The von Hippel-Lindau tumor suppressor protein: roles in cancer and oxygen sensing.

Biallelic inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene is a common event in hereditary (von Hippel- Lindau disease) and sporadic hemangioblastomas and clear-cell renal carcinomas. Germ-line VHL mutations are also linked to some hereditary pheochromocytoma families. The VHL gene product, pVHL, interacts with a number of cellular proteins and is implicated in the control of angiogenesis, extracellular matrix formation, cell metabolism, and mitogenesis. The best understood function of pVHL relates to its role as the substrate recognition unit of an E3 ligase that targets the heterodimeric transcription factor HIF (hypoxia-inducible factor) for destruction in the presence of oxygen. Down-regulation of HIF appears to be both necessary and sufficient for renal tumor suppression by pVHL, and HIF is strongly suspected of contributing to hemangioblastoma development as well. Recent work suggests that pVHL's role in pheochromocytoma is not related to HIF but rather to the ability of pVHL to regulate neuronal apoptosis, which is mediated by c-Jun, when growth factors such as NGF become limiting. Loss of pVHL leads to up-regulation of JunB, which antagonizes c-Jun and blunts apoptosis.