Fig 1.

Overview of the known molecular responses to varying tissue oxygen tension. Cellular oxygen levels are sensed by a family of HIF PHD1–3 that use O₂ as a co-substrate. Upon oxygenated conditions the PHDs hydroxylate the α subunits of HIF at two prolyl residues. These are recognized by pVHL that ubiquitylates HIF causing its proteasomal degradation. When O₂ availability is lowered the hydroxylation and degradation of HIF gradually decreases making HIF stable and transcriptionaly active. Another member of the dioxygenase superfamily, FIH, hydroxylates one asparaginyl residue at the transcriptional domain of HIF causing suppression of the transcriptional activity of HIF.