STANDARD_NAME	TIMOFEEVA_GROWTH_STRESS_VIA_STAT1_DN
SYSTEMATIC_NAME	M2849
COLLECTION	C2:CGP
MSIGDB_URL	https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/TIMOFEEVA_GROWTH_STRESS_VIA_STAT1_DN
NAMESPACE	AFFY_HG_U133
DESCRIPTION_BRIEF	Genes down-regulated in SK-NEP-1 cells (Wilm's tumor ) stably expressing inactivated forms of STAT1 [GeneID=6772] under growth stress (hypoxia or nutritional deprivation).
DESCRIPTION_FULL	Wilms' tumor (WT), one of the most common pediatric solid cancers, arises in the developing kidney as a result of genetic and epigenetic changes that lead to the abnormal proliferation and differentiation of the metanephric blastema. As activation of signal transducers and activators of transcription (STATs) plays an important role in the maintenance/growth and differentiation of the metanephric blastema, and constitutively activated STATs facilitate neoplastic behaviors of a variety of cancers, we hypothesized that dysregulation of STAT signaling may also contribute to WT pathogenesis. Accordingly, we evaluated STAT phosphorylation patterns in tumors and found that STAT1 was constitutively phosphorylated on serine 727 (S727) in 19 of 21 primary WT samples and two WT cell lines. An inactivating mutation of S727 to alanine reduced colony formation of WT cells in soft agar by more than 80% and induced apoptosis under conditions of growth stress. S727-phosphorylated STAT1 provided apoptotic resistance for WT cells via upregulation of expression of the heat-shock protein (HSP)27 and antiapoptotic protein myeloid cell leukemia (MCL)-1. The kinase responsible for STAT1 S727 phosphorylation in WT cells was identified based upon the use of selective inhibitors as protein kinase CK2, not p38, MAP-kinase kinase (MEK)1/2, phosphatidylinositol 3'-kinase, protein kinase C or Ca/calmodulin-dependent protein kinase II (CaMKII). The inhibition of CK2 blocked the anchorage-independent growth of WT cells and induced apoptosis under conditions of growth stress. Our findings suggest that serine-phosphorylated STAT1, as a downstream target of protein kinase CK2, plays a critical role in the pathogenesis of WT and possibly other neoplasms with similar STAT1 phosphorylation patterns.
PMID	16799645
GEOID	
AUTHORS	Timofeeva OA,Plisov S,Evseev AA,Peng S,Jose-Kampfner M,Lovvorn HN,Dome JS,Perantoni AO
CONTRIBUTOR	Arthur Liberzon
CONTRIBUTOR_ORG	MSigDB Team
EXACT_SOURCE	Table 1S: fold change < 1
FILTERED_BY_SIMILARITY	
EXTERNAL_NAMES_FOR_SIMILAR_TERMS	
EXTERNAL_DETAILS_URL	
SOURCE_MEMBERS	200796_s_at,200824_at,200953_s_at,201841_s_at,202344_at,203468_at,204099_at,205483_s_at,206397_x_at,208641_s_at,212983_at,213574_s_at,214743_at,215450_at,217733_s_at,221506_s_at,39729_at
GENE_SYMBOLS	MCL1,GSTP1,CCND2,HSPB1,HSF1,CDK10,SMARCD3,ISG15,GDF1,RAC1,HRAS,KPNB1,CUX1,,TMSB10,TNPO2,PRDX2
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