STANDARD_NAME	KARAKAS_TGFB1_SIGNALING
SYSTEMATIC_NAME	M17300
COLLECTION	C2:CGP
MSIGDB_URL	https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/KARAKAS_TGFB1_SIGNALING
NAMESPACE	HUMAN_GENE_SYMBOL
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.
PMID	16619041
GEOID	
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
CONTRIBUTOR	Arthur Liberzon
CONTRIBUTOR_ORG	MSigDB Team
EXACT_SOURCE	Table 1: up in both
FILTERED_BY_SIMILARITY	
EXTERNAL_NAMES_FOR_SIMILAR_TERMS	
EXTERNAL_DETAILS_URL	
SOURCE_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
GENE_SYMBOLS	BIRC5,BRCA1,BUB1,,CDH2,PPP3R1,,CST6,CUL3,FAP,FN1,FOLR3,,,IGFBP7,IL15,KIF3C,LOX,LY6D,MMP2,MT2A,PLK1,,
FOUNDER_NAMES