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. 2019 Nov 1;43(1):3–15. doi: 10.3892/or.2019.7397

Figure 2.

Figure 2.

O2-dependent and O2-independent regulation of HIF-1α. At normal oxygen levels (+O2), prolyl hydroxylase domain proteins hydroxylate two proline residues of HIFα. pVHL recognizes hydroxylated HIFα and mediates proteasomal degradation. Additionally, FIH hydroxylates the asparagine residue of HIFα, inhibiting its interaction with transcriptional coactivator p300/CBP. Conversely, the hydroxylation and degradation of HIFα is inhibited under hypoxia (-O2), which transfers HIFα to the nucleus, dimerizes with HIFβ, and interacts with P300/CBP transcriptional activator to bind to target gene initiation and HRE and upregulate its expression. 2-OG, 2-oxyglutarate; ASN-OH, hydroxylated asparagine; CBP, CREB-binding protein; FIH, factor inhibiting HIF-1α; HIF, hypoxia-inducible factor; HRE, hypoxia response element; Hsp90, heat shock protein 90; HO-PRO, hydroxylated proline; IGF, insulin-like growth factor; MEK, MAPK/ERK kinase; NO, nitric oxide; PDGF, platelet-derived growth factor; PDK, pyruvate dehydrogenase kinase; pVHL, von Hippel-Lindau tumor suppressor protein; RACK, receptor for activated protein C kinase; Rheb, Ras homolog enriched in brain; RNF4, E3 ubiquitin-protein ligase RNF4; ROS, reactive oxygen species; SUMO, small ubiquitin-related modifier.