The Journal of Experimental Medicine
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Published 15 December 2003. doi:10.1084/jem.20031187
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© Rockefeller University Press, 0022-1007/2003/12/1959 $5.00
The Journal of Experimental Medicine, Volume 198, Number 12, 1959-1964

Brief Definitive Report

The Tumor Suppressor CYLD Interacts with TRIP and Regulates Negatively Nuclear Factor {kappa}B Activation by Tumor Necrosis Factor

Alexandre Regamey1, Daniel Hohl1, Jia Wei Liu1, Thierry Roger2, Priit Kogerman3,4, Rune Toftgård3 and Marcel Huber1

1 Department of Dermatology, Department of Internal Medicine, CHUV, Lausanne 1011, Switzerland
2 Division of Infectious Diseases, Department of Internal Medicine, CHUV, Lausanne 1011, Switzerland
3 Department of Bioscience, NOVUM, Karolinska Institutet, Huddinge 141 57, Sweden
4 Laboratory of Molecular Genetics, National Institute of Chemical Physics and Biophysics, and Department of Gene Technology, Tallinn Technical University, Tallinn 12618, Estonia

Address correspondence to Marcel Huber, Department of Dermatology, CHUV, Avenue Beaumont 29, BT-421, Lausanne 1011, Switzerland. Phone: 41-21-3140374; Fax: 41-21-3140378; email: Marcel.Huber{at}chuv.hospvd.ch

Cylindromas are benign adnexal skin tumors caused by germline mutations in the CYLD gene. In most cases the second wild-type allele is lost in tumor tissue, suggesting that CYLD functions as tumor suppressor. CYLD is a protein of 956 amino acids harboring a functional deubiquitinating domain at the COOH-terminal end. To shed more light on the function of CYLD, we have performed a yeast two hybrid screen using an HaCaT cDNA library that identified the RING finger protein TRIP (TRAF-interacting protein) as interactor with full-length CYLD. Mapping of the interacting domains revealed that the central domain of CYLD binds to the COOH-terminal end of TRIP. Far Western analysis and coimmunoprecipitations in mammalian cells confirmed that full-length CYLD binds to the COOH-terminal domain of TRIP. Because TRIP is an inhibitor of nuclear factor (NF)-{kappa}B activation by tumor necrosis factor (TNF), the effect of CYLD on NF-{kappa}B activation was investigated in HeLa cells. The results established that CYLD down-regulates NF-{kappa}B activation by TNF-{alpha}. The inhibition by CYLD depends on the presence of the central domain interacting with TRIP and its deubiquitinating activity. These findings indicate that cylindromas arise through constitutive NF-{kappa}B activation leading to hyperproliferation and tumor growth.

Key Words: cylindroma • skin tumor • epidermis • keratinocyte • inhibition


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