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J. Biol. Chem., Vol. 281, Issue 35, 25215-25222, September 1, 2006

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p38 MAP Kinase Mediates Apoptosis through Phosphorylation of Bim_EL at Ser-65^*

Beibei Cai, Sandra H. Chang, Esther B. E. Becker, Azad Bonni, and Zhengui Xia^¶1

From the Toxicology Program, Department of Environmental and Occupational Health Sciences, ^¶Graduate Program in Neurobiology and Behavior, University of Washington, Seattle, Washington 98195-7234, and Program in Biological and Biomedical Sciences, Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115

The stress-activated c-Jun N-terminal protein kinase (JNK) and p38 mitogen-activated protein (MAP) kinase (p38) regulate apoptosis induced by several forms of cellular insults. Potential targets for these kinases include members of the Bcl-2 family proteins, which mediate apoptosis generated through the mitochondria-initiated, intrinsic cell death pathway. Indeed, the activities of several Bcl-2 family proteins, both pro- and anti-apoptotic, are controlled by JNK phosphorylation. For example, the pro-apoptotic activity of Bim_EL, a member of the Bcl-2 family, is stimulated by JNK phosphorylation at Ser-65. In contrast, there is no reported evidence that p38-induced apoptosis is due to direct phosphorylation of Bcl-2 family proteins. Here we report evidence that sodium arsenite-induced apoptosis in PC12 cells may be due to direct phosphorylation of Bim_EL at Ser-65 by p38. This conclusion is supported by data showing that ectopic expression of a wild type, but not a non-phosphorylatable S65A mutant of Bim_EL, potentiates sodium arsenite-induced apoptosis and by experiments showing direct phosphorylation of Bim_EL at Ser-65 by p38 in vitro. Furthermore, sodium arsenite induced Bim_EL phosphorylation at Ser-65, which was blocked by p38 inhibition. This study provides the first example whereby p38 induces apoptosis by phosphorylating a member of the Bcl-2 family and illustrates that phosphorylation of Bim_EL on Ser-65 may be a common regulatory point for cell death induced by both JNK and p38 pathways.

Received for publication, November 28, 2005 , and in revised form, June 21, 2006.

^* This work was supported by Grants ES 012215 and NS44069 (to Z. X.) and NS421021 (to A. B.). 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: Dept. of Environmental and Occupational Health Sciences, University of Washington, Box 357234, Seattle, WA 98195-7234. Tel.: 206-616-9433; Fax: 206-685-3990; E-mail: zxia{at}u.washington.edu.

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