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.