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J. Biol. Chem., Vol. 281, Issue 24, 16502-16511, June 16, 2006

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Bone Morphogenetic Protein-2 Stimulates Runx2 Acetylation^*

Eun-Joo Jeon, Kwang-Youl Lee, Nam-Sook Choi, Mi-Hye Lee, Hyun-Nam Kim^¶, Yun-Hye Jin, Hyun-Mo Ryoo, Je-Yong Choi^¶, Minoru Yoshida^||, Norikazu Nishino^**, Byung-Chul Oh, Kyeong-Sook Lee, Yong Hee Lee, and Suk-Chul Bae¹

From the Department of Biochemistry, School of Medicine, and Institute for Tumor Research, Chungbuk National University, Cheongju 361-763, Korea, the Department of Cell and Developmental Biology, School of Dentistry, Seoul National University, Seoul 110-749, Korea, the ^¶Department of Biochemistry, School of Medicine, Kyungpook National University, Taegu 700-422, Korea, the ^||Chemical Genetics Laboratory, Discovery Research Institute, RIKEN Hirosawa 2-1, Wako Saitama 351-0198, Japan, and the ^**Graduate School of Life Science and Systems Engineering, Kyushu Institute of Technology, 2-4, Hibikino, Wakamatsu, Kitakyushu 808-0196, Japan

Runx2/Cbfa1/Pebp2aA is a global regulator of osteogenesis and is crucial for regulating the expression of bone-specific genes. Runx2 is a major target of the bone morphogenetic protein (BMP) pathway. Genetic analysis has revealed that Runx2 is degraded through a Smurf-mediated ubiquitination pathway, and its activity is inhibited by HDAC4. Here, we demonstrate the molecular link between Smurf, HDACs and Runx2, in BMP signaling. BMP-2 signaling stimulates p300-mediated Runx2 acetylation, increasing transactivation activity and inhibiting Smurf1-mediated degradation of Runx2. HDAC4 and HDAC5 dea-cetylate Runx2, allowing the protein to undergo Smurf-mediated degradation. Inhibition of HDAC increases Runx2 acetylation, and potentiates BMP-2-stimulated osteoblast differentiation and increases bone formation. These results demonstrate that the level of Runx2 is controlled by a dynamic equilibrium of acetylation, deacetylation, and ubiquitination. These findings have important medical implications because BMPs and Runx2 are of tremendous interest with regard to the development of therapeutic agents against bone diseases.

Received for publication, November 22, 2005 , and in revised form, April 5, 2006.

^* This work was supported by the Creative Research Grant R16-2003-002-01001-0 from the Korea Science and Engineering Foundation (to S-C. B.) and the Program for the Promotion of Fundamental Studies in Health Science of the National Institute of Biomedical Innovation, Japan (to N. N. and M. Y.). 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: Dept. of Biochemistry, School of Medicine, and Institute for Tumor Research, Chungbuk National University, Cheongju 361-763, Korea. Tel.: 82-43-261-2842; Fax: 82-43-274-8705; E-mail: scbae{at}chungbuk.ac.kr.

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