文章：

VHL遗传性癌症综合征的分子基础

Molecular basis of the VHL hereditary cancer syndrome

原文发布日期：2002-09-01

DOI: 10.1038/nrc885

类型: Review Article

开放获取: 否

要点：

1. The von Hippel–Lindau (VHL) disease is caused by the germ-line mutation of the VHL tumour-suppressor gene.
2. Kidney cancer and blood-vessel tumours (haemangioblastomas) of the central nervous system, are the two leading causes of morbidity and mortality in VHL disease.
3. Somatic VHL mutations are also common in sporadic haemangioblastoma and kidney cancer.
4. The VHL gene product, pVHL, is a component of an SCF (Skp1–Cdc53–F-box)-like ubiquitin-ligase complex that targets the α-subunits of the hypoxia-inducible factor (HIF) heterodimeric transcription factor for polyubiquitylation and proteasomal degradation.
5. pVHL recognizes the HIF α-subunits only after specific proline residues within these subunits are hydroxylated by members of the EGLN family. This, and the fact that the hydroxylation is inherently oxygen dependent, is integral to how mammalian cells sense and respond to changes in oxygen.
6. Overproduction of growth factors encoded by HIF target genes, such as vascular endothelial growth factor (VEGF), platelet-derived growth-factor B chain (PDGFβ) and transforming growth-factor-α (TGFα) probably contribute to tumour formation following pVHL inactivation.

要点翻译：

1. von Hippel-Lindau（VHL）病由VHL肿瘤抑制基因的种系突变引起。
2. 肾癌和中枢神经系统血管肿瘤（血管母细胞瘤）是VHL疾病中发病和死亡的两个主要原因。
3. 体细胞VHL突变在散发性血管母细胞瘤和肾癌中也较为常见。  
4. VHL基因产物pVHL是SCF（Skp1-Cdc53-F-box）类泛素连接酶复合物的组成部分，该复合物靶向缺氧诱导因子（HIF）异源二聚体转录因子的α亚基，使其发生多聚泛素化和蛋白酶体降解。  
5. pVHL仅在这些亚基内特定脯氨酸残基被EGLN家族成员羟基化后识别HIF α亚基。这一特性以及羟基化本身固有的氧依赖性，构成了哺乳动物细胞感知和响应氧变化的核心机制。  
6. 由HIF靶基因编码的生长因子（如血管内皮生长因子VEGF、血小板衍生生长因子B链PDGFβ和转化生长因子α TGFα）的过量产生，可能是pVHL失活后肿瘤形成的重要因素。

英文摘要：

The von Hippel–Lindau hereditary cancer syndrome was first described about 100 years ago. The unusual clinical features of this disorder predicted a role for the von Hippel–Lindau gene (VHL) in the oxygen-sensing pathway. Indeed, recent studies of this gene have helped to decipher how cells sense changes in oxygen availability, and have revealed a previously unappreciated role of prolyl hydroxylation in intracellular signalling. These studies, in turn, are laying the foundation for the treatment of a diverse set of disorders, including cancer, myocardial infarction and stroke.

摘要翻译： 

von Hippel–Lindau遗传性癌症综合征约在100年前首次被描述。该疾病异常的临床特征预示了von Hippel–Lindau基因（VHL）在氧感应通路中的作用。事实上，近期对该基因的研究已帮助阐明了细胞如何感知氧可用性的变化，并揭示了脯氨酸羟化在细胞内信号传导中此前未被重视的作用。这些研究反过来又为治疗包括癌症、心肌梗死和卒中在内的多种疾病奠定了基础。

原文链接：

Molecular basis of the VHL hereditary cancer syndrome