Bone morphogenetic protein-2 stimulates Runx2 acetylation.
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.
Jeon
Eun-Joo
EJ
Department of Biochemistry, School of Medicine, and Institute for Tumor Research, Chungbuk National University, Cheongju 361-763, Korea.
Lee
Kwang-Youl
KY
Choi
Nam-Sook
NS
Lee
Mi-Hye
MH
Kim
Hyun-Nam
HN
Jin
Yun-Hye
YH
Ryoo
Hyun-Mo
HM
Choi
Je-Yong
JY
Yoshida
Minoru
M
Nishino
Norikazu
N
Oh
Byung-Chul
BC
Lee
Kyeong-Sook
KS
Lee
Yong Hee
YH
Bae
Suk-Chul
SC
D000818:Animals; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000378:metabolism / Q000502:physiology*; D001842:Bone and Bones / Q000378:metabolism; D002460:Cell Line; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism*; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D051379:Mice; D010006:Osteoblasts / Q000378:metabolism; D010011:Osteocytes / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000502:physiology*; D025801:Ubiquitin / Q000378:metabolism
C525718:BMP2 protein, human; C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D050659:Core Binding Factor Alpha 1 Subunit; C493709:RUNX2 protein, human; D012097:Repressor Proteins; D016212:Transforming Growth Factor beta; D025801:Ubiquitin; C400300:HDAC4 protein, human; C404500:HDAC5 protein, human; D006655:Histone Deacetylases