Figure 3

The VHL protein and oxygen-dependent ubiquitination of the hypoxia-inducible factor (HIF)-1α. The VHL protein contains two functional domains: alpha (α) and beta (β). The α-domain of the VHL protein binds to Elongin C, which is connected with Elongin B in a multi-protein complex consisting of Cul2, Rbx1 and E2 ubiquitin conjugating enzyme (E2). The β-domain directly binds the substrate, HIF-1α. The VHL protein directs, depending on the amount of available oxygen, the breakdown (ubiquitination) of HIF-1α in the proteasome. In normoxic circumstances, HIF-1α is hydroxylated and binds to an intact VHL protein and is ubiquitinated in the proteasome (left). During hypoxic circumstances HIF-1α is not hydroxylated. The non-hydroxylated HIF-1α does not bind to the VHL protein and accumulates (right). In the case of a defect or absent VHL protein, HIF-1α also accumulates. Subsequently, genes that are regulated by HIF-1α, like vascular endothelial growth factor (VEGF) and erythropoietin (Epo), are upregulated, leading to (neo) angiogenesis and tumour growth. Copyright 2003, The Endocrine Society [16]