FUNCTIONS OF THE VON-HIPPEL-LINDAU TUMOR-SUPPRESSOR PROTEIN

Von Hippel-Lindau disease (VHL) is caused by germline mutations in the VHL tumour suppressor gene. Tumour development in this setting is due to loss or inactivation of the remaining wild-type VHL allele, The VH L gene product (pVHL) resides primarily in the cytoplasm, A frequently mutated region of pVHL can bind to complexes containing elongin B, el ongin C and Cul2. Loss of pVHL leads to an inappropriate accumulation of hypoxia-inducible mRNAs, such as the mRNA encoding vascular endothe lial growth factor (VEGF), under normoxic conditions. This finding is most likely to account for the hypervascular nature of VHL-associated neoplasms, Current studies are focussed on understanding if and how bi nding to elongins and Cul2 is linked to the ability of pVHL to regulat e hypoxia-inducible mRNAs, In this regard, it is perhaps noteworthy th at elongin C and Cul2 are homologous to yeast proteins Skp1 and Cdc53, These latter proteins participate in the formation of complexes that target certain proteins for ubiquitination.