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Carcinogenesis Advance Access published online on October 25, 2006
Carcinogenesis, doi:10.1093/carcin/bgl186
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© 2006 The Author(s)
Received May 28, 2006
Revised September 18, 2006
Accepted September 27, 2006

CARCINOGENESIS

JNK1, but not JNK2, is required for COX-2 induction by nickel compounds

Dongyun Zhang 1, Jingxia Li 1, Kangjian Wu 1, Weiming Ouyang 1, Jin Ding 1, Zheng-gang Liu 2, Max Costa 1, and Chuanshu Huang 1 *

1 Nelson Institute of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, NY 10987
2 Cell and Cancer Biology Branch, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland 20892

* To whom correspondence should be addressed.
Chuanshu Huang, E-mail: chuanshu{at}env.med.nyu.edu


  Abstract

Activation of the signaling pathways leading to gene expression regulation, is critical in the carcinogenic effects of nickel exposure. In the present study, we found nickel exposure could induce cyclooxygenase-2 (COX-2) expression at transcriptional and protein levels in both human bronchoepithelial cells (Beas-2B) and murine embryonic fibroblasts (MEFs). We further provided direct evidence for the specific involvement of the JNK1 signaling pathway in the COX-2 induction using specific gene knockout approaches. Our results demonstrated that COX2 induction by nickel was impaired in JNK1-/- MEFs, but not in JNK2-/- MEFs. Moreover, re-constitutional expression of JNK1 restored COX-2 induction, confirming the specific requirement of JNK1 in COX-2 induction. Further investigation revealed that JNK1 mediated the nickel-induced COX-2 expression in a c-Jun/AP-1-dependent manner. Ectopic expression of TAM67, a c-Jun dominant negative mutant, also suppressed the COX-2 induction. Our results demonstrate that the JNK1/c-Jun/AP-1 pathway, but not the JNK2 pathway, plays a critical role in nickel-induced COX-2 expression.

Keywords: COX-2; gene regulation; JNKs; signal transduction pathways; nickel.
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