Multiple Components of the VHL Tumor Suppressor Complex Are Frequently Affected by DNA Copy Number Loss in Pheochromocytoma
Figure 1
Schematic illustration of the role of the VHL elongin BC complex in the HIF1 pathway in normoxic, hypoxic, and pseudohypoxic conditions. Under normal physiological conditions (a), HIF1- becomes hydroxylated on two prolyl residues. Hydroxylation of HIF1- generates a binding site for the VHL elongin BC complex, consisting of elongin B, elongin C, CUL2 or CUL5, RBX1, and VHL, which directs the polyubiquitination of HIF1- and targets it for proteasomal degradation [35]. In hypoxic conditions (b), PHD proteins no longer hydroxylate HIF1- and VHL cannot add destabilizing ubiquitin polymers to HIF1-. HIF1- can then heterodimerize with HIF1-β and translocates into the nucleus where it binds to hypoxia response elements (HRE) and promotes the expression of genes, such as PDK1, PFKL, GLUT1, and VEGF, that mediate the cellular response to hypoxic conditions. Similarly, in some cancer types, such as PCC and RCC (c), a loss of function event (such as DNA sequence mutation or copy number loss) of VHL can result in an upregulation of HIF1-target genes independent of the oxygenation status of the tumor cells.
