VHL是抑癌基因，编码两种VHL蛋白（PVHL30和PVHL19）。VHL蛋白与转录延伸因子C和B形成复合物。该复合物对于VHL蛋白功能是至关重要的，稳定了蛋白质并防止蛋白酶体降解。破坏这种复合物的VHL突变会形成不稳定的VHL蛋白，会被异常降解。VHL的丧失导致HIF下游靶基因的不适当激活，从而促进常氧条件下的肿瘤发生。VHL缺失与遗传性的和散发性的von Hippel-Lindau疾病相关，其与透明细胞肾细胞癌、视网膜血管母细胞瘤、嗜铬细胞瘤和胰腺神经内分泌肿瘤有关。

VHL is an E3 ligase that functions predominantly as a tumor suppressor gene. The VHL protein forms a ternary complex with transcription elongation factors B and C, which is critical for the stabilization and activity of VHL. VHL mutations that disrupt this complex lead to an unstable VHL protein that is aberrantly degraded. Under normal oxygen conditions, VHL plays a crucial role in the regulation of the hypoxia-inducible transcription factors (HIFs); VHL binds HIF proteins and targets them for ubiquitination and degradation via the proteasome. HIFs are responsible for transcription of numerous genes in response to hypoxic conditions, including pro-angiogenic factors such as vascular endothelial growth factor (VEGF). Loss of VHL leads to activation of HIF downstream target genes and can promote tumorigenesis in normoxic conditions. VHL loss can cause hereditary and sporadic forms of von Hippel-Lindau disease, which is associated with clear cell renal cell carcinoma, retinal hemangioblastomas, phaeochromocytomas and pancreatic neuroendocrine tumors . Somatic functional inactivation of VHL has been reported through bi-allelic loss of the VHL gene in cases of 3p deletion, heterozygous VHL mutations or promoter methylation in human cancers. Inhibitors that target VEGF receptors and HIF proteins may have therapeutic efficacy in tumors with VHL loss.

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