Molecular basis of the VHL hereditary cancer syndrome

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Abstract
The von Hippel–Lindau (VHL) disease is caused by the germ-line mutation of the VHL tumour-suppressor gene. Kidney cancer and blood-vessel tumours (haemangioblastomas) of the central nervous system, are the two leading causes of morbidity and mortality in VHL disease. Somatic VHL mutations are also common in sporadic haemangioblastoma and kidney cancer. 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. 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. 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.