Bone morphogenetic protein-2 stimulates RUNX2 acetylation

doi:10.1074/jbc.M512494200

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Papers In Press, published online ahead of print April 13, 2006
J. Biol. Chem, 10.1074/jbc.M512494200
Submitted on November 22, 2005
Accepted on April 13, 2006

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 Bae

Biochemistry, College of Medicine, Chungbuk National University, Cheongju, Chungbuk 361-763

Corresponding Author: scbae{at}chungbuk.ac.kr

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 deacetylate 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 since BMPs and Runx2 are of tremendous interest with regard to the development of therapeutic agents against bone diseases.

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