New Insights into von Hippel-Lindau Function Highlighted by Investigation of the Trichloroethylene-Induced p.P81S Hotspot Mutation.
New Insights into von Hippel-Lindau Function Highlighted by Investigation of the Trichloroethylene-Induced p.P81S Hotspot Mutation.
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三氯乙烯诱导的 p.P81S 热点突变的研究凸显了对 von Hippel-Lindau 功能的新见解。
DOI：
10.1093/jnci/djt240
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发表时间：
2013
期刊：
影响因子：
--
通讯作者：
MarstonLinehan,W
中科院分区：
文献类型：
--
作者：
Neckers,Len;Ricketts,ChristopherJ;MarstonLinehan,W
von Hippel-Lindau基因（VHL）由三个外显子组成，编码一种具有多种肿瘤抑制活性的蛋白质pVHL。在von Hippel-Lindau（VHL）患者中发现了生殖系VHL突变，VHL是一种常染色体显性遗传性癌症综合征，受影响的个体有发生高度血管化良性和恶性肿瘤的风险，包括中枢神经系统血管母细胞瘤、视网膜血管瘤、透明细胞肾癌（ccRCC）、嗜铬细胞瘤和胰腺神经内分泌肿瘤（1）。VHL的双等位基因失活，无论是通过突变还是启动子甲基化，都存在于VHL相关肿瘤和近90%的散发性ccRCC肿瘤（最常见的散发性肾癌形式）中（2，3）。在其活性中，pVHL作为多蛋白泛素连接酶复合物的底物识别模块发挥作用，并通过将缺氧诱导因子（HIF）1α和2α募集到该复合物中，介导其氧依赖性降解（4）。干扰HIF-α识别的VHL突变促进有氧糖酵解并支持新血管生成，这可能是pVHL丢失的最深入研究的结果。然而，HIF-α表达的调节不太可能是pVHL肿瘤抑制功能的唯一机制。鉴于其作为多蛋白复合物的底物识别模块的作用，可以合理地假设pVHL具有依赖于与HIF稳定无关（或可能互补）的蛋白质-蛋白质相互作用的额外活性，并且这些活性中的一种或多种的失调可能以组织特异性方式促成肿瘤形成。事实上，pVHL已经涉及许多似乎不依赖HIF的细胞过程，包括细胞周期调节、细胞外基质组装和细胞骨架稳定性（5）XccRCC的发展与遗传（例如，VHL种系突变）和环境因素，特别是长期暴露于工业溶剂三氯乙烯（TCE）相关。尽管TCE暴露不会影响散发性ccRCC的组织病理学，但其在TCE暴露个体中的发病较早，并且这些肿瘤中相当大比例的VHL基因在核苷酸454处含有胞嘧啶至胸苷的特异性突变，导致氨基酸81处丝氨酸取代脯氨酸（p. P81 S）（6）。在TCE暴露个体的散发性ccRCC肿瘤中发现了近40%的热点突变，但在未暴露个体的散发性肿瘤中未观察到，在VHL疾病患者中很少发现，并且不存在
The von Hippel-Lindau gene (VHL), composed of three exons, encodes a protein, pVHL, with diverse tumor suppressor activities. Germline VHL mutations are found in patients with von Hippel-Lindau (VHL), an autosomal dominant hereditary cancer syndrome in which affected individuals are at risk for the development of highly vascularized benign and malignant tumors including central nervous system hemangioblastomas, retinal hemangiomas, clear cell renal carcinomas (ccRCCs), pheochromocytomas, and pancreatic neuroendocrine tumors (1). Biallelic inactivation of VHL, whether via mutation or promoter methylation, is found in VHL-associated tumors and in nearly 90% of sporadic ccRCC tumors (2, 3), the most common form of sporadic kidney cancer. Among its activities, pVHL functions as the substrate recognition module of a multiprotein ubiquitin ligase complex, and, by recruiting hypoxia-inducible factor (HIF) 1α and 2α to this complex, mediates their oxygen-dependent degradation (4). VHL mutations that interfere with HIF-α recognition promote aerobic glycolysis and support neoangiogenesis, perhaps the most intensively studied consequences of pVHL loss. However, regulation of HIF-α expression is unlikely to be the sole mechanism underlying the tumor suppressor function of pVHL. Given its role as the substrate recognition module of a multiprotein complex, it is reasonable to assume that pVHL has additional activities that depend on protein–protein interactions unrelated to (or perhaps complementary with) HIF stabilization, and that deregulation of one or more of these activities contributes to tumor formation, likely in a tissue-specific manner. Indeed, pVHL has been implicated in a number of cellular processes that appear to be HIF independent, including cell cycle regulation, extracellular matrix assembly, and cytoskeleton stability (5).The development of ccRCC is associated with both genetic (eg, VHL germline mutation) and environmental factors, particularly long-term exposure to the industrial solvent trichloroethylene (TCE). Although TCE exposure does not affect the histopathology of sporadic ccRCC, its onset is earlier in TCE-exposed individuals, and the VHL gene in a substantial percentage of these tumors contains a specific mutation of a cytosine to thymidine at nucleotide 454, resulting in the substitution of serine for proline at amino acid 81 (p. P81S)(6). This hotspot mutation is found in nearly 40% of sporadic ccRCC tumors from TCE-exposed individuals, but it was not observed in sporadic tumors from unexposed individuals, is rarely found in patients with VHL disease, and was not present
影响因子：
64.8
作者：
Varela, Ignacio;Tarpey, Patrick;Raine, Keiran;Huang, Dachuan;Ong, Choon Kiat;Stephens, Philip;Davies, Helen;Jones, David;Lin, Meng-Lay;Teague, Jon;Bignell, Graham;Butler, Adam;Cho, Juok;Dalgliesh, Gillian L.;Galappaththige, Danushka;Greenman, Chris;Hardy, Claire;Jia, Mingming;Latimer, Calli;Lau, King Wai;Marshall, John;McLaren, Stuart;Menzies, Andrew;Mudie, Laura;Stebbings, Lucy;Largaespada, David A.;Wessels, L. F. A.;Richard, Stephane;Kahnoski, Richard J.;Anema, John;Tuveson, David A.;Perez-Mancera, Pedro A.;Mustonen, Ville;Fischer, Andrej;Adams, David J.;Rust, Alistair;Chan-on, Waraporn;Subimerb, Chutima;Dykema, Karl;Furge, Kyle;Campbell, Peter J.;Teh, Bin Tean;Stratton, Michael R.;Futreal, P. Andrew
通讯作者：
Futreal, P. Andrew
德国 von Hippel-Lindau 家族中的 VHL2C 表型，同时存在 VHL 种系突变 P81S 和 L188V。
影响因子：
5.8
作者：
G. Weirich;Bettina Klein;T. Wöhl;D. Engelhardt;H. Brauch
通讯作者：
H. Brauch