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J. Biol. Chem., Vol. 280, Issue 38, 32683-32692, September 23, 2005

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Cyclic GMP-dependent Protein Kinase Regulates CCAAT Enhancer-binding Protein Functions through Inhibition of Glycogen Synthase Kinase-3^*

From the Department of Medicine and Cancer Center, University of California at San Diego, La Jolla, California 92093

The CCAAT enhancer-binding protein (C/EBP) plays an important role in the regulation of gene expression during cell proliferation, differentiation, and apoptosis. We previously showed that C/EBP participates in cGMP-regulated transcription of c-fos in osteoblasts (Chen, Y., Zhuang, S., Cassenaer, S., Casteel, D. E., Gudi, T., Boss, G. R., and Pilz, R. B. (2003) Mol. Cell. Biol. 23, 4066–4082). In the present work, we show that cGMP/cGMP-dependent protein kinase (PKG) induced dephosphorylation and activation of C/EBP by inhibiting glycogen synthase kinase-3 (GSK-3). Phosphorylation of GSK-3 on Ser⁹ negatively regulates the enzyme activity, and we found that PKG phosphorylated this site both in vitro and in vivo; the in vivo phosphorylation occurred rapidly and preceded C/EBP dephosphorylation. Previous studies with GSK-3 inhibitors suggest that GSK-3 is a C/EBP kinase in resting cells. We determined that GSK-3 phosphorylated C/EBP in vitro on Thr¹⁸⁹, Ser¹⁸⁵, Ser¹⁸¹, and Ser¹⁷⁷; C/EBP was phosphorylated on these same sites in intact, unstimulated osteoblasts, and phosphorylation was decreased in cGMP-treated cells. Mutation of the GSK-3 phosphorylation sites in C/EBP prevented C/EBP phosphorylation in resting cells, enhanced C/EBP DNA binding, and led to increased target gene transactivation, mimicking the stimulatory effects of cGMP on C/EBP. cGMP regulation of C/EBP was disrupted by a mutant GSK-3(Ala⁹) resistant to cGMP/PKG phosphorylation and inhibition. We conclude that cGMP increases the DNA binding potential of C/EBP by preventing the negative effects of GSK-3 phosphorylation.

Received for publication, May 19, 2005 , and in revised form, July 20, 2005.

^* This work was supported in part by United States Public Health Service Grants GM55586 and AR51300 (to R. B. P.) and CA90932 (to G. R. B.). 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.

¹ To whom correspondence should be addressed: Dept. of Medicine, University of California San Diego, 9500 Gilman Dr., La Jolla, CA 92093-0652. Tel.: 858-534-8805; Fax: 858-534-1421; E-mail: rpilz{at}ucsd.edu.

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