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J. Biol. Chem., Vol. 278, Issue 23, 21221-21231, June 6, 2003

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The Mitogen-activated Protein Kinase Cascade Promotes Myoblast Cell Survival by Stabilizing the Cyclin-dependent Kinase Inhibitor, p21^WAF1 Protein^*

Olga Ostrovsky and Eyal Bengal 

From the Department of Biochemistry, Rappaport Institute for Research in the Medical Sciences, Faculty of Medicine, Technion-Israel Institute of Technology, P. O. Box 9649, Haifa 31096, Israel

During myogenesis, proliferating myoblasts withdraw from the cell cycle and are either eliminated by programmed cell death or differentiate into mature myotubes. Previous studies indicate that mitogen-activated protein kinase (MAPK) activity is significantly induced with the onset of terminal differentiation of C2 myoblasts. We have investigated the part played by the MAPK pathway in the differentiation of C2 myoblasts. Specific activation of MAPK by expression of an active Raf1-estrogen receptor chimera protein reduced significantly the number of myoblasts undergoing programmed cell death in the differentiation medium. Activation of Raf1 prevented the proteolytic activation of the proapoptotic caspase 9-protein during differentiation. The antiapoptotic function of Raf1 correlated with accumulation of the p21^WAF1 protein resulting from its increased stability. Antisense expression of p21 was used to determine whether the p21^WAF1 protein mediated the antiapoptotic activity of Raf1. Reduction of p21^WAF1 protein in muscle cells abolished the antiapoptotic activity of the MAPK pathway. We conclude that MAPK contributes to muscle differentiation by preventing apoptotic cell death of differentiating myoblasts and that this activity is mediated by stabilization of the p21^WAF1 protein.

Received for publication, November 7, 2002 , and in revised form, February 6, 2003.

^* This work was supported by a grant from the Israel Science Foundation (to E. B.), by a grant from United States-Israel Binational Science Foundation (to E. B.), by funds from the Rappaport Foundation for Medical Research, and by funds from the Foundation for the Promotion of Research in the Technion, Israel Institute of Technology. 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.

To whom correspondence should be addressed. Tel.: 972-4-8295-287; Fax: 972-4-8553-299; E-mail: bengal{at}tx.technion.ac.il.

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