Figure 1.

Regulation of the stability and transcription activity of HIF. In the presence of oxygen or normoxia, PHDs hydroxylate two prolyl residues of HIF-α. The hydroxylated HIF-α then binds to VHL-E3-ubiquitin ligase complex, leading to poly-ubiquitination and proteosomal degradation. Meanwhile, FIH hydroxylates an asparaginyl residue of HIF-α. Asparaginyl hydroxylated HIF-α prevents the recruitment of CBP/p300 coactivators, which is required for the full transcriptional activity of HIF. In the absence of O₂ or hypoxia, PHD-mediated prolyl residue hydroxylation is inhibited, resulting in HIF-α stabilization. The stabilized HIF-α translocates into nucleus and then dimerizes with HIF-β to transactivate target genes. Meanwhile, FIH-mediated asparaginyl residue hydroxylation is also inhibited, causing the recruitment of CBP/p300 coactivators to enhance the transcription activity of HIF. In addition to oxygen, phosphorylation and ROS may play dual roles in HIF-α regulation; HSP90 inhibitors, HDACIs, RACK1, and sumoylation can decrease the stability of HIF-α, while NO-mediated S-nitrosylation can enhance the stability of HIF-α. Abbreviations: hypoxia-inducible factor (HIF), prolyl hydroxylase domain-containing protein (PHD), von Hippel–Lindau (VHL), factor inhibiting HIF (FIH), CREB-binding protein (CBP), hypoxia response element (HRE), reactive oxygen species (ROS), histone deacetylase inhibitors (HDACIs), receptor of activated protein kinase C 1 (RACK1), phosphorylation (P), glycogen synthase kinase-3beta (GSK-3β), polo-like kinase 3 (Plk3), protein kinase A (PKA), and nitric oxide (NO).