FIGURE 2. Oxygen sensors contribute to the destruction and inactivation of HIF-1.

The transcription factor HIF (hypoxia-inducible factor) is a member of the basic-helix–loop–helix PerArntSim (bHLH–PAS) family of proteins with two PAS domains, A and B. HIF is a heterodimer of an oxygen-sensitive -subunit and an oxygen-insensitive -subunit. Two oxygen sensors termed prolyl-hydroxylase domain (PHD) protein and factor inhibiting HIF-1 (FIH) determine, respectively, the stability and activity of HIF-1. The PHDs, by hydroxylating two proline residues (402 and 564) in a region called the oxygen-dependent degradation domain (ODDD), initiate the binding of a component of an E3 ubiquitin ligase, the von Hippel–Lindau (VHL) protein, which marks HIF-1 for destruction by the proteasome. FIH, by hydroxylating an asparagine residue in the carboxy-terminal transcriptional activation domain (C-TAD) of HIF-1, inhibits the binding of cofactors, such as p300, that are required for the transcription of certain HIF-dependent genes. A second transcriptional activation domain, N-TAD, which overlaps the ODDD, is FIH independent and might be implicated in distinct gene expression.