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Molecular and Cellular Biology, June 2003, p. 4066-4082, Vol. 23, No. 12
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.12.4066-4082.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Synergism between Calcium and Cyclic GMP in Cyclic AMP Response Element-Dependent Transcriptional Regulation Requires Cooperation between CREB and C/EBP-ß

Yongchang Chen, Shunhui Zhuang, Stijn Cassenaer, Darren E. Casteel, Tanima Gudi, Gerry R. Boss, and Renate B. Pilz*

Department of Medicine and Cancer Center, University of California at San Diego, La Jolla, California 92093-0652

Received 24 September 2002/ Returned for modification 18 November 2002/ Accepted 18 March 2003

Calcium induces transcriptional activation of the fos promoter by activation of the cyclic AMP response element (CRE)-binding protein (CREB), and in some cells its effect is enhanced synergistically by cyclic GMP (cGMP) through an unknown mechanism. We observed calcium-cGMP synergism in neuronal and osteogenic cells which express type II cGMP-dependent protein kinase (G-kinase); the effect on the fos promoter was mediated by the CRE and proportional to G-kinase activity. Dominant negative transcription factors showed involvement of CREB- and C/EBP-related proteins but not of AP-1. Expression of C/EBP-ß but not C/EBP-{alpha} or -{delta} enhanced the effects of calcium and cGMP on a CRE-dependent reporter gene. The transactivation potential of full-length CREB fused to the DNA-binding domain of Gal4 was increased synergistically by calcium and cGMP, and overexpression of C/EBP-ß enhanced the effect, while a dominant negative C/EBP inhibited it. With a mammalian two-hybrid system, coimmunoprecipitation experiments, and in vitro binding studies, we demonstrated that C/EBP-ß and CREB interacted directly; this interaction involved the C terminus of C/EBP-ß but occurred independently of CREB's leucine zipper domain. CREB Ser133 phosphorylation was stimulated by calcium but not by cGMP; in cGMP-treated cells, 32PO4 incorporation into C/EBP-ß was decreased and C/EBP-ß/CRE complexes were increased, suggesting regulation of C/EBP-ß functions by G-kinase-dependent dephosphorylation. C/EBP-ß and CREB associated with the fos promoter in intact cells, and the amount of promoter-associated C/EBP-ß was increased by calcium and cGMP. We conclude that calcium and cGMP transcriptional synergism requires cooperation of CREB and C/EBP-ß, with calcium and cGMP modulating the phosphorylation states of CREB and C/EBP-ß, respectively.

* Corresponding author. Mailing address: Department of Medicine and Cancer Center, University of California at San Diego, 9500 Gilman Dr., La Jolla, CA 92093-0652. Phone: (858) 534-8805. Fax: (858) 534-1421. E-mail: rpilz{at}ucsd.edu.

Molecular and Cellular Biology, June 2003, p. 4066-4082, Vol. 23, No. 12
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.12.4066-4082.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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