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)-κB activation by tumor necrosis factor (TNF), the effect of CYLD on NF-κB activation was investigated in HeLa cells. The results established that CYLD down-regulates NF-κB activation by TNF-α. 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-κB activation leading to hyperproliferation and tumor growth.
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15 December 2003
Brief Definitive Report|
December 15 2003
The Tumor Suppressor CYLD Interacts with TRIP and Regulates Negatively Nuclear Factor κB Activation by Tumor Necrosis Factor
Alexandre Regamey,
Alexandre Regamey
1Department of Dermatology, Department of Internal Medicine, CHUV, Lausanne 1011, Switzerland
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Daniel Hohl,
Daniel Hohl
1Department of Dermatology, Department of Internal Medicine, CHUV, Lausanne 1011, Switzerland
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Jia Wei Liu,
Jia Wei Liu
1Department of Dermatology, Department of Internal Medicine, CHUV, Lausanne 1011, Switzerland
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Thierry Roger,
Thierry Roger
2Division of Infectious Diseases, Department of Internal Medicine, CHUV, Lausanne 1011, Switzerland
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Priit Kogerman,
Priit Kogerman
3Department of Bioscience, NOVUM, Karolinska Institutet, Huddinge 141 57, Sweden
4Laboratory of Molecular Genetics, National Institute of Chemical Physics and Biophysics, and Department of Gene Technology, Tallinn Technical University, Tallinn 12618, Estonia
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Rune Toftgård,
Rune Toftgård
3Department of Bioscience, NOVUM, Karolinska Institutet, Huddinge 141 57, Sweden
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Marcel Huber
Marcel Huber
1Department of Dermatology, Department of Internal Medicine, CHUV, Lausanne 1011, Switzerland
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Alexandre Regamey
1Department of Dermatology, Department of Internal Medicine, CHUV, Lausanne 1011, Switzerland
Daniel Hohl
1Department of Dermatology, Department of Internal Medicine, CHUV, Lausanne 1011, Switzerland
Jia Wei Liu
1Department of Dermatology, Department of Internal Medicine, CHUV, Lausanne 1011, Switzerland
Thierry Roger
2Division of Infectious Diseases, Department of Internal Medicine, CHUV, Lausanne 1011, Switzerland
Priit Kogerman
3Department of Bioscience, NOVUM, Karolinska Institutet, Huddinge 141 57, Sweden
4Laboratory of Molecular Genetics, National Institute of Chemical Physics and Biophysics, and Department of Gene Technology, Tallinn Technical University, Tallinn 12618, Estonia
Rune Toftgård
3Department of Bioscience, NOVUM, Karolinska Institutet, Huddinge 141 57, Sweden
Marcel Huber
1Department of Dermatology, Department of Internal Medicine, CHUV, Lausanne 1011, Switzerland
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: [email protected]
Received:
July 16 2003
Accepted:
October 17 2003
Online ISSN: 1540-9538
Print ISSN: 0022-1007
The Rockefeller University Press
2003
J Exp Med (2003) 198 (12): 1959–1964.
Article history
Received:
July 16 2003
Accepted:
October 17 2003
Citation
Alexandre Regamey, Daniel Hohl, Jia Wei Liu, Thierry Roger, Priit Kogerman, Rune Toftgård, Marcel Huber; The Tumor Suppressor CYLD Interacts with TRIP and Regulates Negatively Nuclear Factor κB Activation by Tumor Necrosis Factor . J Exp Med 15 December 2003; 198 (12): 1959–1964. doi: https://doi.org/10.1084/jem.20031187
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