The tumor suppressor CYLD interacts with TRIP and regulates negatively nuclear factor kappaB activation by tumor necrosis factor.
The tumor suppressor CYLD interacts with TRIP and regulates negatively nuclear factor kappaB activation by tumor necrosis factor.
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DOI：
10.1084/jem.20031187
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发表时间：
2003-12-15
期刊：
影响因子：
--
通讯作者：
Huber M
中科院分区：
文献类型：
--
作者：
Regamey A;Hohl D;Liu JW;Roger T;Kogerman P;Toftgard R;Huber M
圆柱瘤是由CYLD基因的种系突变引起的良性皮肤附件肿瘤。在大多数病例中，肿瘤组织中第二个野生型等位基因缺失，这表明CYLD具有肿瘤抑制功能。CYLD是一种含956个氨基酸的蛋白质，在羧基末端具有一个有功能的去泛素化结构域。为了进一步阐明CYLD的功能，我们利用HaCaT cDNA文库进行了酵母双杂交筛选，鉴定出环指蛋白TRIP（TRAF相互作用蛋白）是与全长CYLD相互作用的蛋白。对相互作用结构域的定位显示，CYLD的中心结构域与TRIP的羧基末端结合。远西方分析和哺乳动物细胞中的免疫共沉淀实验证实，全长CYLD与TRIP的羧基末端结构域结合。由于TRIP是肿瘤坏死因子（TNF）激活核因子（NF）-κB的抑制剂，我们在HeLa细胞中研究了CYLD对NF -κB激活的影响。结果表明，CYLD下调TNF -α对NF -κB的激活。CYLD的抑制作用取决于与TRIP相互作用的中心结构域的存在及其去泛素化活性。这些发现表明，圆柱瘤是通过持续性NF -κB激活导致细胞过度增殖和肿瘤生长而产生的。
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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DOI：
10.1073/pnas.95.5.2307
发表时间：
1998-03-03
影响因子：
11.1
作者：
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通讯作者：
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影响因子：
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影响因子：
5.3
作者：
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HERSHEY, JWB