Jeon Eun-Joo, Lee Kwang-Youl, Choi Nam-Sook, Lee Mi-Hye, Kim Hyun-Nam, Jin Yun-Hye, Ryoo Hyun-Mo, Choi Je-Yong, Yoshida Minoru, Nishino Norikazu, Oh Byung-Chul, Lee Kyeong-Sook, Lee Yong Hee, Bae Suk-Chul
Department of Biochemistry, School of Medicine, and Institute for Tumor Research, Chungbuk National University, Cheongju 361-763, Korea.
J Biol Chem. 2006 Jun 16;281(24):16502-11. doi: 10.1074/jbc.M512494200. Epub 2006 Apr 13.
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.
Runx2/Cbfa1/Pebp2aA是成骨作用的全局调节因子，对调节骨特异性基因的表达至关重要。Runx2是骨形态发生蛋白（BMP）信号通路的主要靶点。遗传分析表明，Runx2通过Smurf介导的泛素化途径降解，其活性受到HDAC4的抑制。在此，我们展示了BMP信号传导中Smurf、HDAC与Runx2之间的分子联系。BMP-2信号传导刺激p300介导的Runx2乙酰化，增加反式激活活性并抑制Smurf1介导的Runx2降解。HDAC4和HDAC5使Runx2去乙酰化，使该蛋白能够经历Smurf介导的降解。抑制HDAC可增加Runx2乙酰化，并增强BMP-2刺激的成骨细胞分化并增加骨形成。这些结果表明，Runx2的水平由乙酰化、去乙酰化和泛素化的动态平衡控制。这些发现具有重要的医学意义，因为BMP和Runx2在抗骨疾病治疗药物的开发方面备受关注。
