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J. Biol. Chem., Vol. 279, Issue 53, 55161-55167, December 31, 2004

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Negative Regulation of JNK Signaling by the Tumor Suppressor CYLD^*

William Reiley, Minying Zhang, and Shao-Cong Sun¶

From the Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033

CYLD is a tumor suppressor that is mutated in familial cylindromatosis, an autosomal dominant predisposition to multiple tumors of the skin appendages. Recent studies suggest that transfected CYLD has deubiquitinating enzyme activity and inhibits the activation of transcription factor NF-B. However, the role of endogenous CYLD in regulating cell signaling remains poorly defined. Here we report a critical role for CYLD in negatively regulating the c-Jun NH₂-terminal kinase (JNK). CYLD knockdown by RNA interference results in hyper-activation of JNK by diverse immune stimuli, including tumor necrosis factor-, interleukin-1, lipopolysaccharide, and an agonistic anti-CD40 antibody. The JNK-inhibitory function of CYLD appears to be specific for immune receptors because the CYLD knockdown has no significant effect on stress-induced JNK activation. Consistently, CYLD negatively regulates the activation of MKK7, an upstream kinase known to mediate JNK activation by immune stimuli. We further demonstrate that CYLD also negatively regulates IB kinase, although this function of CYLD is seen in a receptor-dependent manner. These findings identify the JNK signaling pathway as a major downstream target of CYLD and suggest a receptor-dependent role of CYLD in regulating the IB kinase pathway.

Received for publication, September 27, 2004

^* This work was partially supported by National Institutes of Health Research Grants CA094922 and AI45045 (to S.-C. S) and AI45045 (to M. Z.). 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.

These authors contributed equally to this work.

Supported by National Institutes of Health predoctoral/postdoctoral training Grant 5 T32CA60395-09.

^¶ To whom correspondence should be addressed. Tel.: 717-531-4164; Fax: 717-531-6522; E-mail: sxs70{at}psu.edu.

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