von Hippel-Lindau Disease

von Hippel-Lindau disease, which is characterized by an increased risk of hemangioblastomas, clear cell renal carcinomas, and pheochromocytomas, is caused by inactivating mutations of the VHL tumor suppressor gene. The VHL gene product, pVHL, has multiple functions, but the best documented, and the one most clearly linked to tumor development, relates to its role as the substrate recognition module of a ubiquitin ligase complex that targets hypoxia-inducible factor (HIF) for destruction. pVHL function is often compromised in sporadic kidney cancers, and inhibitors of the HIF-responsive growth factor (vascular endothelial growth factor) are active against this disease. pVHL, by inhibiting atypical protein kinase C and hence JunB, also affects neuronal survival, as do the products of the other genes linked to familial pheochromocytoma or paraganglioma (NF1, RET, SDHB, SDHC, and SDHD). It is hypothesized that tumor-associated alleles of these genes allow primitive sympathoadrenal precursors to escape developmental culling, and that such cells are at increased risk of forming tumors.