title: A GSK-3-mediated transcriptional network maintains repression of immediate early genes in quiescent cells.
abstract: Glycogen synthase kinase-3 (GSK-3) plays a central role in cell survival and proliferation, in part by the regulation of transcription. Unlike most protein kinases, GSK-3 is active in quiescent cells in the absence of growth factor signaling. In a recent series of studies, we employed a systems-level approach to understanding the transcription network regulated by GSK-3 in a quiescent cell model. We identified a group of immediate early genes that were upregulated in quiescent cells solely by the inhibition of GSK-3 in the absence of growth factor stimulation. Computational analysis of the upstream sequences of these genes identified statistically over-represented binding sites for the transcription factors CREB, NFκB and AP-1, and the roles of these factors in regulating expression of GSK-3 target genes were verified by chromatin immunoprecipitation and RNA interference. In quiescent cells, GSK-3 inhibits CREB, NFκB and AP-1, thereby maintaining repression of their target genes and contributing to maintenance of cell cycle arrest.
authors: Boston University, Boston, MA, USA.
authors: John W
authors: JW
authors: Tullai
authors: Julie R
authors: JR
authors: Graham
authors: Geoffrey M
authors: GM
authors: Cooper
mesh_terms: D000375:Aging; D001665:Binding Sites; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D019295:Computational Biology; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D017781:Genes, Immediate-Early; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D052002:NF-kappa B p50 Subunit / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D034622:RNA Interference; D017479:Receptors, Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D052002:NF-kappa B p50 Subunit; C489548:NFKB1 protein, human; D012097:Repressor Proteins; D018808:Transcription Factor AP-1; D019869:Phosphatidylinositol 3-Kinases; C099852:PDGF receptor tyrosine kinase; D017479:Receptors, Platelet-Derived Growth Factor; D038362:Glycogen Synthase Kinase 3