A deluge of recent evidence suggests that the abundance, and therefore activity, of oncogene and tumor suppressor gene products is controlled by the ubiquitin-proteasome degradation system. Cancer targets that are regulated by the ubiquitin system range from cell cycle regulators to signaling proteins to transcription factors (1). These and many other substrates are targeted for degradation upon the covalent attachment of the small protein ubiquitin, an event catalyzed by the now-famous cascade of ubiquitin transferase enzymes, E1 3 E2 3 E3 (1). Assembly of a polyubiquitin chain on the substrate leads to its capture and degradation by an abundant protease particle, the 26 S proteasome (2). The crucial substrate recognition step in ubiquitindependent proteolysis is mediated by the diverse family of E3 enzymes, also known as ubiquitin ligases.

In many instances, oncogenic mutations stabilize the encoded gene products, yet a component of the ubiquitin machinery has never been directly implicated in tumor suppression. But now reports by Iwai et al. in this issue of PNAS (3), and by Lisztwan et al. in a recent issue of Genes and Development (4), tightly link the notorious VHL tumor suppressor protein to ubiquitin ligase activity. In von Hippel-Lindau (VHL) syndrome, mutation of one germline copy of the VHL gene predisposes individuals to a wide range of tumors, including renal cell carcinoma, pheochromocytoma, cerebellar hemangioblastomas, and retinal angioma, which arise upon somatic loss of the remaining wildtype VHL gene, in accord with the classical two-hit definition of a tumor suppressor (5, 6). In addition, both somatic copies of the VHL gene are mutated in the majority of sporadic clear cell renal carcinomas (6). A hallmark of VHL tumors is their high degree of vascularization, which arises from constitutive expression of a suite of hypoxia-inducible genes, including the crucial vascular endothelial growth factor (VEGF)(6). VHL also is required for cell cycle exit upon serum withdrawal and so may serve as a gatekeeper in the proliferation of renal cells (7).