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J. Biol. Chem., Vol. 283, Issue 28, 19826-19835, July 11, 2008

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Cooperative Roles of c-Abl and Cdk5 in Regulation of p53 in Response to Oxidative Stress^*

From the Department of Life Science, Division of Molecular and Life Science, Systems-Biodynamics National Care Research Center, Pohang University of Science and Technology, Pohang 790-784, Republic of Korea

The p53 tumor suppressor protein, a critical modulator of cellular stress responses, is activated through diverse mechanisms that result in its stabilization and transcriptional activation. p53 activity is controlled by transcriptional, translational, and post-translational regulation. The major mechanisms of p53 regulation occur primarily through interactions with HDM2, an E3 ubiquitin ligase that leads to p53 nuclear export and degradation. Here, we demonstrate that hydrogen peroxide-induced oxidative stress elicits down-regulation of HDM2. c-Abl mediates down-regulation of HDM2, leading to an increase of p53 level. Moreover, Cdk5 (cyclin-dependent kinase 5), a proline-directed Ser/Thr kinase, additionally increases p53 stability via post-translational modification of p53 in response to hydrogen peroxide. The p53 protein stabilized by c-Abl and Cdk5 is transcriptionally active; however, transcription of its target gene is differentially regulated with selective binding of p53 on promoter regions of its target genes by c-Abl. In addition, c-Abl modulates Cdk5 activity via phosphorylation of tyrosine 15 in cooperation with cleavage of p35 to p25. Our results show that c-Abl and Cdk5 cooperatively regulate maximal activation of p53, resulting in neuronal death in response to oxidative stress by hydrogen peroxide. These findings aid in clarifying the mechanism underlying the occurrence of neuronal apoptosis as a result of c-Abl and Cdk5-mediated p53 stabilization and transcriptional activation.

Received for publication, July 27, 2007 , and in revised form, May 16, 2008.

^* This work was supported by the Frontier Research for Functional Human Genome, and the Systems Bio-Dynamics National Core Research Center sponsored by the Korean Ministry of Science and Technology. This work is also supported by the Brain Korea 21 Program of the Korean Ministry of Education. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1-4.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: Dept. of Life Science, Pohang University of Science and Technology, San 31, Hyoja Dong, Pohang 790-784, Republic of Korea. Tel.: 82-54-279-2297; Fax: 82-54-279-2199; E-mail: ktk{at}postech.ac.kr.

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