Role of the ubiquitin proteasome system in renal cell carcinoma

Abstract

Renal cell carcinoma (RCC) accounts for approximately 2.6% of all cancers in the United States. While early stage disease is curable by surgery, the median survival of metastatic disease is only 13 months. In the last decade, there has been considerable progress in understanding the genetics of RCC. The VHL tumor suppressor gene is inactivated in the majority of RCC cases. The VHL protein (pVHL) acts as an E3 ligase that targets HIF-1, the hypoxia inducible transcription factor, for degradation by the ubiquitin proteasome system (UPS). In RCC cases with mutant pVHL, HIF-1 is stabilized and aberrantly expressed in normoxia, leading to the activation of pro-survival genes such as vascular endothelial growth factor (VEGF). This review will focus on the defect in the UPS that underlies RCC and describe the development of novel therapies that target the UPS. Publication history: Republished from Current BioData's Targeted Proteins database (TPdb; http://www.targetedproteinsdb.com).

Figure 1

The ubiquitin proteasome system. In step 1, ubiquitin is activated by a ubiquitin activating enzyme, E1. In step 2, activated ubiquitin is transferred to a ubiquitin conjugating enzyme, E2. In step 3, ubiquitin is subsequently conjugated to target proteins in a process mediated by an E3 ubiquitin ligase. In step 4, the polyubiquitylated substrate protein is degraded by the 26S proteasome. A single E1 enzyme can transfer ubiquitin to all of the E2s in the cell, and each of the E2s associates with a restricted set of E3s that confer substrate specificity.

Figure 2

Model for the E3 ligase function of pVHL in normoxia. A In normal cells, HIFα proteins are hydroxylated by prolyl-4 hydroxylases (PHDs) that require oxygen for activity. pVHL, in a complex with multiple proteins including Elongin C and Cul-2, binds to hydroxylated HIFα proteins and delivers them to the 26S proteasome for destruction. B In RCC, VHL gene mutations often disrupt pVHL–HIFα binding and/or the pVHL–Elongin C–Cul-2 complex. The consequence is that stable HIFα proteins dimerize with Hif1β and the resulting HIF-1 complex binds to a hypoxia-response element (HRE) to activate pro-survival genes, such as VEGF, EPO and Glut1.