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.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Aging
-
Binding Sites
-
Cell Line, Tumor
-
Chromatin Immunoprecipitation
-
Computational Biology
-
Cyclic AMP Response Element-Binding Protein / genetics
-
Cyclic AMP Response Element-Binding Protein / metabolism
-
Gene Expression Regulation, Neoplastic*
-
Gene Regulatory Networks*
-
Genes, Immediate-Early*
-
Glycogen Synthase Kinase 3 / genetics
-
Glycogen Synthase Kinase 3 / metabolism*
-
Humans
-
NF-kappa B p50 Subunit / genetics
-
NF-kappa B p50 Subunit / metabolism
-
Phosphatidylinositol 3-Kinases / genetics
-
Phosphatidylinositol 3-Kinases / metabolism
-
Phosphorylation
-
RNA Interference
-
Receptors, Platelet-Derived Growth Factor / genetics
-
Receptors, Platelet-Derived Growth Factor / metabolism
-
Repressor Proteins / genetics
-
Repressor Proteins / metabolism*
-
Signal Transduction
-
Transcription Factor AP-1 / metabolism
-
Transcription, Genetic
Substances
-
CREB1 protein, human
-
Cyclic AMP Response Element-Binding Protein
-
NF-kappa B p50 Subunit
-
NFKB1 protein, human
-
Repressor Proteins
-
Transcription Factor AP-1
-
Phosphatidylinositol 3-Kinases
-
PDGF receptor tyrosine kinase
-
Receptors, Platelet-Derived Growth Factor
-
Glycogen Synthase Kinase 3