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J. Biol. Chem., Vol. 281, Issue 40, 29703-29710, October 6, 2006

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The Protein Kinase C Catalytic Fragment Targets Mcl-1 for Degradation to Trigger Apoptosis^*

From the Department of Pathology and the Oncology Institute, Skin Cancer Research Program, Loyola University Medical Center, Maywood, Illinois 60153

Proteolytic cleavage and subsequent activation of protein kinase C (PKC) is required for apoptosis induced by a variety of genotoxic agent, including UV radiation. In addition, overexpression of the constitutively active PKC catalytic fragment (PKC-cat) is sufficient to trigger Bax activation, cytochrome c release, and apoptosis. While PKC is a key apoptotic effector, the downstream target(s) responsible for the mitochondrial apoptotic cascade are not known. We found that expression of the active PKC-cat in HaCaT cells triggers a reduction in the anti-apoptotic protein Mcl-1, similar to UV radiation. The down-regulation of Mcl-1 induced by PKC-cat was not at the mRNA level but was due to decreased protein half-life. Overexpression of Mcl-1 protected HaCaT cells from both UV and PKC-cat-induced apoptosis and blocked the release of cytochrome c from the mitochondria, indicating that Mcl-1 down-regulation was required for apoptosis signaling. Indeed, down-regulation of Mcl-1 with siRNA slightly increased the basal apoptotic rate of HaCaT cells and dramatically sensitized them to UV or PKC-cat-induced apoptosis. HaCaT cells with down-regulated Mcl-1 had higher activated Bax protein, as measured by Bax cross-linking, indicating that Mcl-1 down-regulation is sufficient for Bax activation. Finally, recombinant PKC could phosphorylate Mcl-1 in vitro, identifying Mcl-1 as a direct target for PKC. Overall our results identify Mcl-1 as an important target for PKC-cat that can mediate its pro-apoptotic effects on mitochondria to amplify the apoptotic signaling induced by a wide range of apoptotic stimuli.

Received for publication, August 2, 2006

^* This work was supported by a grant from the Potts Foundation and National Institutes of Health Grant CA83784 (to M. F. D.). 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: Cardinal Bernardin Cancer Center, Rm. 304, Loyola University Medical Center, 2160 S. First Ave., Maywood, IL 60153. Tel.: 708-327-3358; Fax: 708-327-3158; E-mail: mdennin{at}lumc.edu.

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