Hypoxia-inducible factor
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Hypoxia-inducible factors (HIFs) are
Discovery
The HIF transcriptional complex was discovered in 1995 by Gregg L. Semenza and postdoctoral fellow Guang Wang.[5][6][7] In 2016, William Kaelin Jr., Peter J. Ratcliffe and Gregg L. Semenza were presented the Lasker Award for their work in elucidating the role of HIF-1 in oxygen sensing and its role in surviving low oxygen conditions.[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]
Structure
Oxygen-breathing species express the
- N-terminus – a bHLH domain for DNA binding
- central region – Per-ARNT-Sim (PAS) domain, which facilitates heterodimerization
- C-terminus – recruits transcriptional coregulatory proteins
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Members
The following are members of the human HIF family:
Member | Gene | Protein |
---|---|---|
HIF-1α | HIF1A | hypoxia-inducible factor 1, alpha subunit |
HIF-1β | ARNT | aryl hydrocarbon receptor nuclear translocator |
HIF-2α | EPAS1 | endothelial PAS domain protein 1 |
HIF-2β | ARNT2 | aryl-hydrocarbon receptor nuclear translocator 2 |
HIF-3α | HIF3A | hypoxia inducible factor 3, alpha subunit |
HIF-3β
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ARNT3 | aryl-hydrocarbon receptor nuclear translocator 3 |
Function
HIF1α expression in
The HIF signaling cascade mediates the effects of hypoxia, the state of low oxygen concentration, on the cell. Hypoxia often keeps cells from
In general, HIFs are vital to development. In mammals, deletion of the HIF-1 genes results in perinatal death.[19] 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. HIF plays a central role in the regulation of human metabolism.[20]
Mechanism
The alpha subunits of HIF are
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-1α. This is termed pseudohypoxia.
HIF-1, when stabilized by hypoxic conditions, upregulates several genes to promote survival in low-oxygen conditions. These include
It has been shown that muscle
The advanced knowledge of the molecular regulatory mechanisms of HIF1 activity under hypoxic conditions contrast sharply with the paucity of information on the mechanistic and functional aspects governing
Repair, regeneration and rejuvenation
In normal circumstances after injury HIF-1a is degraded by
As a therapeutic target
Anemia
Several drugs that act as selective HIF prolyl-hydroxylase inhibitors have been developed.[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.[53] Other significant compounds from this family, which are used in research but have not been developed for medical use in humans, include MK-8617,[54] YC-1,[55] IOX-2,[56] 2-methoxyestradiol,[57] GN-44028,[58] AKB-4924,[59] Bay 87-2243,[60] FG-2216[61] and FG-4497.[62] By inhibiting prolyl-hydroxylase enzyme, the stability of HIF-2α in the kidney is increased, which results in an increase in endogenous production of erythropoietin.[63] Both FibroGen compounds made it through to Phase II clinical trials, but these were suspended temporarily in May 2007 following the death of a trial participant taking FG-2216 from fulminant hepatitis (liver failure), however it is unclear whether this death was actually caused by FG-2216. The hold on further testing of FG-4592 was lifted in early 2008, after the FDA reviewed and approved a thorough response from FibroGen.[64] Roxadustat, vadadustat, daprodustat and molidustat have now all progressed through to Phase III clinical trials for treatment of renal anemia.[48][49][50]
Inflammation and cancer
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.[65][66][67] It has also been shown that chronic inflammation is self-perpetuating and that it distorts the microenvironment as a result of aberrantly active transcription factors. As a consequence, alterations in growth factor, chemokine, cytokine, and ROS balance occur within the cellular milieu that in turn provide the axis of growth and survival needed for de novo development of cancer and metastasis. These results have numerous implications for a number of pathologies where NF-κB and HIF-1 are deregulated, including rheumatoid arthritis and cancer.[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.[29][74]
HIF activity is involved in angiogenesis required for cancer tumor growth, so HIF inhibitors such as phenethyl isothiocyanate and Acriflavine[75] are (since 2006) under investigation for anti-cancer effects.[76][77][78]
Neurology
Research conducted on mice suggests that stabilizing HIF using an HIF prolyl-hydroxylase inhibitor enhances hippocampal memory, likely by increasing erythropoietin expression.[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.[80][81]
von Hippel–Lindau disease-associated renal cell carcinoma
Belzutifan is an hypoxia-inducible factor-2α inhibitor[82] under investigation for the treatment of von Hippel–Lindau disease-associated renal cell carcinoma.[83][84][85][86]
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External links
- Hypoxia-Inducible+Factor+1 at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- PDBe-KB provides an overview of all the structure information available in the PDB for Human Hypoxia-inducible factor 1-alpha
- PDBe-KB provides an overview of all the structure information available in the PDB for Human Aryl hydrocarbon receptor nuclear translocator
- PDBe-KB provides an overview of all the structure information available in the PDB for Human Endothelial PAS domain-containing protein 1
- PDBe-KB provides an overview of all the structure information available in the PDB for Human Hypoxia-inducible factor 3-alpha
- short scientific animation visualises the crystal structure of the Heterodimeric HIF-1a:ARNT Complex with HRE DNA