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J. Biol. Chem., Vol. 282, Issue 29, 21487-21496, July 20, 2007

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A Critical Role for IB Kinase in Metallothionein-1 Expression and Protection against Arsenic Toxicity^*

Zhimin Peng, Li Peng, Yunxia Fan, Ebrahim Zandi, Howard G. Shertzer, and Ying Xia¹

From the Department of Environmental Health, University of Cincinnati Medical Center, Cincinnati, Ohio 45267-0056 and Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, California 90033

Arsenic is a widespread environmental toxic agent that has been shown to cause diverse tissue and cell damage and at the same time to be an effective anti-cancer therapeutic agent. The objective of this study is to explore the signaling mechanisms involved in arsenic toxicity. We show that the IB kinase (IKK) plays a crucial role in protecting cells from arsenic toxicity. Ikk^-/- mouse 3T3 fibroblasts have decreased expression of antioxidant genes, such as metallothionein 1 (Mt1). In contrast to wild type and IKK-reconstituted Ikk^-/- cells, IKK-null cells display a marked increase in arsenic-induced reactive oxygen species (ROS) accumulation, which leads to activation of the MKK4-c-Jun NH₂-terminal kinase (JNK) pathway, c-Jun phosphorylation, and apoptosis. Pretreatment with the antioxidant N-acetylcysteine (NAC) and expression of MT1 in the Ikk^-/- cells prevented JNK activation; moreover, NAC pretreatment, MT1 expression, MKK4 ablation, and JNK inhibition all protected cells from death induced by arsenic. Our data show that two signaling pathways appear to be important for modulating arsenic toxicity. First, the IKK-NF-B pathway is crucial for maintaining cellular metallothionein-1 levels to counteract ROS accumulation, and second, when this pathway fails, excessive ROS leads to activation of the MKK4-JNK pathway, resulting in apoptosis.

Received for publication, March 23, 2007 , and in revised form, May 23, 2007.

^* This work was supported in part by National Institutes of Health Grants ES11798 (to Y. X.). 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 Environmental Health, University of Cincinnati, 123 E. Shields St., Cincinnati, OH 45267-0056. Tel.: 513-558-0371; Fax: 513-558-0974; E-mail: xiay{at}email.uc.edu.

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