VHL is a classical two-hit tumor suppressor. Tumors in the familial syndrome involve somatic inactivation of the second allele, while most sporadic clear cell renal cell carcinomas and a proportion of phaeochromocytomas also exhibit biallelic inactivation of VHL. VHL disease is subclassified based on the risk of renal cell carcinoma, haemangioblastoma and phaeochromocytoma.
The best-characterised function of VHL is regulation of Hypoxia-Inducible Factor (HIF)-alpha subunits. Hypoxia-Inducible Factor is a transcription control complex which is activated when oxygenation is reduced and operates in all cell types studies to date. It underlies a broad range of adaptive responses, including increasing glucose uptake, glycolysis, and angiogenic signalling, and decreasing mitochondrial respiration. VHL acts as recognition component of an E3 ligase complex which specifically recognises HIF-a that has been subjected to enzymatic prolyl hydroxylation in the presence of oxygen.
In the absence of VHL, HIF is constitutively active leading to high level expression of genes usually expressed in hypoxia, including VEGF. This probably accounts for the very vascular nature of VHL defective tumors. HIF activation is detectable in pre-malignant lesions in the kidney and the CNS of VHL patients, consistent with HIF activation linking VHL loss of function and tumorigenesis. Interestingly, VHL loss-of-function has little effect on proliferation of renal cells, but is necessary for normal junction formation and maintenance of a primary cilium.
In some VHL kindreds (Type IIC) there is familial pheochromocytoma without other manifestations. The underlying mutations in these kindreds appear not to alter VHLs ability to regulate HIF. VHL alterations predicted to be complete loss-of-function alleles are associated with low risk of pheochromocytoma. Taken together, these suggest that a different mechanism leads to VHL-related pheochromocytoma which is likely to independent of HIF activation.
Other genetic alterations in the cellular oxygen sensing pathway have been recognised recently. Autosomal recessive erythrocytosis can be caused by homozygosity for a hypomorphic VHL allele. The sensitivity of red cell production to alterations in this pathway is further illustrated by a mutation in the HIF prolyl hydroxylase, PHD2, in a family with autosomal dominant erythrocytosis.