Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 279, Issue 41, Pages 42438-42444Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M405549200
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- NIAMS NIH HHS [AR39201] Funding Source: Medline
- NIDDK NIH HHS [DK56310] Funding Source: Medline
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Transcription factor CCAAT/enhancer-binding protein beta (C/EBPbeta) plays an important role in hormone-dependent gene expression. In osteoblasts C/EBPbeta 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/EBPbeta itself in these cells. We initially showed that prostaglandin E-2 (PGE(2)) rapidly enhances C/EBPbeta mRNA and protein expression, and in this study we identified a 3'-proximal region of the C/EBPbeta promoter containing a 541-bp upstream sequence that could account for this effect. PGE(2)-dependent activation of C/EBPbeta 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 PGE(2), 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 PGE(2) rapidly induced Fra-2 mRNA and protein expression. Consistent with these findings, over-expression of Fra-2 significantly increased C/EBPbeta promoter activity in PGE(2)-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/EBPbeta gene expression, and indirectly, through downstream C/EBP sensitive genes.
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