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J. Biol. Chem., Vol. 280, Issue 27, 25788-25801, July 8, 2005

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Mirk/Dyrk1B Mediates Survival during the Differentiation of C2C12 Myoblasts^*

Stephen E. Mercer, Daina Z. Ewton, Xiaobing Deng, Seunghwan Lim, Thomas R. Mazur, and Eileen Friedman

From the Department of Pathology, Upstate Medical University, State University of New York, Syracuse, New York 13210

The kinase Mirk/dyrk1B is essential for the differentiation of C2C12 myoblasts. Mirk reinforces the G₀/G₁ arrest state in which differentiation occurs by directly phosphorylating and stabilizing p27^Kip1 and destabilizing cyclin D1. We now demonstrate that Mirk is anti-apoptotic in myoblasts. Knockdown of endogenous Mirk by RNA interference activated caspase 3 and decreased myoblast survival by 75%, whereas transient overexpression of Mirk increased cell survival. Mirk exerts its anti-apoptotic effects during muscle differentiation at least in part through effects on the cell cycle inhibitor and pro-survival molecule p21^Cip1. Overexpression and RNA interference experiments demonstrated that Mirk phosphorylates p21 within its nuclear localization domain at Ser-153 causing a portion of the typically nuclear p21 to localize in the cytoplasm. Phosphomimetic GFP-p21-S153D was pancellular in both cycling C2C12 myoblasts and NIH3T3 cells. Endogenous Mirk in myotubes and overexpressed Mirk in NIH3T3 cells were able to cause the pancellular localization of wild-type GFP-p21 but not the nonphosphorylatable mutant GFP-p21-S153A. Translocation to the cytoplasm enables p21 to block apoptosis through inhibitory interaction with pro-apoptotic molecules. Phosphomimetic p21-S153D was more effective than wild-type p21 in blocking the activation of caspase 3. Transient expression of p21-S153D also increased myoblast viability in colony forming assays, whereas the p21-S153A mutant had no effect. This Mirk-dependent change in p21 intracellular localization is a natural part of myoblast differentiation. Endogenous p21 localized exclusively to the nuclei of proliferating myoblasts but was also found in the cytoplasm of post-mitotic multinucleated myotubes and adult human skeletal myofibers.

Received for publication, December 2, 2004 , and in revised form, March 29, 2005.

^* This work was supported by United States Public Health Service Award RO1 CA67405 (to E. F.). 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: Pathology Dept., Upstate Medical University, 750 East Adams St., Syracuse, NY 13210. Tel.: 315-464-7138; Fax: 315-464-8419; E-mail: friedmae{at}upstate.edu.

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