathways including caspases and mitochondria. A cellular response that is characteristic of apoptosis is fragmentation of the nuclear genome to create a nucleosomal ladder. This activity is conducted by multiple nucleases activated by apoptotic signaling pathways. One nuclease involved in apoptosis is DNA fragmentation factor (DFF), a caspase-activated DNAse (CAD). DFF/CAD is activated through cleavage of its associated inhibitor ICAD by caspases proteases during apoptosis. DFF/CAD interacts with chromatin components such as topo II and histone H1 to condense chromatin structure and perhaps recruit CAD to chromatin. Another apoptosis activated protease is endonuclease G, EndoG. EndoG is encoded in the nuclear genome but is localized to mitochondria in normal cells. EndoG may play a role in the replication of the mitochondrial genome, as well as in apoptosis. Apoptotic signaling causes the release of EndoG from mitochondria. Mitochondria are involved in apoptotic signaling in other ways as well, through the release of cytochrome c induced by Bid to activate the caspase protease cascade. These pathways are independent since the EndoG pathway still occurs in cells lacking DFF.


description_brief: Apoptotic Signaling in Response to DNA Damage
systematic_name: M3873
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_chemicalPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  The cellular activation of the caspase cascade resulting in cell death is triggered by chemical damage to DNA which stimulates a sequence resulting in the cleavage of Bid in a manner similar to the binding of so called death-receptors or directly initiates the permeability transition of the mitochondrial membrane. The permiability transition releases several factors including cytochrome c, AIF and other factors in to the cytoplasm. Cytochrome c, a key protein in electron transport, is released from mitochondria in response to apoptotic signals, and activates Apaf-1, a protease released from mitochondria. Activated Apaf-1 activates caspase-9 and the rest of the caspase cascade. The caspases are a class of cysteine proteases that includes several representatives involved in apoptosis. The caspases convey the apoptotic signal in a proteolytic cascade, with caspases cleaving and activating other caspases that then degrade other cellular targets that lead to cell death.


description_brief: Aspirin Blocks Signaling Pathway Involved in Platelet Activation
systematic_name: M8731
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_sppaPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Activation of the protease-activated GPCRs in platelets contributes to platelet activation in clotting. The protease-activated receptors PAR1 and PAR4 are cleaved by the protease thrombin, releasing a tethered peptide ligand that activates the receptor and triggers intracellular calcium release. Platelets from mice lacking the PAR4 gene are not activated by thrombin and are impaired in clotting, supporting the importance of thrombin signaling through PAR4 in clotting. Human platelets express both PAR1 and PAR4, with PAR1 playing a more dominant role in clotting in humans. Calcium release induced by PARs activates PKC, modulating integrin alpha IIB beta 3 (glycoprotein IIb/IIIa) and opening integrin ligand binding sites to contribute to platelet aggregation. Intracellular calcium increases induced by thrombin activates phospholipase A2, liberating arachidonic acid, the first step in prostaglandin and thromboxane biosynthesis. Ras/Map kinase activation by the PAR receptors also activates phospholipase A2. The activation of PAR-induced platelet aggregation is inhibited by aspirin, indicating that thromboxane production induced by PAR signaling contributes to platelet activation. Arachidonic acid is converted to the prostaglandin PGG2 by the enzyme Cox-1 in platelets, and Cox-1 is inhibited by aspirin, reducing thromboxane A2 production by platelets. Thromboxane is a potent vasoconstrictor and platelet activator, so inhibition of Cox-1 in platelets by aspirin may explain some of the cardioprotective actions of aspirin.


description_brief: ATM Signaling Pathway
systematic_name: M10628
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_atmPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  The ataxia telangiectasia-mutated gene (ATM) encodes a protein kinase that acts as a tumor suppressor. ATM activation by ionizing radiation damage to DNA stimulates DNA repair and blocks progression through the cell cycle. Mutation of the ATM gene causes the disease ataxia telangiectasia which which involves an inherited predisposition to some cancers. To play this role ATM interacts with a broad network of proteins, including checkpoint factors (chk1, chk2), tumor suppressors (p53 and BRCA), DNA repair factors (RAD50, RAD51, GADD45), and other signaling molecules (c-Abl and NF-kB). In addition to regulating DNA repair and the cell cycle, ATM can also trigger apoptosis in radiation treated cells.


description_brief: Attenuation of GPCR Signaling
systematic_name: M19829
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_agpcrPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  The G-protein coupled receptor (GPCR) family transduces extracellular signals across the plasma membrane, activating cellular responses through a variety of second messenger cascades. These receptors provide rapid responses to a variety of stimuli, and are often rapidly attenuated in their signaling. Failure to attenuate GPCR signaling can have dramatic consequences. One method to attenuate GPCR signaling is by removal of the stimulus from the extracellular fluid. At the synapse, removal of neurotransmitter or peptide signaling molecules is accomplished by either reuptake or degradation. Acetylcholine is removed from synapses through degradation by the enzyme acetylcholinesterase. Inhibition of acetylcholinesterase results in prolonged signaling at the neuromuscular junction, and uncontrollable spasms in humans caused by nerve gas or in insects by some insecticides. Inhibition of acetylcholinesterase is also used therapeutically to treat Alzheimer's disease, compensating for the loss of cholinergic neurons. Transporters for serotonin, dopamine, GABA and noradrenaline remove these neurotransmitters from the synapse to terminate signaling. Antidepressants such as Prozac inhibit reuptake of serotonin and many drugs of abuse such as cocaine act by blocking reuptake of dopamine or adrenaline. Reuptake not only terminates signaling, but can also conserve neurotransmitter through recycling back into the presynaptic cell. The next step in the attenuation of GPCR signaling is receptor desensitization, in which receptors are modified to no longer transduce a signal even if the stimulus is still present. Desensitization of GPCRs occurs through protein kinases that phosphorylate the GPCR to turn off signaling. Downstream protein kinases such as PKA and PKC turned on by GPCR signaling can phosphorylate the activated GPCR and other GPCRs to prevent further signaling. G-protein receptor kinases (GRKs) are a family of kinases that specifically phosphorylate only agonist-occupied GPCRs. GRKs attenuate GPCR signaling in concert with arrestins, proteins that bind GRK-phosphorylated GPCRs to disrupt interaction with G-protein and to terminate signaling. Reducing the number of receptor expressed on the cell surface can also attenuate receptor signaling. Many GPCRs are removed from the cell surface by receptor-mediated endocytosis when they are activated. Endocytosis of activated GPCRs appears to be stimulated by GRKs and arrestins. Once internalized, receptors can either be degraded in lysosomes or they can be recycled back to the cell surface.


description_brief: B Cell Survival Pathway
systematic_name: M4835
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_bcellsurvivalPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Physical interactions between intergrin alpha4beta1 heterodimer expressed on B cells and counter receptors on stroma cells are key mediators of the survival of normal and malignant B cells. Recent data indicate that integrin stimulation increases FBI-1, XIAP, surviving, and CCT4 expression but inhibits Requiem, c-Fos, and caspase 3 and 7 induction.


description_brief: BCR Signaling Pathway
systematic_name: M9494
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_bcrPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Significant progress has been made towards delineation of the intrinsic molecular processes that regulate B lymphocyte immune function. Recent observations have provided a clearer picture of the interactive signaling pathways that emanate from the mature B cell antigen receptor (BCR) complex and the different precursor complexes that are expressed during development. Studies have also revealed that the net functional response to a given antigenic challenge is affected by the combined action of BCR-dependent signaling pathways, as well as those originating from various coreceptors expressed by B cells (e.g. CD19, CD22, FcgRIIb and PIR-B). It is now well established that reversible tyrosine phosphorylation plays an important role in regulating B cell biology. In particular, binding of antigen to the BCR promotes the activation of several protein tyrosine kinases (PTK) that, in conjunction with protein tyrosine phosphatases (PTP), alter the homeostasis of reversible tyrosine phosphorylation in the resting B cell. The net effect is a transient increase in protein tyrosine phosphorylation that facilitates the phosphotyrosine dependent formation of effector protein complexes, promotes targeting of effector proteins to specific microenvironments within the B cell and initiates the catalytic activation of downstream effector proteins. Studies have demonstrated that Src family PTKs are activated initially and serve to phosphorylate CD79a and CD79b thereby creating phosphotyrosine motifs that recruit downstream signaling proteins. In particular, phosphorylation of the BCR complex leads to the recruitment and activation of the PTK Syk, which in turn promotes phosphorylation of PLCg, Shc and Vav. Additionally, the Tec family member Btk is recruited to the plasma membrane where it is involved in activation of PLCg. Initiation of B lymphocyte activation is dependent on the tyrosine phosphorylation-dependent formation of multi-molecular effector protein complexes that activate downstream signaling pathways. The formation of such complexes was initially hypothesized to occur primarily via effector protein binding to the BCR complex itself. However, recent studies have demonstrated that productive signaling via the BCR is in fact dependent on tyrosine phosphorylation of one or more adapter proteins that play a crucial role in recruitment and organization of effector proteins at the plasma membrane. The SLP-65/BLNK adapter protein has recently been shown to play a crucial role in recruitment and activation of key signal transducing effector proteins in the B cell. After the BCR has been engaged by antigen and the activation response has been initiated, numerous second messengers and intermediate signal transducing proteins are activated. These include the production of lipid second messengers by phosphatidylinositol 3-kinase, and the PLC-dependent hydrolysis of phosphatidylinositol 4,5-bisphosphate to yield diacylglycerol and 1,4,5-inositoltrisphosphate (IP3). DAG is important for activation of PKC whereas IP3 promote release of calcium from the endoplasmic reticulum and the subsequent influx Ca2+ from the extracellular space. Numerous intermediate signaling proteins are also activated including the Ras and Rap1, which are small molecular weight GTPases and these ultimately lead to the activation of MAP kinases including Erk, JNK and p38. The net effect of second messenger production and activation of intermediate signaling proteins is the concerted regulation of several transcription factors that mediate gene transcription in the B cell.


description_brief: Bioactive Peptide Induced Signaling Pathway
systematic_name: M13494
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_biopeptidesPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Many different peptides act as signaling molecules, including the proinflammatory peptide bradykinin, the protease enzyme thrombin, and the blood pressure regulating peptide angiotensin. While these three proteins are distinct in their sequence and physiology, and act through different cell surface receptors, they share in a common class of cell surface receptors called G-protein coupled receptors (GPCRs). Other polypeptide ligands of GPCRs include vasopressin, oxytocin, somatostatin, neuropeptide Y, GnRH, leutinizing hormone, follicle stimulating hormone, parathyroid hormone, orexins, urotensin II, endorphins, enkephalins, and many others. GPCRs are a broad and diverse gene family that respond not only to peptide ligands but also small molecule neurotransmitters (acetylcholine, dopamine, serotonin and adrenaline), light, odorants, taste, lipids, nucleotides, and ions. The main signaling mechanism used by GPCRs is to interact with G-protein GTPase proteins coupled to downstream second messenger systems including intracellular calcium release and cAMP production. The intracellular signaling systems used by peptide GPCRs are similar to those used by all GPCRs, and are typically classified according to the G-protein they interact with and the second messenger system that is activated. For Gs-coupled GPCRs, activation of the G-protein Gs by receptor stimulates the downstream activation of adenylate cyclase and the production of cyclic AMP, while Gi-coupled receptors inhibit cAMP production. One of the key results of cAMP production is activation of protein kinase A. Gq-coupled receptors stimulate phospholipase C, releasing IP3 and diacylglycerol. IP3 binds to a receptor in the ER to cause the release of intracellular calcium, and the subsequent activation of protein kinase C, calmodulin-dependent pathways. In addition to these second messenger signaling systems for GPCRs, GPCR pathways exhibit crosstalk with other signaling pathways including tyrosine kinase growth factor receptors and map kinase pathways. Transactivation of either receptor tyrosine kinases like the EGF receptor or focal adhesion complexes can stimulate ras activation through the adaptor proteins Shc, Grb2 and Sos, and downstream Map kinases activating Erk1 and Erk2. Src kinases may also play an essential intermediary role in the activation of ras and map kinase pathways by GPCRs.


description_brief: Bone Remodelling
systematic_name: M2602
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_ranklPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Bone density and structure is maintained through a balance of bone resorption by osteoclasts and bone deposition by osteoblasts. The combination of simultaneous resorption and deposition creates continual remodeling of bone while excess osteoclast activity leads to an imbalance and a loss of bone density, causing osteoporosis. RANK (receptor activator of NF-kB ligand) is a receptor in the TNF receptor gene family that is involved in osteoclast differentiation. RANK-ligand, also called osteoprotegerin-ligand, binds to RANK, induces receptor dimerization, and activates downstream signaling. Osteoprotegerin is a decoy receptor for RANK-ligand that suppresses osteoclast activity and bone remodeling, helping to maintain balanced bone remodeling. RANK-ligand and osteoprotegerin are produced by osteoblasts and some factors regulate osteoclast activity indirectly through their action on the expression of these factors by osteoblasts. Binding of RANK-ligand to RANK activates signaling through TRAF-6. TRAF-6 induces several downstream signaling events, including activation of NF-kB, c-Fos and the kinase JNK1. Jnk-1 activation contribute to fos activation by RANK-ligand and may be involved in the modulation of RANK-ligand by other factors such as estrogen. Mice lacking the c-Fos gene have overly dense bone and decreased bone resorption due to reduced osteoclast differentiation, indicating that c-Fos is an important mediator of osteoclast differentiation. One of the results of c-Fos induction is transcriptional activation of interferon-beta. Interferon-beta binds to its receptor on neighboring osteoclast precursor cells to block RANK-ligand signaling and down-regulate c-Fos expression, inhibiting further osteoclast differentiation. Mice lacking interferon-beta or the interferon-beta receptor lose bone due to uncontrolled osteoclast activity, demonstrating the importance of this mechanism in vivo. Interferon-beta signaling could be used as a mechanism to prevent osteoporosis and other conditions involving excessive osteoclast resorption of bone.


description_brief: Ca++/ Calmodulin-dependent Protein Kinase Activation
systematic_name: M3412
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_CaCaMPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  The calcium/calmodulin-dependent kinases (CaMKs) are involved in a large number of cellular responses induced by hormones, neurotransmitters and other signalling. Elevation of calcium functions as a major second messenger, where the intracellular concentration of calcium can be maintained at extremely low levels and susequently increased following specific calcium-mobilizing stimuli. There are many buffers to the calcium fluxuations including membrane pumps and calcium-binding proteins that create discrete spatial control of its effectors and their targets. The current family of multifunctional calcium/calmodulin (CaM)-dependent protein kinases (CaMKs) consists of CaMKI, CaMKII and CaMKIV. These kinases translate and co-ordinate the calcium fluxuations into the appropriate cellular responses via phosphorylation. These kinases are partially regulated by the intracellular calcium receptor calmodulin (CaM), have common as well as unique features in their structure, regulation and activation. CaMKII, CaMKI and CaMKIV, have an autoregulatory domain that restricts or inhibits enzymic activity in the absence of calcium/CaM. Calcium/CaM binding alone produces maximal activity of CaMKII, whereas CaMKI and CaMKIV have an activation loop that requires phosphorylation of a threonine residue by CaMK kinase (CaMKK) for maximal activity. Two genes (alpha and beta) for CaMKK, which is also regulated by CaM, have been identified. The highest expression of these isoforms occurs in the brain but the activity of the CaMKs has been identified in most cell types. CaMKIV has a post-calmodulin autophosphorylation step that is not observed in CaMKI. The CaMKII multimer can autophosphorylate either the autoregulatory domain or the CaM-binding domain, producing diverse effects in its regulation and sensitivity to Calcium/CaM. Autophosphorylation of CaMKII can produce Calcium/CaM- independent activity (autonomous activity), without affecting its maximal Calcium/CaM-stimulated activity. The CaMKII autophosphorylation involves a kinase cascade of sorts, with each subunit of the multimeric enzyme acting as both kinase and kinase kinase. Autophosphorylation establishes a 1000-fold increase in the affinity for its activator Calcium/CaM (also known as CaM trapping); however, autophosphorylation within the CaM-binding domain following CaM dissociation of activated/autophosphorylated enzyme restricts or prevents CaM from rebinding (CaM capping). The mechanisms and consequences of autophosphorylation are central to the CaMKII enzyme's complex regulatory behavior enabling it to become differentially activated at different frequencies and levels of calcium spikes. The target proteins for the CaMKs are very similar. An example target of the CaMKs is the transcriptional activating protein CREB. The phosphorylation states of CREB after CaMK phosphorlyation differ by the additional phosphorylation of CREB at serine 142 that functions as an additional inhibitory site. This difference appears to be the result of adjacent amino acids.


description_brief: Cadmium induces DNA synthesis and proliferation in macrophages
systematic_name: M4388
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_cdmacPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Exposure to divalent cadmium ions (Cd2+) is a known cancer risk factor, but the molecular mechanisms responsible for the inappropriate induction of cellular proliferation by cadmium are still being figured out. One cellular model used to study this process is macrophages grown in culture. In cultured macrophages, cadmium acts both at the cell surface and in the cytoplasm to induce proliferation. At the cell surface, cadmium interacts with a pertussis-sensitive cell surface receptor, probably a Gi-coupled GPCR, to stimulate proliferation. Cadmium can enter cells through calcium ion channels and once in cells affects calcium release by the ER. In addition to changes in intracellular calcium, the proliferative effects of cadmium are mediated by the Ras/Map kinase pathway, and also NF-kB. Inhibition of phospholipase C, map kinases, or NF-kB with a variety of pharmacological inhibitors all blocked the activation of cellular proliferation by cadmium. Protein kinase C is also activated by cadmium, upstream of the Map kinase pathway. Changes in transcription induced by cadmium include induction of immediate early genes like fos, jun, and myc. In addition to inducing cellular proliferation, cadmium also is slightly genotoxic due to inhibition of DNA repair, activates stress genes, and inhibits the immune system. The immuno-modulatory effects observed with cadmium treatment may also involvement transcriptional disregulation, including the expression of cytokines such as IL-4, IL-10, and TNF-alpha. Although macrophages have been used for many studies, other cell types are also the target of cadmiums toxicity.


description_brief: Caspase Cascade in Apoptosis
systematic_name: M17902
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_caspasePathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Apoptosis, programmed cell death, is triggered by a variety of stimuli, including cell surface receptors like FAS, mitochondrial response to stress, and cytotoxic T cells. Caspases are a class of cysteine proteases that includes several representatives involved in apoptosis. The caspases convey the apoptotic signal in a proteolytic cascade, with caspases cleaving and activating other caspases that then degrade other cellular targets that lead to cell death. The caspases at the upper end of the cascade include caspase-8 and caspase-9. Caspase-8 is the initial caspase involved in response to receptors with a death domain like FAS. The mitochondrial stress pathway begins with the release of cytochrome c from mitochondria, which then interacts with Apaf-1, causing self-cleavage and activation of caspase-9. Caspase-3, -6 and-7 are downstream caspases that are activated by the upstream proteases and act themselves to cleave cellular targets. Granzyme B and perforin proteins released by cytotoxic T cells induce apoptosis in target cells, forming transmembrane pores, and triggering apoptosis, perhaps through cleavage of caspases, although caspase-independent mechanisms of Granzyme B mediated apoptosis have been suggested.


description_brief: CBL mediated ligand-induced downregulation of EGF receptors
systematic_name: M16973
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_cblPathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  As with many cell-surface receptors, activation of the EGF receptor can result in receptor internalization through receptor-mediated endocytosis, desensitizing further receptor signaling. This process requires clathrin and occurs in clathrin-coated pits, which pinch off from the plasma membrane to form vesicles that move to the early endosome. From the early endosome, receptors can either be recycled back to the cell surface, or they can move through the late endosome to the lysosome for proteolytic degradation. The sorting of receptors in the early endosome for degradation requires the tyrosine kinase activity of activated growth factor receptor, and involves ubiquitination of the receptor. Targeting of receptors for degradation requires members of the Cbl gene family. Cbl proteins bind to tyrosine phosphorylated EGF receptor, and are E3 ubiquitination ligases that label receptor for degradation. Cbl also recruits Cin85 to the receptor complex, and blocking Cin85 interaction blocks receptor internalization and degradation. Endophilins are also a member of this receptor-bound protein complex. In its role as a ubiquitin ligase and docking protein, Cbl desensitizes EGF signaling and also opposes cellular proliferation induced by EGF. EGF activation also appears to activate the tyrosine kinase Src, which phosphorylates Cbl, and helps to activate the ubiquitination and degradation of EGF receptor. PKC activation and threonine phosphorylation of the EGF receptor can induce heterologous receptor internalization, but opposes Cbl-mediated receptor degradation. PKC phosphorylated receptors are sorted for recycling to the cell surface, and directed away from the late endosome and proteosome. Other growth factor receptors are regulated in a similar manner, including the PDGF receptor, HGF receptor and the CSF-1 receptor, indicating that this is a fairly general regulatory mechanism. The importance of Cbl in the down-regulation of growth factor signaling means that it will have an important role in cellular transformation and the development and treatment of cancer.


description_brief: CCR3 signaling in Eosinophils
systematic_name: M9152
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_ccr3Pathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  Eosinophils are a key class of leukocytes involved in inflammatory responses, including allergic reactions in skin and airway. The eosinophil response in inflammation is absent in mice lacking CCR3, indicating the key role of this G protein coupled receptor in inflammation and allergic responses. Eotaxin is a chemokine ligand for CCR3 that recruits eosinophils to the site of inflammation and activates them. Other chemokine ligands of CCR3 include eotaxin-2, MCP-3, MCP-4, and RANTES. Multiple signaling pathways activated by CCR3 participate in the inflammatory response of eosinophils. Eotaxin stimulates intracellular calcium release, production of reactive oxygen species, and changes in actin polymerization through a pertussis sensitive pathway. Rho and ROCK regulate actin stress fiber formation and are required for eosinophil chemotaxis. Rho is a G protein that activates ROCK, a protein kinase. Map kinase pathways are also involved in chemotaxis. Another key action of activated eosinophils is the release of reactive oxygen species, causing tissue damage during chronic inflammatory responses. Blocking eosinophil activation and the signaling pathways that lead to chemotaxis, degranulation and reactive oxygen release may alleviate inflammatory conditions and inflammation-associated tissue damage.


description_brief: CD40L Signaling Pathway
systematic_name: M16697
external_details_URL: https://data.broadinstitute.org/gsea-msigdb/msigdb/biocarta/human/h_cd40Pathway.gif
source_species_code: HS
contributor: BioCarta
contrib_organization: BioCarta
description_full:
  The CD40 receptor was first associated with expression in B cells and the role it plays through its ligand CD40L (CD154) in moderating T cell activation. Broader expression may indicate a broader role for CD40 and CD40L in immune function and disease states such as transplant rejection and HIV infection. Disruption of CD40 interaction with CD40L may prove therapeutic in the treatment of autoimmune disorders or heart disease and modulation of the interaction may in the future be exploited in cancer treatment. As a member of the TNF receptor family, CD40 relies on interaction with TRAF proteins to mediate an intracellular signal in response to CD40L binding. The pathway downstream of TRAFs activates the transcription factor NF-kappaB through a kinase pathway involving map kinases, NIK (NF-kappaB inducing kinase) and I-kappa B kinases. Some CD40 responses like regulation of immunoglobulin expression might be mediated by NF-kappaB transcriptional activation.


