Figure 3.

Regulation of hypoxia-inducible factor (HIF)-1 oxygen in children – what level. Regulation of HIF-1 adapted from Imtiyaz and Simon (19) and Semenza (20). HIF transcription factors are heterodimers consisting of an oxygen-regulated alpha chain bound to the constitutive beta subunit (aryl hydrocarbon receptor nuclear translocator). Under normoxic conditions, the alpha chain hydroxylated by the HIF prolyl hydroxylases leading to recognition by the von Hippel–Lindau (VHL) E3 ubiquitin ligase complex VHL which recruits elongins B and C, Cullin 2, and RBX1 (R) to constitute a functional E3 ubiquitin-protein ligase complex. Polyubiquitylation occurs and the alpha chain is degraded by the proteasome. Under hypoxic conditions, the HIF alpha chains are maintained and target gene transcription is enhanced. HIF-1 dimerizes and escapes prolyl hydroxylation, ubiquitination, and degradation. The HIF-1 heterodimer binds to hypoxia response elements containing recognition sequence 5_-RCGTG-3_ and recruits coactivator molecules resulting in increased transcription initiation complex formation. mRNA synthesis production and translation of proteins to mediate physiologic responses to hypoxia. TF = transcription factors.