THE VON-HIPPEL-LINDAU TUMOR-SUPPRESSOR GENE-PRODUCT FORMS A STABLE COMPLEX WITH HUMAN CUL-2, A MEMBER OF THE CDC53 FAMILY OF PROTEINS

The inactivation of the von Hippel-Lindau (VHL) gene predisposes affec ted individuals to VHL syndrome and is an early genetic event associat ed with sporadic renal cell carcinoma and CNS hemangioblastomas. The V HL protein (pVHL) has been shown to form a stable complex with elongin B and elongin C, two factors that stabilize and activate the transcri ption elongation factor elongin A. Here, Hs-CUL-2, a member of the rec ently identified multigene family, the cullins, is shown to specifical ly associate with the trimeric pVHL-elongin B-C (VBC) complex in vitro and in vivo. Nearly 70% of naturally occurring cancer-predisposing mu tations of VHL disrupt this interaction, The pVHL-Hs-CUL-2 association is strictly dependent on the integrity of the trimeric VBC complex, I mmunofluorescence studies show Hs-CUL-2 to be a cytosolic protein that can be translocated to the nucleus by pVHL, Recently it has been show n that a yeast Ns-CUL-2 homolog, Cdc53, is part of a ubiquitin protein ligase complex that targets cell cycle proteins for degradation by th e ubiquitin proteolytic pathway. In Caenorhabditis elegans, a null mut ation of another Hs-cul-2 homolog, Ce-cul-1, results in hyperplasia in all tissues and is required for cell cycle exit, Hence, Hs-cul-2 may be required for VHL function and, therefore, may be a candidate human tumor-suppressor gene.