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The Tumor Suppressor CYLD Interacts with TRIP and Regulates Negatively Nuclear Factor κB Activation by Tumor Necrosis Factor

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...

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Autores principales: Regamey, Alexandre, Hohl, Daniel, Liu, Jia Wei, Roger, Thierry, Kogerman, Priit, Toftgård, Rune, Huber, Marcel
Formato: Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2003
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2194148/
https://www.ncbi.nlm.nih.gov/pubmed/14676304
http://dx.doi.org/10.1084/jem.20031187
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author Regamey, Alexandre
Hohl, Daniel
Liu, Jia Wei
Roger, Thierry
Kogerman, Priit
Toftgård, Rune
Huber, Marcel
author_facet Regamey, Alexandre
Hohl, Daniel
Liu, Jia Wei
Roger, Thierry
Kogerman, Priit
Toftgård, Rune
Huber, Marcel
author_sort Regamey, Alexandre
collection PubMed
description 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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spelling pubmed-21941482008-04-11 The Tumor Suppressor CYLD Interacts with TRIP and Regulates Negatively Nuclear Factor κB Activation by Tumor Necrosis Factor Regamey, Alexandre Hohl, Daniel Liu, Jia Wei Roger, Thierry Kogerman, Priit Toftgård, Rune Huber, Marcel J Exp Med Brief Definitive Report 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. The Rockefeller University Press 2003-12-15 /pmc/articles/PMC2194148/ /pubmed/14676304 http://dx.doi.org/10.1084/jem.20031187 Text en Copyright © 2003, The Rockefeller University Press This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Brief Definitive Report
Regamey, Alexandre
Hohl, Daniel
Liu, Jia Wei
Roger, Thierry
Kogerman, Priit
Toftgård, Rune
Huber, Marcel
The Tumor Suppressor CYLD Interacts with TRIP and Regulates Negatively Nuclear Factor κB Activation by Tumor Necrosis Factor
title The Tumor Suppressor CYLD Interacts with TRIP and Regulates Negatively Nuclear Factor κB Activation by Tumor Necrosis Factor
title_full The Tumor Suppressor CYLD Interacts with TRIP and Regulates Negatively Nuclear Factor κB Activation by Tumor Necrosis Factor
title_fullStr The Tumor Suppressor CYLD Interacts with TRIP and Regulates Negatively Nuclear Factor κB Activation by Tumor Necrosis Factor
title_full_unstemmed The Tumor Suppressor CYLD Interacts with TRIP and Regulates Negatively Nuclear Factor κB Activation by Tumor Necrosis Factor
title_short The Tumor Suppressor CYLD Interacts with TRIP and Regulates Negatively Nuclear Factor κB Activation by Tumor Necrosis Factor
title_sort tumor suppressor cyld interacts with trip and regulates negatively nuclear factor κb activation by tumor necrosis factor
topic Brief Definitive Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2194148/
https://www.ncbi.nlm.nih.gov/pubmed/14676304
http://dx.doi.org/10.1084/jem.20031187
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