The primary transcriptional regulator of both cellular and systemic hypoxic responses is the heterodimeric transcription factor hypoxia inducible factor (HIF). HIF heterodimers consist of an alpha subunit (HIFα) and a beta subunit (HIFβ also known as ARNT [aryl hydrocarbon nuclear translocator]). Both subunits contain basic helix-loop-helix (bHLH) and PER-ARNT-SIM homology (PAS) domains that mediate dimerization. HIF dimerization is essential for HIF transcriptional activity.
The HIF protein family is complex in that three genes encode HIFα subunits (HIF-lα, -2α, and -3α) and three genes encode HIFβ subunits (ARNT/HIF-1β, ARNT2, and ARNT3). However, not all family members are involved in activating transcription in the response to hypoxia and dimerization between different subunits can be limited by ex
ARNT and HIF-lα are expressed ubiquitously, whereas the other subunits exhibit a more tissue-restricted pattern of ex
HIF Target Genes
Under hypoxic conditions (<6% O2), HIF induces the ex
The ability of HIF to activate transcription is regulated by the stability of the HIFα subunit. Under normal O2 conditions or “normoxia” (21%), HIFα subunits are ubiquitinated and degraded via the 26S proteasome pathway through interaction with an E3 ubiquitin ligase complex containing the von Hippel-Lindau tumor suppressor protein (pVHL). The mechanisms and factors involved in the HIF regulatory pathway have been intensely investigated. HIFα subunits are hydroxylated on key proline residues by an oxygen dependent family of prolyl hydroxylases (PHDs). The HIF-PHDs are evolutionarily conserved from nematodes to mammals. To date, three HIF-PHD homologs with different activities, specificities, and ex
However, under hypoxic conditions, the HIF-PHDs are not active. Therefore, pVHL cannot interact with HIFα subunits and, as a result, the HIFα subunits are stabilized, translocate into the nucleus, and heterodimerize with a HIFβ subunit to form a HIF complex. HIF transactivation is then achieved by the recruitment of coactivators, such as p300/CBP. Under normoxia, HIF and p300 interaction is blocked by an additional hydroxylation reaction that is mediated by a HIF asparaginyl hydroxylase known as FIH (factor inhibiting HIF). In summary, this regulation ensures that decreases in O2 lead to a finely tuned and proportional increase in the accumulation of HIFα subunits.