Hypoxia-inducible factor

[8] In 2019, the same three individuals were jointly awarded the Nobel Prize in Physiology or Medicine for their work in elucidating how HIF senses and adapts cellular response to oxygen availability.

[9] Oxygen-breathing species express the highly conserved transcriptional complex HIF-1, which is a heterodimer composed of an alpha and a beta subunit, the latter being a constitutively-expressed aryl hydrocarbon receptor nuclear translocator (ARNT).

These include glycolysis enzymes, which allow ATP synthesis in an oxygen-independent manner, and vascular endothelial growth factor (VEGF), which promotes angiogenesis.

[27] It has been shown that muscle A kinase–anchoring protein (mAKAP) organized E3 ubiquitin ligases, affecting stability and positioning of HIF-1 inside its action site in the nucleus.

Depletion of mAKAP or disruption of its targeting to the perinuclear (in cardiomyocytes) region altered the stability of HIF-1 and transcriptional activation of genes associated with hypoxia.

It was shown that NF-κB (nuclear factor κB) is a direct modulator of HIF-1α expression in the presence of normal oxygen pressure.

Finally, it was shown that, when endogenous NF-κB is induced by TNFα (tumour necrosis factor α) treatment, HIF-1α levels also change in an NF-κB-dependent manner.

[33] Researchers at the Stanford University School of Medicine demonstrated that HIF1A activation was able to prevent and treat chronic wounds in diabetic and aged mice.

[41] Based on the patent-pending HSF ("HIF strengthening factor") active ingredient, products have been developed that are supposed to promote skin and hair regeneration.

[46][47] The most notable compounds are: Roxadustat (FG-4592);[48] Vadadustat (AKB-6548),[49] Daprodustat (GSK1278863),[50] Desidustat (ZYAN-1),[51] and Molidustat (Bay 85-3934),[52] all of which are intended as orally acting drugs for the treatment of anemia.

[48][49][50] In other scenarios and in contrast to the therapy outlined above, research suggests that HIF induction in normoxia is likely to have serious consequences in disease settings with a chronic inflammatory component.

[68][69][70][71][72][73] Therefore, it is thought that understanding the cross-talk between these two key transcription factors, NF-κB and HIF, will greatly enhance the process of drug development.

[79] HIF pathway activators such as ML-228 may have neuroprotective effects and are of interest as potential treatments for stroke and spinal cord injury.

Nobel Prize in Physiology or Medicine 2019: How Cells Sense and Adapt to Oxygen Availability. Under normoxic conditions, Hif-1 alpha is hydroxylated at two proline residues. It then associates with VHL and is tagged with ubiquitin resulting in proteasomal degradation. Under hypoxic conditions, Hif-1 alpha translocates to the cell nucleus and associates with Hif-1 beta. This complex then binds to the HRE region of the DNA resulting in the transcription of genes that are involved in a multitude of processes including erythropoesis, glycolysis, and angiogenesis.