Inactivation of the pVHL is linked to the development of familiar and sporadic hypervascular neoplasms, including renal cell carcinomas (RCC), central nervous system hemangioblastomas and pheochromocytomas. pVHL suppresse tumor formation in vivo, likely by destabilizing hypoxia-inducible mRNAs and negatively regulating their corresponding proteins. Some of these proteins are angiogenic factors. Binding of pVHL to a complex formed between Elongins C/B and the putative E3-like ubiquitin ligase cul-2 is necessary for such a regulation. The human pVHL/ElonginsC/B/cul-2 complex may, by virtue of its homology to the yeast cdc53/skp 1/cdc34 complex, target certain proteins for destruction via ubiquitin-dependent proteolysis. Some of these proteins may be critical for the regulation of hypoxia-inducible genes. The goal of this proposal is to determine the role of cul-2 in regulation of hypoxia-inducible genes and/or tumor suppression by pVHL. The applicant will characterize the endogenous human cul-2 under conditions of normoxia and hypoxia. We will map the cul-2 residues required for its entrance into pVHL/ElonginsC/B/cul-2 complex, in order to assess its role in regulation of hypoxia-inducible proteins and tumor suppression by pVHL. To gain further insight into the mechanism by which cul-2 participates in this regulation, cellular cul-2 associated proteins will be identified and cloned.
| Zimmer, Michael; Doucette, Darrell; Siddiqui, Naila et al. (2004) Inhibition of hypoxia-inducible factor is sufficient for growth suppression of VHL-/- tumors. Mol Cancer Res 2:89-95 |
