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J. Biol. Chem., Vol. 282, Issue 6, 3799-3808, February 9, 2007

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Myostatin Induces Cyclin D1 Degradation to Cause Cell Cycle Arrest through a Phosphatidylinositol 3-Kinase/AKT/GSK-3 Pathway and Is Antagonized by Insulin-like Growth Factor 1^*

Wei Yang, Yong Zhang, Yanfeng Li, Zhenguo Wu, and Dahai Zhu^¶1

From the National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, 5 Dong Dan San Tiao, Beijing 100005, China, the ^¶Molecular and Cellular Developmental Biology Laboratory, Harbin Institute of Technology, Harbin 150001, China, and the Department of Biochemistry, Hong Kong University of Science and Technology, Clearwater Bay, Kowloon, Hong Kong 999077, China

Myostatin is a transforming growth factor superfamily member and is known as an inhibitor of skeletal muscle cell proliferation and differentiation. Exposure to myostatin induces G₁ phase cell cycle arrest. In this study, we demonstrated that myostatin down-regulates Cdk4 activity via promotion of cyclin D1 degradation. Overexpression of cyclin D1 significantly blocked myostatin-induced proliferation inhibition. We further showed that phosphorylation at threonine 286 by GSK-3 was required for myostatin-stimulated cyclin D1 nuclear export and degradation. This process is dependent upon the activin receptor IIB and the phosphatidylinositol 3-kinase/Akt pathway but not Smad3. Insulin-like growth factor 1 (IGF-1) treatment or Akt activation attenuated the myostatin-stimulated cyclin D1 degradation as well as the associated cell proliferation repression. In contrast, attenuation of IGF-1 signaling caused C2C12 cells to undergo apoptosis in response to myostatin treatment. The observation that IGF-1 treatment increases myostatin expression through a phosphatidylinositol 3-kinase pathway suggests a possible feedback regulation between IGF-1 and myostatin. These findings uncover a novel role for myostatin in the regulation of cell growth and cell death in concert with IGF-1.

Received for publication, October 31, 2006 , and in revised form, November 24, 2006.

^* This work was supported by National Basic Research Program of China Grants 2005CB522400 and 2005CB522507 and National Natural Science Foundation of China Grants 30025027, 30400231, 30570984, 30429002, and 30330430. 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: National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, 5 Dong Dan San Tiao, Beijing 100005, China. Tel.: 86-10-65296949; Fax: 86-10-65105083; E-mail: dhzhu{at}pumc.edu.cn.

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