Hypoxia inducible factors

Hypoxia inducible factors (HIFs) are transcription factors that respond to changes in available oxygen in the cellular environment, specifically to decreases in oxygen, or hypoxia.

Structure
Most, if not all, oxygen breathing species express the highly conserved transcriptional complex HIF-1, which is a heterodimer composed of an alpha and beta subunit, the latter being a constituitively expressed aryl hydrocarbon receptor nuclear translocator (ARNT). HIF-1 belongs to the PER-ARNT-SIM (PAS) subfamily of the basic-helix-loop-helix (bHLH) family of transcription factors.

Responsive action
The alpha subunit of HIF-1 is a target for prolyl hydroxylation by HIF prolyl-hydroxylase, which makes HIF-1 α a target for degradation by the E3 ubiquitin ligase complex, leading to quick degradation by the proteasome. This occurs only in normoxic conditions. In hypoxic conditions, HIF prolyl-hydroxylase is inhibited since it utilizes oxygen as a cosubstrate.

Hypoxia also results in a build up of succinate, due to inhibition of the electron transport chain in the mitochondria. The build up of succinate further inhibits HIF prolyl-hydroxylase action since it is an end product of HIF hydoxylation. Similarly, inhibition of electron transfer in the succinate dehydrogenase complex due to mutations in the SDHB or SDHD genes can cause a build-up of succinate that inhibits HIF prolyl-hydroxylase, stabilizing HIF-1 α. This is termed pseudohypoxia.

HIF-1, when stabilized by hypoxic conditions, upregulates several genes to promote survival in low oxygen conditions. These include glycolysis enzymes, which allow ATP synthesis in an oxygen-independent manner, and vascular endothelial growth factor (VEGF), which promotes angiogenesis. HIF-1 acts by binding to HIF responsive elements (HREs) in promoters which contain the sequence NCGTG.

HIFs are generally vital to development. In mammals, deletion of the HIF-1 genes results in perinatal death. HIF-1 has been shown to be vital to chondrocyte survival, allowing the cells to adapt to low oxygen conditions within the growth plates of bones.