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First published online 27 June 2006
doi: 10.1242/jcs.03014

Journal of Cell Science 119, 2985-2994 (2006)
Published by The Company of Biologists 2006
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Research Article

NFAT3 is specifically required for TNF-{alpha}-induced cyclooxygenase-2 (COX-2) expression and transformation of Cl41 cells

Yan Yan1,*, Jingxia Li1,*, Weiming Ouyang1,*, Qian Ma1, Yu Hu1, Dongyun Zhang1, Jin Ding1, Qingshan Qu1, Kotha Subbaramaiah2 and Chuanshu Huang1,{ddagger}

1 Nelson Institute of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, NY 10987, USA
2 Department of Medicine F-203A, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10021, USA

{ddagger} Author for correspondence (e-mail: chuanshu{at}env.med.nyu.edu)

Accepted 6 April 2006

NFAT family is recognized as a transcription factor for inflammation regulation by inducing the expression of proinflammatory cytokines, such as tumor necrosis factor-{alpha} (TNF-{alpha}), the key mediator of inflammation, which was reported to induce cell transformation in mouse epidermal Cl41 cells. In this study, we demonstrated that TNF-{alpha} was able to induce NFAT activation, as well as the expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS). The induction of COX-2 by TNF-{alpha} was abolished by knockdown of NFAT3 with its siRNA, while the induction of iNOS was not effected. Moreover, TNF-{alpha}-induced anchorage-independent cell growth was significantly inhibited by NFAT3 siRNA and cyclosporine A, a chemical inhibitor for the calcineurin/NFAT pathway, which suggests the importance of NFAT3 in regulating TNF-{alpha}-induced anchorage-independent cell growth. Consequently, impairment of COX-2 by its siRNA or selective inhibitor also inhibited TNF-{alpha}-induced anchorage-independent cell growth. Taken together, our results indicate that NFAT3 plays an important role in the regulation of TNF-{alpha}-induced anchorage-independent cell growth, at least partially, by inducing COX-2 expression in Cl41 cells. These findings suggest that NFAT3/cyclooxygenase-2 act as a link between inflammation and carcinogenesis by being involved in the tumor promotion stage.

Key words: TNF-{alpha}, Cyclooxygenase-2, NFAT3, Cell transformation, Carcinogenesis




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[Abstract] [Full Text] [PDF]


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