Glycogen synthase kinase-3 represses cyclic AMP response element-binding protein (CREB)-targeted immediate early genes in quiescent cells.
Despite its central role in cell survival and proliferation, the transcriptional program controlled by GSK-3 is poorly understood. We have employed a systems level approach to characterize gene regulation downstream of PI 3-kinase/Akt/GSK-3 signaling in response to growth factor stimulation of quiescent cells. Of 31 immediate-early genes whose induction was dependent on PI 3-kinase signaling, 12 were induced directly by inhibition of GSK-3. Most of the GSK-3-regulated genes encoded transcription factors, growth factors, and signaling molecules. Binding sites for CREB were highly over-represented in the upstream regions of these genes, with 9 genes containing CREB sites that were conserved in mouse orthologs. Binding sites predicted in 6 genes were confirmed by CREB chromatin immunoprecipitation and forskolin induction of CBP binding. Moreover, CREB siRNA substantially blocked induction of 5 genes by forskolin and of 3 genes following inhibition of GSK-3. These results indicate that GSK-3 actively represses gene expression in quiescent cells, with inhibition of CREB playing a key role in this transcriptional response.
Tullai
John W
JW
Department of Biology, Boston University, Boston, Massachusetts 02215.
Chen
Jie
J
Department of Biology, Boston University, Boston, Massachusetts 02215.
Schaffer
Michael E
ME
Bioinformatics Program, Boston University, Boston, Massachusetts 02215.
Kamenetsky
Eliza
E
Department of Biology, Boston University, Boston, Massachusetts 02215.
Kasif
Simon
S
Bioinformatics Program, Boston University, Boston, Massachusetts 02215; Department of Biomedical Engineering, Boston University, Boston, Massachusetts 02215.
Cooper
Geoffrey M
GM
Department of Biology, Boston University, Boston, Massachusetts 02215; Bioinformatics Program, Boston University, Boston, Massachusetts 02215. Electronic address: gmcooper@bu.edu.
D000595:Amino Acid Sequence; D000818:Animals; D045744:Cell Line, Tumor; D017362:Cyclic AMP Response Element-Binding Protein / Q000037:antagonists & inhibitors* / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D017781:Genes, Immediate-Early; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000502:physiology*; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D016192:Resting Phase, Cell Cycle / Q000235:genetics*
C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D038362:Glycogen Synthase Kinase 3