Figure 1.

The structural domains of hypoxia inducible factor (HIF)-1/2/3α and their transcriptional binding partner, HIF-1β/ARNT (aryl hydrocarbon nuclear translocator)that together, form the HIF-1, HIF-2 and HIF-3 transcriptional complexes, respectively. The basic helix-loop-helix (bHLH) and per-Arnt-SIM (PAS) domains are involved in DNA binding and heterodimerization; the oxygen -dependent degradation (ODD) domain is required for oxygen-dependent hydroxylation and degradation; and the N -terminal and C-terminal transactivation domains (TAD-N and TAD-C, respectively) are required for transcriptional activation. The binding domains of known modulators of HIF-α are depicted, along with the effectsof these interactions on activity of the HIF transcriptional complex( red font indicates inhibitory interactions, green font indicates activating interactions). The von Hippel Lindau protein (pVHL) E3 ligase complex regulates the oxygen-dependent degradation of all three major HIF-α subunits. Factor inhibiting HIF-1 (FIH-1)hydroxylates HIF -2α at a lower efficiency (broken oval) than HIF-1α(unbroken oval). Receptor for activated protein kinase C 1 (RACK1) promotes the degradation of HIF-1α when heat shock protein 90 (Hsp90)is inhibited, such as by Hsp90 inhibitors. The hypoxia-associated factor (HAF)selectively binds to HIF-1α and HIF-2α, mediating degradation and transactivation, respectively. Hsp70 promotes the binding of carboxyl terminus of Hsp70-interacting protein (CHIP)to HIF-1α, resulting in HIF-1α degradation. Sirtuin 1 (SIRT1)deacetylates HIF -2α, resulting inactivation.