title: The tumor suppressor CYLD interacts with TRIP and regulates negatively nuclear factor kappaB activation by tumor necrosis factor.
abstract: 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)-kappaB activation by tumor necrosis factor (TNF), the effect of CYLD on NF-kappaB activation was investigated in HeLa cells. The results established that CYLD down-regulates NF-kappaB 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-kappaB activation leading to hyperproliferation and tumor growth.
authors.affiliation: Department of Dermatology, CHUV, Lausanne, Switzerland.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Regamey
authors.forename: Daniel
authors.initials: D
authors.lastname: Hohl
authors.forename: Jia Wei
authors.initials: JW
authors.lastname: Liu
authors.forename: Thierry
authors.initials: T
authors.lastname: Roger
authors.forename: Priit
authors.initials: P
authors.lastname: Kogerman
authors.forename: Rune
authors.initials: R
authors.lastname: Toftgard
authors.forename: Marcel
authors.initials: M
authors.lastname: Huber
mesh_terms: D000818:Animals; D019556:COS Cells; D000074749:Deubiquitinating Enzyme CYLD; D006367:HeLa Cells; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000737:chemistry / Q000502:physiology*; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology*; D015398:Signal Transduction; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D025521:Tumor Suppressor Proteins / Q000502:physiology*
chemical_list: C114370:LRRFIP1 protein, human; D016328:NF-kappa B; D016601:RNA-Binding Proteins; D018124:Receptors, Tumor Necrosis Factor; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; D014409:Tumor Necrosis Factor-alpha; D025521:Tumor Suppressor Proteins; C409984:CYLD protein, human; D000074749:Deubiquitinating Enzyme CYLD