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Carcinogenesis Advance Access originally published online on October 25, 2006
Carcinogenesis 2007 28(4):883-891; doi:10.1093/carcin/bgl186
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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

Dongyun Zhang, Jingxia Li, Kangjian Wu, Weiming Ouyang, Jin Ding, Zheng-gang Liu1, Max Costa and Chuanshu Huang*

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

*To whom correspondence should be addressed. Tel: +1 845 731 3519; Fax: +1 845 351 2320; Email: chuanshu{at}env.med.nyu.edu

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 COX-2 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.

Abbreviations: AP-1, activator protein-1; Beas-2B, human bronchoepithelial cells; COX-2, cyclooxygenase-2; JNKs, c-Jun N-terminal kinases; MEFs, mouse embryonic fibroblasts

Received May 28, 2006; revised September 18, 2006; accepted September 27, 2006.


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