Figure 1

Experimental and modelling advances in the HIF pathway. (A) Historical profile of the major findings in the core components of the HIF pathway, alongside the major modelled behaviours. Numbers refer to the references. (B) Core elements of the HIF pathway: in normoxia, HIF-α is hydroxylated by PHD in presence of molecular oxygen (O₂). This allows the binding of von Hippel–Lindau protein (VHL), eventually leading to HIF proteosomal degradation. HIF-α can also be hydroxylated by FIH, which interferes with the interaction with transcriptional coactivators p300 and CBP. In hypoxia, when demand of oxygen exceeds supply, the oxygen-sensitive PHD and FIH enzymes are inhibited. Thus HIF-α can accumulate, translocate into the nucleus and associate with HIF-β and p300/CBP, leading to formation of a transcriptional complex recognising hypoxia responsive elements (HRE) on the promoter of target genes. One such gene upregulated encodes for PHD, which creates a negative feedback loop.