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J. Biol. Chem., Vol. 283, Issue 38, 25928-25935, September 19, 2008

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Activation of Polo-like Kinase 3 by Hypoxic Stresses^*

Ling Wang, Jie Gao, Wei Dai, and Luo Lu¹

From the Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Torrance, California 90502 and the Department of Environmental Medicine, New York University School of Medicine, Tuxedo, New York 10987

Hypoxia/reoxygenation stress induces the activation of specific signaling proteins and activator protein 1 (AP-1) to regulate cell cycle regression and apoptosis. In the present study, we report that hypoxia/reoxygenation stress activates AP-1 by increasing c-Jun phosphorylation and DNA binding activity through activation of Polo-like-kinase 3 (Plk3) resulting in apoptosis. The specific effect of hypoxia/reoxygenation stress on Plk3 activation resulting in c-Jun phosphorylation was the opposite of UV irradiation-induced responses that are meanly independent on activation of the stress-induced JNK signaling pathway in human corneal epithelial (HCE) cells. The effect of hypoxia/reoxygenation stress-induced Plk3 activation on increased c-Jun phosphorylation and apoptosis was also mimicked by exposure of cells to CoCl₂. Hypoxia/reoxygenation activated Plk3 in HCE cells to directly phosphorylate c-Jun proteins at phosphorylation sites Ser-63 and Ser-73, and to increase DNA binding activity of c-Jun, detected by EMSA. Further evidence demonstrated that Plk3 and phospho-c-Jun were immunocolocalized in the nuclear compartment of hypoxia/reoxygenation stress-induced cells. Increased Plk3 activity by overexpression of wild-type and dominantly positive Plk3 enhanced the effect of hypoxia/reoxygenation on c-Jun phosphorylation and cell death. In contrast, knocking-down Plk3 mRNA suppressed hypoxia-induced c-Jun phosphorylation. Our results provide a new mechanism indicating that hypoxia/reoxygenation induces Plk3 activation instead of the JNK effect to directly phosphorylate and activate c-Jun, subsequently contributing to apoptosis in HCE cells.

Received for publication, February 19, 2008 , and in revised form, July 22, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants EY12953 (to L. L.) and CA074229 (to W. 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: Dept. of Medicine, David Geffen School of Medicine at UCLA, 1124 W. Carson St., C-2, Torrance, CA 90502. Tel.: 310-787-6853; Fax: 310-222-3781; E-mail: lluou{at}ucla.edu.

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