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J. Biol. Chem., Vol. 282, Issue 23, 16860-16870, June 8, 2007

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The Retinoblastoma Protein Is an Essential Mediator of Osteogenesis That Links the p204 Protein to the Cbfa1 Transcription Factor Thereby Increasing Its Activity^*

Yi Luan, Xiu-Ping Yu, Ke Xu, Bo Ding^¶, Jin Yu^¶, Yan Huang^||, Ning Yang, Peter Lengyel^¶, Paul E. Di Cesare^**, and Chuan-ju Liu¹

From the Department of Orthopedic Surgery, New York University Medical Center, New York, New York 10003, the Institute of Pathogenic Biology, Shandong University School of Medicine, Jinan, Shandong 250012, China, the Departments of ^¶Molecular Biophysics and Biochemistry and ^||Internal Medicine and Cardiology, Yale University School of Medicine, New Haven, Connecticut 06520-8024, the ^**Department of Orthopedic Surgery, University of California Davis Medical Center, Davis, California 95817, and the Department of Cell Biology, New York University School of Medicine, New York, New York 10016

Bone formation requires the coordinated activity of numerous proteins including the transcription factor core-binding factor 1 (Cbfa1). Deregulation of Cbfa1 results in metabolic bone diseases including osteoporosis and osteopetrosis. The retinoblastoma protein (pRb) that is required for osteogenesis binds Cbfa1. We reported earlier that the p200 family protein p204, which is known to be involved in the differentiation of skeletal muscle myotubes, cardiac myocytes, and macrophages, also serves as a cofactor of Cbfa1 and promotes osteogenesis. In this study we established that suppression of p204 expression by an adenovirus construct encoding p204 antisense RNA inhibited osteoblast-specific gene activation by Cbfa1 in an osteogenesis assay involving the pluripotent C2C12 mesenchymal cell line. Using protein-protein interaction assays we established that Cbfa1, pRb, and p204 form a ternary complex in which pRb serves as a linker connecting p204 and Cbfa1. Chromatin immunoprecipitation assays revealed the binding of such a p204-pRb-Cbfa1 transcription factor complex to the promoter of the osteocalcin gene. The pRb requirement of the stimulation of Cbfa1 activity by p204 was established in experiments involving p204 mutants lacking one or two pRb binding (LXCXE) motifs. Such mutants failed to enhance the Cbfa1-dependent transactivation of gene expression as well as osteogenesis. Furthermore, as revealed in reporter gene and in vitro osteogenesis assays p204 synergized with pRb in the stimulation of Cbfa1-dependent gene activation and osteoblast differentiation.

Received for publication, November 28, 2006 , and in revised form, April 16, 2007.

^* This work was supported by National Institutes of Health Research Grants AR050620 (to C. J. L.), AR052022 (to C. J. L.), and AI-12320 (to P. L.) and a New York Chapter of the Arthritis Foundation Dorothy W. Goldstein Young Scholar Award (to C. J. L.). 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.

¹ To whom correspondence should be addressed: Rm. 1608, HJD, Dept. of Orthopedic Surgery, 301 E. 17th St., New York University Medical Center, New York, NY 10003. Tel.: 212-598-6103; Fax: 212-598-6096; E-mail: chuanju.liu{at}med.nyu.edu.

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