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J. Biol. Chem., Vol. 282, Issue 13, 9482-9491, March 30, 2007

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Glycogen Synthase Kinase-3 Represses Cyclic AMP Response Element-binding Protein (CREB)-targeted Immediate Early Genes in Quiescent Cells^*

John W. Tullai¹, Jie Chen¹, Michael E. Schaffer, Eliza Kamenetsky, Simon Kasif^¶, and Geoffrey M. Cooper²

From the Department of Biology, the Bioinformatics Program, and the ^¶Department of Biomedical Engineering, Boston University, Boston, Massachusetts 02215

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.

Received for publication, January 3, 2007 , and in revised form, February 1, 2007.

^* The study was supported in part by National Institutes of Health Grants 1R01-CA18689 and 1R33-HG002850 and NSF Grant ITR-048715. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2 and Tables S1 and S2.

¹ These authors contributed equally to this study.

² To whom correspondence should be addressed: Boston University, Dept. of Biology, 5 Cummington St., Boston, MA 02215. Tel.: 617-353-8735; Fax: 617-353-8484; E-mail: gmcooper{at}bu.edu.

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