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J. Biol. Chem., Vol. 279, Issue 41, 42438-42444, October 8, 2004

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Fos-related Antigen 2 Controls Protein Kinase A-induced CCAAT/Enhancer-binding Protein Expression in Osteoblasts^*

Weizhong Chang, Amar Rewari, Michael Centrella, and Thomas L. McCarthy

From the Section of Plastic Surgery, Department of Surgery, Yale University School of Medicine, New Haven, Connecticut 06520

Transcription factor CCAAT/enhancer-binding protein (C/EBP) plays an important role in hormone-dependent gene expression. In osteoblasts C/EBP can increase insulin-like growth factor I (IGF-I) transcription following treatment with hormones that activate protein kinase A, but little is known as yet about the expression of C/EBP itself in these cells. We initially showed that prostaglandin E₂ (PGE₂) rapidly enhances C/EBP mRNA and protein expression, and in this study we identified a 3'-proximal region of the C/EBP promoter containing a 541-bp upstream sequence that could account for this effect. PGE₂-dependent activation of C/EBP was blocked by expression of a mutated regulatory subunit of protein kinase A or by mutation of two previously identified cAMP-sensitive cis-acting regulatory elements within the promoter between bp –111 and –61. Nuclear protein binding to these elements was induced by PGE₂, required new protein synthesis, and was sensitive to antibody to the transcription factor termed Fos-related antigen 2 (Fra-2). Fra-2 cDNA generated from rat osteoblasts by reverse transcriptase PCR was 95% homologous to human Fra-2, and PGE₂ rapidly induced Fra-2 mRNA and protein expression. Consistent with these findings, over-expression of Fra-2 significantly increased C/EBP promoter activity in PGE₂-induced osteoblasts, whereas expression of Fra-2 lacking its activation domain had a dominant negative inhibitory effect. Together, these results reveal a significant, hormone-dependent role for Fra-2 in osteoblast function, both directly, through its ability to increase new C/EBP gene expression, and indirectly, through downstream C/EBP sensitive genes.

Received for publication, May 18, 2004 , and in revised form, July 12, 2004.

^* This study was supported by Public Health Service Grants DK56310 and AR39201. 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 nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AY622611.

To whom correspondence should be addressed: Dept. of Surgery, Yale University School of Medicine, P. O. Box 208041, New Haven, CT 06520-8041. Tel.: 203-785-4927; Fax: 203-785-5714; E-mail: thomas.mccarthy{at}yale.edu.

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