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J. Biol. Chem., Vol. 282, Issue 44, 31900-31908, November 2, 2007

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Role of MAPK Phosphatase-1 in Sustained Activation of JNK during Ethanol-induced Apoptosis in Hepatocyte-like VL-17A Cells^*

Senthil K. Venugopal, Jenny Chen, Yanhong Zhang, Dahn Clemens, Antonia Follenzi^¶, and Mark A. Zern¹

From the Department of Internal Medicine, Transplant Research Program, UC Davis Medical Center, Sacramento, California 95817, the Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska 68198, and the ^¶Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, New York 10461

Ethanol metabolism plays a central role in activating the mitogen-activated protein kinase (MAPK) cascade leading to inflammation and apoptosis. Sustained activation of c-Jun N-terminal kinase (JNK), one of the MAPKs, has been shown to induce apoptosis in hepatocytes. MAPK phosphatase-1 (MKP-1) has been shown to dephosphorylate MAPKs in several cells. The aim of the study is to evaluate the role of MKP-1 in sustained JNK activation as a mechanism to explain ethanol-induced hepatocyte apoptosis. VL-17A cells (HepG2 cells overexpressing alcohol dehydrogenase and cytochrome P450-2E1) were exposed to ethanol for different time periods. Western blots were performed for MKP-1, phospho-JNK, phosphotyrosine, and protein kinase C (PKC). Electrophoretic mobility shift assays for AP-1 were performed. Apoptosis was measured by caspase-3 activity assay, TUNEL, and 4',6-diamidino-2-phenylindole staining. Reactive oxygen species were neutralized by overexpressing both superoxide dismutase-3 and catalase genes using lentiviral vectors in VL-17A cells. Ethanol incubation markedly decreased the MKP-1 protein levels to 15% of control levels and was associated with sustained phosphorylation of p46 JNK and p54 JNK, as well as increased apoptosis. VL-17A cells overexpressing superoxide dismutase-3 and catalase, treatment with a tyrosine kinase inhibitor, or incubation of the cells with PKC small interference RNAs significantly inhibited the ethanol-induced MKP-1 degradation and apoptosis. Ethanol-induced oxidative stress enhanced the tyrosine phosphorylation of PKC, which in turn caused the proteasomal degradation of MKP-1, leading to sustained JNK activation and increased apoptosis in VL-17A cells.

Received for publication, May 7, 2007 , and in revised form, September 5, 2007.

^* This work was supported by National Institutes of Health Grant RO1 AA006386 (to M. A. Z.). 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: University of California at Davis Medical Center, 4635 2nd Ave., Rm. 1001, Sacramento, CA 95817. Tel.: 916-734-8063; Fax: 916-734-8097; E-mail: mazern{at}ucdavis.edu.

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