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J. Biol. Chem., Vol. 279, Issue 51, 53167-53174, December 17, 2004

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Nuclear Orphan Receptor Nurr1 Directly Transactivates the Osteocalcin Gene in Osteoblasts^*

Flavia Q. Pirih¶, Alan Tang||, Ibrahim C. Ozkurt, Jeanne M. Nervina**, and Sotirios Tetradis

From the Division of Diagnostic and Surgical Sciences and ^**Section of Orthodontics, School of Dentistry, the Molecular Biology Institute, University of California Los Angeles, California 90095

Nurr1, an NGFI-B nuclear orphan receptor, which transactivates promoters through an NGFI-B response element (NBRE), is strongly induced by parathyroid hormone through the cAMP-protein kinase A signaling pathway in osteoblasts. Here, we demonstrate that multiple agents activating diverse signaling pathways in osteoblasts induce Nurr1. The strongest Nurr1 inducers were activators of cAMP-protein kinase A-coupled signaling, followed by protein kinase C- and calcium-coupled signaling activators. Receptor tyrosine kinase activators had minimal effect, whereas serine/threonine kinase activators had no effect on basal Nurr1 mRNA levels. Computer analysis of osteoblastic promoters indicated two potential NBREs in the rat osteocalcin (Ocn) promoter. Intriguingly, the proximal site maps to the cAMP-responsive cis-element. We tested whether Nurr1 induces Ocn expression through the NBRE-like site. Recombinant and endogenous Nurr1 protein from primary mouse osteoblasts bound to a consensus NBRE in EMSAs. Nurr1 induced a consensus 3xNBRE-luciferase reporter construct in mouse osteoblasts. Recombinant and endogenous Nurr1 protein bound to the proximal NBRE-like site in the Ocn promoter in EMSAs. Endogenous Nurr1 protein bound to this site as a monomer, because neither retinoid X receptor nor retinoid X receptor antibody supershifted the protein-DNA complex. Ocn promoter-luciferase constructs lacking or containing a mutated proximal NBRE-like site had markedly blunted responses to Nurr1 overexpression. Finally, adenovirally expressed Nurr1 protein bound to the proximal NBRE-like site in chromatin immunoprecipitation assays and induced Ocn mRNA in primary rat osteoblasts. We conclude that Ocn is a Nurr1 target gene, which positions Nurr1 in the core of transcriptional factors regulating osteoblastic gene expression.

Received for publication, May 21, 2004 , and in revised form, August 26, 2004.

^* This work was supported in part by NIDCR, National Institutes of Health (NIH) Grant R01-DE13316. 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.

Both authors contributed equally to this work.

^¶ Supported by NIDCR, NIH Institutional Training Grant T32 DE007296.

^|| Recipient of a student research fellowship from the American Academy of Dental Research.

To whom correspondence should be addressed: Division of Diagnostic and Surgical Sciences, School of Dentistry, Rm. 53-068 CHS, University of California, Los Angeles, CA 90095-1668. Tel.: 310-825-5712; Fax: 310-206-6485; E-mail: sotirist{at}dent.ucla.edu.

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