pVHL 19 is a biologically active product of the von Hippel–Lindau gene arising from internal translation initiation

Abstract

The von Hippel–Lindau (VHL) gene encodes a protein consisting of 213 amino acid residues with an apparent molecular mass of 30 kDa (pVHL₃₀). Here we show that cells also produce a VHL protein (pVHL₁₉) that appears to arise as a result of internal translation from the second methionine within the VHL ORF. pVHL₃₀ resides primarily in the cytosol, with less amounts found in the nucleus or associated with cell membranes. In contrast pVHL₁₉, in biochemical fractionation experiments, is equally distributed between the nucleus and cytosol and is not found in association with membranes. pVHL₁₉, like pVHL₃₀, can bind to elongin B, elongin C, and Hs-Cul2 in coimmunoprecipitation assays and can inhibit the production of hypoxia-inducible proteins such as vascular endothelial growth factor (VEGF) and GLUT1 when reintroduced into renal carcinoma cells that lack a wild-type VHL allele. Thus, cells contain two biologically active VHL gene products.