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Papers In Press, published online ahead of print October 20, 2004
Microbiology and Immunology, Penn State University College of Medicine, Hershey, PA 17033
Corresponding Author: sxs70{at}psu.edu
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 N-terminal kinase (JNK). CYLD knockdown by RNA interference results in hyper activation of JNK by diverse immune stimuli, including TNF-a, interleukin-1, lipopolysaccharide, and an agonistic anti-CD40 antibody. The JNK-inhibitory function of CYLD appears to be specific for immune receptors, since 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 (IKK), 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 IKK pathway.
J. Biol. Chem, 10.1074/jbc.M411049200
Submitted on September 27, 2004
Revised on October 20, 2004
Accepted on October 20, 2004
Negative regulation of JNK signaling pathway by the tumor suppressor CYLD
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