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<MSIGDB BUILD_DATE="Jan 29, 2026" VERSION="2026.1.Hs" NAME="export">
    <GENESET STANDARD_NAME="KARAKAS_TGFB1_SIGNALING" SYSTEMATIC_NAME="M17300" HISTORICAL_NAMES="" PMID="16619041" AUTHORS="Karakas B,Weeraratna A,Abukhdeir A,Blair BG,Konishi H,Arena S,Becker K,Wood W 3rd,Argani P,De Marzo AM,Bachman KE,Park BH" GEOID="" EXACT_SOURCE="Table 1: up in both" GENESET_LISTING_URL="" EXTERNAL_DETAILS_URL="" CHIP="HUMAN_GENE_SYMBOL" CONTRIBUTOR="Arthur Liberzon" CONTRIBUTOR_ORG="MSigDB Team" DESCRIPTION_BRIEF="Genes up-regulated by TGFB1 [GeneID=7040] in MCF10A cells (breast cancer): both wild-type and those lacking p21 [GeneID=1026]." DESCRIPTION_FULL="Transforming growth factor-beta type 1 (TGF-beta) has been implicated as both a tumor suppressor and a tumor promoter in many solid epithelial cancers. We have previously demonstrated that the cyclin dependent kinase (CDK) inhibitor p21 acts as a molecular switch in determining a growth inhibitory versus growth proliferative response to TGF-beta in the spontaneously immortalized human mammary epithelial cell line MCF-10A. We now demonstrate that this proliferative effect of TGF-beta is mediated through the proinflammatory cytokine, interleukin-1alpha (IL-1alpha). Using gene expression array analysis, we identified IL-1alpha as a cytokine specifically upregulated only in cells lacking p21 and only upon TGF-beta stimulation. Cell proliferation assays verified that recombinant IL-1alpha was capable of inducing a growth proliferative response in p21 null MCF-10A cells, while neutralizing antibodies against IL-1alpha prevented the growth proliferative effects of TGF-beta. Mechanistically, both the CDK and proliferating cell nuclear antigen (PCNA) inhibitory functions of p21 were responsible for preventing TGF-beta induced cell proliferation, but only PCNA inhibition by p21 regulated IL-1alpha gene expression. These studies demonstrate a novel role for IL-1alpha in mediating a proliferative response to TGF-beta signaling, and suggest that therapies directed against IL-1alpha could abate the growth proliferative effects of TGF-beta without compromising its tumor suppressive function." TAGS="" MEMBERS="BIRC5,BRCA1,BUB1,CDC28,CDH2,CNB1,COL4,CST6,CUL3,FAP,FN1,FOLR3,HSP70,HSP90,IGFBP7,IL-15,KIF3C,LOX,LY6D,MMP2,MT2A,PLK,SRPN1,TSPN2" MEMBERS_SYMBOLIZED="BIRC5,BRCA1,BUB1,CDH2,CST6,CUL3,FAP,FN1,FOLR3,IGFBP7,IL15,KIF3C,LOX,LY6D,MMP2,MT2A,PLK1,PPP3R1" MEMBERS_EZID="1000,1474,2191,2335,2352,332,3490,3600,3797,4015,4313,4502,5347,5534,672,699,8452,8581" MEMBERS_MAPPING="BIRC5,BIRC5,332|BRCA1,BRCA1,672|BUB1,BUB1,699|CDC28,null,null|CDH2,CDH2,1000|CNB1,PPP3R1,5534|COL4,null,null|CST6,CST6,1474|CUL3,CUL3,8452|FAP,FAP,2191|FN1,FN1,2335|FOLR3,FOLR3,2352|HSP70,null,null|HSP90,null,null|IGFBP7,IGFBP7,3490|IL-15,IL15,3600|KIF3C,KIF3C,3797|LOX,LOX,4015|LY6D,LY6D,8581|MMP2,MMP2,4313|MT2A,MT2A,4502|PLK,PLK1,5347|SRPN1,null,null|TSPN2,null,null" FILTERED_BY_SIMILARITY="" FOUNDER_NAMES="" REFINEMENT_DATASETS="" VALIDATION_DATASETS="" CATEGORY_CODE="C2" ORGANISM="Homo sapiens" SUB_CATEGORY_CODE="CGP"/>
</MSIGDB>
