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.
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.
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.
Hypomorphic VHL, hypomorphic PHD2 and hypermorphic HIF2α mutations have been linked to familial polycythaemia.
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.
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.
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.
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W.G.K. is supported by the Doris Duke Charitable Foundation as a Distinguished Clinical Scientist and by the National Institutes of Health, the Howard Hughes Medical Institute and the Breast Cancer Research Foundation.
W.G.K. owns equity in, and consults for, Fibrogen, Inc. (South San Francisco, California, USA). Fibrogen, Inc. is developing drugs targeting prolyl hydroxylases.
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Kaelin Jr, W. The von Hippel–Lindau tumour suppressor protein: O2 sensing and cancer. Nat Rev Cancer 8, 865–873 (2008). https://doi.org/10.1038/nrc2502
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