PVHL(19) IS A BIOLOGICALLY-ACTIVE PRODUCT OF THE VON-HIPPEL-LINDAU GENE ARISING FROM INTERNAL TRANSLATION INITIATION

The von Hippel-Lindau (VHL) gene encodes a protein consisting of 213 a mino acid residues with an apparent molecular mass of 30 kDa (pVHL(30) ). Here we show that cells also produce a VHL protein (pVHL(19)) that appears to arise as a result of internal translation from the second m ethionine within the VHL ORF, pVHL(30) resides primarily in the cytoso l, with less amounts found in the nucleus or associated with cell memb ranes. In contrast pVHL(19), in biochemical fractionation experiments, is equally distributed between the nucleus and cytosol and is not fou nd in association with membranes. pVHL(19), like pVHL(30), can bind to elongin B, elongin C, and Hs-Cul2 in coimmunoprecipitation assays and can inhibit the production of hypoxia-inducible proteins such as vasc ular endothelial growth factor (VEGF) and GLUT1 when reintroduced into renal carcinoma cells that lack a wild-type VHL allele, Thus, cells c ontain two biologically active VHL gene products.