Myostatin induces p300 degradation to silence cyclin D1 expression through the PI3K/PTEN/Akt pathway.
Myostatin is a negative regulator of skeletal muscle growth and affects numerous genes expression involved in cell proliferation, differentiation and metabolism. However, the molecular mechanisms underlying myostatin-regulated genes expression remain to be elucidated. In this study, we showed that myostatin blocked the recruitment of p300 to the cyclin D1 promoter, resulting in the silence of cyclin D1 expression. Our data further demonstrated that myostatin decreased the protein level of p300 by inducing p300 degradation via the ubiquitin-proteasome system. In addition, we provided experimental evidence to show that myostatin-induced p300 degradation was mediated by the phosphatidylinositol 3-kinase/PTEN/Akt signaling pathway and this could be antagonized by IGF-1 or insulin. Results presented in this study uncovered an epigenetic control of genes expression in response to myostatin.
Ji
Ming
M
National Laboratory of Medical Molecular Biology and Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Tsinghua University, 5 Dong Dan San Tiao, Beijing 100005, PR China.
Zhang
Qiang
Q
Ye
Jianwei
J
Wang
Xueyan
X
Yang
Wei
W
Zhu
Dahai
D
D000818:Animals; D002460:Cell Line; D019938:Cyclin D1 / Q000235:genetics*; D020868:Gene Silencing; D007328:Insulin / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D051379:Mice; D032446:Myoblasts / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D055435:Myostatin; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011401:Promoter Regions, Genetic; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D025801:Ubiquitin / Q000378:metabolism; D050880:p300-CBP Transcription Factors / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D000099224:p300-CBP-Associated Factor
D019938:Cyclin D1; D007328:Insulin; D007334:Insulin-Like Growth Factor I; D055435:Myostatin; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D046988:Proteasome Endopeptidase Complex; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D025801:Ubiquitin; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C525912:Mstn protein, mouse