von Hippel-Lindau, (VHL), is a tumor suppressor gene. Patients with mutations in VHL are predisposed to a variety of tumors, including renal cell carcinomas, pheochromocytomas, and vascular tumors of the central nervous system. VHL forms a multiprotein complex with elongins B &C and Cult, which have E3-like ubiquitin conjugating activity. This complex targets other proteins for degradation through the ubiquitin- proteasome pathway. Hypoxia Inducible Factor-1 (HIF-1), a heterodimer of basic helix-loop-helix transcription factors, is regulated in an oxygen dependent manner. The HIF-1alpha subunit is ubiquinated and degraded in low oxygen i.e. hypoxic conditions, while the beta subunit (ARNT), is constitutively expressed. Renal cell carcinomas, which lack the VHL protein product pVHL, exhibit constitutive HIF-1alpha protein levels. However loss of pVHL, per se, has yet to be shown sufficient for upregulation of HIF-1alpha and its downstream targets. VHL-/- mice have been generated and exhibit embryonic lethality at E10.5. Vascular defects of the placenta contribute to this lethality. Although a lack of embryonic endothelium and vessels are seen in the placental labyrinthine layer, a detailed analysis of the placenta needs to be performed. The following experiments will elucidate a role for pVHL in placental development, angiogenesis and tumorigenesis.
