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J. Biol. Chem., Vol. 281, Issue 45, 34113-34123, November 10, 2006

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Coordination of JNK1 and JNK2 Is Critical for GADD45 Induction and Its Mediated Cell Apoptosis in Arsenite Responses^*

From the Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York 10987

Arsenite is a well documented environmental pathogen, whereas it has also been applied as medication to treat various neoplasmas. The pathogenic and therapeutic effects of arsenite are associated with cellular apoptotic responses. However, the molecular mechanisms of arsenite-induced apoptosis are not very well understood. Our previous study has shown that arsenite exposure is able to activate JNKs, which subsequently mediate the apoptotic outcome. The present study further revealed that the coordination of JNK1 and JNK2 was critical for the arsenite-induced expression of GADD45 (growth arrest and DNA damage 45), which in turn mediated the cellular apoptosis. The arsenite-induced apoptosis and GADD45 expression were significantly impaired in mouse embryonic fibroblasts deficient in either jnk1 (JNK1^–/–) or jnk2 (JNK2^–/–). Knockdown of GADD45 by its specific small interfering RNA also dramatically reduced the apoptotic responses, and overexpression of GADD45 in either JNK1^–/– or JNK2^–/– mouse embryonic fibroblasts partially resensitized the cell death. Furthermore, it was found that the regulation of GADD45 by JNK1 and JNK2 was achieved through mediating the activation of c-Jun, since in the JNK1^–/– and JNK2^–/– cells the c-Jun activation was impaired, and overexpression of the dominant negative mutant of c-Jun (TAM67) in wild type cells could also block GADD45 induction as well as cellular apoptosis. Our results demonstrate that the coordination of JNK1 and JNK2 is critical for c-Jun/GADD45-mediated cellular apoptosis induced by arsenite.

Received for publication, March 24, 2006 , and in revised form, September 6, 2006.

^* This work was supported in part by NCI, National Institutes of Health (NIH), Grants CA094964, CA112557, and CA103180 and NIEHS, NIH, Grants ES012451 and ES000260. 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: Nelson Institute of Environmental Medicine, New York University School of Medicine, 57 Old Forge Rd., Tuxedo, NY 10987. Tel.: 845-731-3519; Fax: 845-351-2320; E-mail: chuanshu{at}env.med.nyu.edu.

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