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J. Biol. Chem., Vol. 283, Issue 43, 28897-28908, October 24, 2008

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AMP-activated Protein Kinase Contributes to UV- and H₂O₂-induced Apoptosis in Human Skin Keratinocytes^*

Cong Cao¹, Shan Lu¹, Rebecca Kivlin, Brittany Wallin, Elizabeth Card, Andrew Bagdasarian, Tyrone Tamakloe, Wen-ming Chu, Kun-liang Guan^¶, and Yinsheng Wan²

From the Department of Biology, Providence College, Providence, Rhode Island 02918, the Department of Molecular Microbiology and Immunology, Brown University, Providence, Rhode Island 02903, and the ^¶Department of Pharmacology, University of California, San Diego, California 90293

AMP-activated protein kinase or AMPK is an evolutionarily conserved sensor of cellular energy status, activated by a variety of cellular stresses that deplete ATP. However, the possible involvement of AMPK in UV- and H₂O₂-induced oxidative stresses that lead to skin aging or skin cancer has not been fully studied. We demonstrated for the first time that UV and H₂O₂ induce AMPK activation (Thr¹⁷² phosphorylation) in cultured human skin keratinocytes. UV and H₂O₂ also phosphorylate LKB1, an upstream signal of AMPK, in an epidermal growth factor receptor-dependent manner. Using compound C, a specific inhibitor of AMPK and AMPK-specific small interfering RNA knockdown as well as AMPK activator, we found that AMPK serves as a positive regulator for p38 and p53 (Ser¹⁵) phosphorylation induced by UV radiation and H₂O₂ treatment. We also observed that AMPK serves as a negative feedback signal against UV-induced mTOR (mammalian target of rapamycin) activation in a TSC2-dependent manner. Inhibiting mTOR and positively regulating p53 and p38 might contribute to the pro-apoptotic effect of AMPK on UV- or H₂O₂-treated cells. Furthermore, activation of AMPK also phosphorylates acetyl-CoA carboxylase or ACC, the pivotal enzyme of fatty acid synthesis, and PFK2, the key protein of glycolysis in UV-radiated cells. Collectively, we conclude that AMPK contributes to UV- and H₂O₂-induced apoptosis via multiple mechanisms in human skin keratinocytes and AMPK plays important roles in UV-induced signal transduction ultimately leading to skin photoaging and even skin cancer.

Received for publication, May 30, 2008 , and in revised form, August 15, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grant P20 RR016457 from the INBRE Program of the National Center for Research Resources. This work was also supported by grants for biomedical research from the Rhode Island Foundation and the Slater Center for Environmental Biotechnology. 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 Both authors contributed equally to this paper.

² To whom correspondence should be addressed: Providence College, 549 River Ave., Providence, RI 02918-0001. Tel.: 401-865-2507; Fax: 401-865-1438; E-mail: yswan{at}providence.edu.

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