Cyclic GMP-dependent protein kinase regulates CCAAT enhancer-binding protein beta  functions through inhibition of glycogen synthase kinase-3

doi:10.1074/jbc.M505486200

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Papers In Press, published online ahead of print July 29, 2005
J. Biol. Chem, 10.1074/jbc.M505486200
Submitted on May 19, 2005
Revised on July 20, 2005
Accepted on July 29, 2005

Cyclic GMP-dependent protein kinase regulates CCAAT enhancer-binding protein $beta$ functions through inhibition of glycogen synthase kinase-3

Xin Zhao, Shunhui Zhuang, Yongchang Chen, Gerry R. Boss, and Renate B. Pilz

Department of Medicine, University of California San Diego, La Jolla, CA 92093-0652

Corresponding Author: rpilz{at}ucsd.edu

The CCAAT enhancer-binding protein C/EBP $beta$ plays an important role in the regulation of gene expression during cell proliferation, differentiation, and apoptosis. We previously showed that C/EBP $beta$ participates in cGMP-regulated transcription of c-fos in osteoblasts (Chen et al., Mol. Cell. Biol. 23:4066-82, 2003). In the present work, we show that cGMP/cGMP-dependent protein kinase (PKG) induced de-phosphorylation and activation of C/EBP $beta$ by inhibiting glycogen synthase kinase-3 $beta$ (GSK-3 $beta$ ). Phosphorylation of GSK-3 $beta$ on Ser9 negatively regulates the enzyme’s 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 $beta$ de-phosphorylation. Previous studies with GSK-3 inhibitors suggest that GSK-3 $beta$ is a C/EBP $beta$ kinase in resting cells. We determined that GSK-3 $beta$ phosphorylated C/EBP $beta$ in vitro on Thr189, Ser185, Ser181, and Ser177; C/EBP $beta$ 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 $beta$ prevented C/EBP $beta$ phosphorylation in resting cells, enhanced C/EBP $beta$ DNA binding and led to increased target gene transactivation, mimicking the stimulatory effects of cGMP on C/EBP $beta$ . cGMP regulation of C/EBP $beta$ was disrupted by a mutant GSK-3 $beta$ (Ala9) resistant to cGMP/PKG phosphorylation and inhibition. We conclude that cGMP increases the DNA binding potential of C/EBP $beta$ by preventing the negative effects of GSK-3 phosphorylation.

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Cyclic GMP-dependent protein kinase regulates CCAAT enhancer-binding protein functions through inhibition of glycogen synthase kinase-3

Cyclic GMP-dependent protein kinase regulates CCAAT enhancer-binding protein $beta$ functions through inhibition of glycogen synthase kinase-3