文章：

von Hippel-Lindau肿瘤抑制蛋白：O₂传感与癌症

The von Hippel–Lindau tumour suppressor protein: O₂ sensing and cancer

原文发布日期：2008-10-16

DOI: 10.1038/nrc2502

类型: Review Article

开放获取: 否

要点：

1. Germline mutations that inactivate the VHL tumour suppressor gene cause a variety of tumours including clear cell renal carcinomas, haemangioblastomas and pheochromocytomas. VHL mutations are also common in sporadic clear cell renal carcinomas and haemangioblastomas.
2. The product of VHL has multiple functions, including directing the polyubiquitylation of hypoxia-inducible factor-α (HIFα). Recognition by VHL requires that the HIFα subunit be modified by O₂-dependent prolyl hydroxylase (Phd) family members.
3. Inappropriate accumulation of HIFα, and especially the HIF2α subunit, has a causal role in VHL^−/− renal carcinomas and its involvement is suspected in VHL^−/− haemangioblastomas. Genotype–phenotype correlations suggest that these two tumours differ with respect to the level of HIFα activation required for tumorigenesis.
4. Hypomorphic VHL, hypomorphic PHD2 and hypermorphic HIF2α mutations have been linked to familial polycythaemia.
5. VHL binds to microtubules and is required for maintenance of a specialized structure called the primary cilium. Loss of this activity probably contributes to the development of visceral cysts in VHL disease.
6. Pheochromocytomas are intra-adrenal paragangliomas (sympathetic nervous system tumours). The genes linked to familial paraganglioma, including VHL, NF1, RET and succinate dehydrogenase subunit genes, encode proteins that regulate neuronal apoptosis in response to loss of growth factors such as nerve growth factor.

要点翻译：

1. 生殖细胞中VHL肿瘤抑制基因的失活突变可引发多种肿瘤，包括透明细胞肾癌、血管母细胞瘤和嗜铬细胞瘤。VHL突变在散发性透明细胞肾癌和血管母细胞瘤中也较为常见。
2. VHL基因产物具有多种功能，包括引导缺氧诱导因子-α（HIFα）的多聚泛素化。VHL对HIFα的识别需要该亚基经过氧气依赖性脯氨酰羟化酶（Phd）家族成员的修饰。
3. HIFα（尤其是HIF2α亚基）的异常积聚在VHL−/−肾癌中具有致病作用，并疑似参与VHL−/−血管母细胞瘤的发生。基因型-表型相关性分析表明，这两种肿瘤在肿瘤发生所需的HIFα激活水平上存在差异。
4. 低效能VHL突变、低效能PHD2突变及高效能HIF2α突变均与家族性红细胞增多症相关。
5. VHL与微管结合，是维持初级纤毛这一特殊结构所必需的。该功能的缺失可能导致VHL病患者内脏囊肿的形成。
6. 嗜铬细胞瘤属于肾上腺内副神经节瘤（交感神经系统肿瘤）。与家族性副神经节瘤相关的基因（包括VHL、NF1、RET和琥珀酸脱氢酶亚基基因）所编码的蛋白质，能够调控神经元在失去神经生长因子等生长因子后的凋亡过程。

英文摘要：

The von Hippel–Lindau disease is caused by inactivating germline mutations of the VHL tumour suppressor gene and is associated with an increased risk of a variety of tumours in an allele-specific manner. The role of the heterodimeric transcription factor hypoxia-inducible factor (HIF) in the pathogenesis of VHL-defective tumours has been more firmly established during the past 5 years. In addition, there is now a greater appreciation of HIF-independent VHL functions that are relevant to tumour development, including maintenance of the primary cilium, regulation of extracellular matrix formation and turnover, and modulation of cell death in certain cell types following growth factor withdrawal or in response to other forms of stress.

摘要翻译： 

von Hippel–Lindau病是由VHL抑癌基因的失活性种系突变引起的，并以等位基因特异方式增加多种肿瘤的风险。过去5年中，异源二聚体转录因子缺氧诱导因子（HIF）在VHL缺陷肿瘤发病机制中的作用已得到更明确的证实。此外，人们现在更加认识到HIF非依赖性的VHL功能与肿瘤发生相关，包括维持初级纤毛、调节细胞外基质的形成与更新，以及在特定细胞类型中于生长因子撤除或其他形式应激后调控细胞死亡。

原文链接：

The von Hippel–Lindau tumour suppressor protein: O2 sensing and cancer