Hypoxia-inducible factor (HIF) function. HIFs are transcription factors regulated post-transcriptionally by oxygen levels in the cell through hydroxylation on specific proline and asparaginyl amino acid residues. These HIF-specific hydroxylases are the direct oxygen sensors as they use molecular oxygen (in addition to iron and oxoglutarate) to function. Prolyl hydroxylase domain (PHD) enzymes hydroxylate specific proline residues, which target the HIF-α subunit for Von Hippel-Lindau tumour suppressor protein (VHL)-mediated proteosomal degradation. In addition, Factor inhibiting HIF (FIH) hydroxylates a specific asparaginyl residue, which prevents recruitment of co-activator p300/CBP, and thus decreases HIF's transcriptional activity. When oxygen levels are limiting (that is, in hypoxia), these hydroxylases are inhibited, and hence HIF-α escapes degradation, and can heterodimerise with HIF-1β and migrate to the nucleus to activate transcription of target genes through binding to their hypoxia response elements (HREs).