Hypoxia-inducible factor

Last updated

hypoxia-inducible factor 1, alpha subunit
Identifiers
Symbol HIF1A
NCBI gene 3091
HGNC 4910
OMIM 603348
RefSeq NM_001530
UniProt Q16665
Other data
Locus Chr. 14 q21-q24
Search for
Structures Swiss-model
Domains InterPro
aryl hydrocarbon receptor nuclear translocator
Identifiers
Symbol ARNT
Alt. symbolsHIF1B, bHLHe2
NCBI gene 405
HGNC 700
OMIM 126110
RefSeq NM_001668
UniProt P27540
Other data
Locus Chr. 1 q21
Search for
Structures Swiss-model
Domains InterPro
endothelial PAS domain protein 1
Identifiers
Symbol EPAS1
Alt. symbolsHIF2A, MOP2, PASD2, HLF
NCBI gene 2034
HGNC 3374
OMIM 603349
RefSeq NM_001430
UniProt Q99814
Other data
Locus Chr. 2 p21-p16
Search for
Structures Swiss-model
Domains InterPro
aryl-hydrocarbon receptor nuclear translocator 2
Identifiers
Symbol ARNT2
Alt. symbolsHIF2B, KIAA0307, bHLHe1
NCBI gene 9915
HGNC 16876
OMIM 606036
RefSeq NM_014862
UniProt Q9HBZ2
Other data
Locus Chr. 1 q24
Search for
Structures Swiss-model
Domains InterPro
hypoxia-inducible factor 3, alpha subunit
Identifiers
Symbol HIF3A
NCBI gene 64344
HGNC 15825
OMIM 609976
RefSeq NM_152794
UniProt Q9Y2N7
Other data
Locus Chr. 19 q13
Search for
Structures Swiss-model
Domains InterPro

Hypoxia-inducible factors (HIFs) are transcription factors that respond to decreases in available oxygen in the cellular environment, or hypoxia. [1] [2] They also respond to instances of pseudohypoxia, such as thiamine deficiency. [3] [4] Both hypoxia and pseudohypoxia leads to impairment of adenosine triphosphate (ATP) production by the mitochondria.

Contents

Discovery

The HIF transcriptional complex was discovered in 1995 by Gregg L. Semenza and postdoctoral traduction 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 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). [6] [10] HIF-1 belongs to the PER-ARNT-SIM (PAS) subfamily of the basic helix-loop-helix (bHLH) family of transcription factors. The alpha and beta subunit are similar in structure and both contain the following domains: [11] [12] [13]

Hypoxia-inducible factor-1
PDB 1lm8 EBI.jpg
Structure of a HIF-1a-pVHL-ElonginB-ElonginC Complex. [14]
Identifiers
SymbolHIF-1
Pfam PF11413
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary
HIF-1 alpha C terminal transactivation domain
PDB 1l3e EBI.jpg
Structure of hypoxia-inducible factor-1 alpha subunit. [15]
Identifiers
SymbolHIF-1a_CTAD
Pfam PF08778
InterPro IPR014887
SCOP2 1l3e / SCOPe / SUPFAM
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary
PDB 1h2k ​, 1h2l ​, 1l3e ​, 1l8c ​

Members

The following are members of the human HIF family:

MemberGeneProtein
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 ARNT3 aryl-hydrocarbon receptor nuclear translocator 3

Function

HIF1α expression in haematopoietic stem cells explains the quiescence nature of stem cells [16] for being metabolically maintaining at a low rate so as to preserve the potency of stem cells for long periods in a life cycle of an organism.

The HIF signaling cascade mediates the effects of hypoxia, the state of low oxygen concentration, on the cell. Hypoxia often keeps cells from differentiating. However, hypoxia promotes the formation of blood vessels, and is important for the formation of a vascular system in embryos and tumors. The hypoxia in wounds also promotes the migration of keratinocytes and the restoration of the epithelium. [17] It is therefore not surprising that HIF-1 modulation was identified as a promising treatment paradigm in wound healing. [18]

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

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. HIF Nobel Prize Physiology Medicine 2019 Hegasy ENG.png
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.

The alpha subunits of HIF are hydroxylated at conserved proline residues by HIF prolyl-hydroxylases, allowing their recognition and ubiquitination by the VHL E3 ubiquitin ligase, which labels them for rapid degradation by the proteasome. [21] [22] This occurs only in normoxic conditions. In hypoxic conditions, HIF prolyl-hydroxylase is inhibited, since it utilizes oxygen as a cosubstrate. [23] [24]

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 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 hypoxia-responsive elements (HREs) in promoters that contain the sequence 5'-RCGTG-3' (where R is a purine, either A or G). Studies demonstrate that hypoxia modulates histone methylation and reprograms chromatin. [25] This paper was published back-to-back with that of 2019 Nobel Prize in Physiology or Medicine winner for Medicine William Kaelin Jr. [26] This work was highlighted in an independent editorial. [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. Thus, "compartmentalization" of oxygen-sensitive signaling components may influence the hypoxic response. [28]

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 NF-κB-mediated HIF1 regulation under normoxic conditions. However, HIF-1α stabilization is also found in non-hypoxic conditions through an unknown mechanism. It was shown that NF-κB (nuclear factor κB) is a direct modulator of HIF-1α expression in the presence of normal oxygen pressure. siRNA (small interfering RNA) studies for individual NF-κB members revealed differential effects on HIF-1α mRNA levels, indicating that NF-κB can regulate basal HIF-1α expression. 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. [29] HIF-1 and HIF-2 have different physiological roles. HIF-2 regulates erythropoietin production in adult life. [30]

Repair, regeneration and rejuvenation

In normal circumstances after injury HIF-1a is degraded by prolyl hydroxylases (PHDs). In June 2015, scientists found that the continued up-regulation of HIF-1a via PHD inhibitors regenerates lost or damaged tissue in mammals that have a repair response; and the continued down-regulation of Hif-1a results in healing with a scarring response in mammals with a previous regenerative response to the loss of tissue. The act of regulating HIF-1a can either turn off, or turn on the key process of mammalian regeneration. [31] [32] One such regenerative process in which HIF1A is involved is skin healing. [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. Not only did the wounds in the mice heal more quickly, but the quality of the new skin was even better than the original. [34] [35] [36] Additionally the regenerative effect of HIF-1A modulation on aged skin cells was described [37] [38] and a rejuvenating effect on aged facial skin was demonstrated in patients. [39] HIF modulation has also been linked to a beneficial effect on hair loss. [40] The biotech company Tomorrowlabs GmbH, founded in Vienna in 2016 by the physician Dominik Duscher and pharmacologist Dominik Thor, makes use of this mechanism. [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. [42] [43] [44] [45]

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]

Related Research Articles

<span class="mw-page-title-main">Succinic acid</span> Dicarboxylic acid

Succinic acid is a dicarboxylic acid with the chemical formula (CH2)2(CO2H)2. In living organisms, succinic acid takes the form of an anion, succinate, which has multiple biological roles as a metabolic intermediate being converted into fumarate by the enzyme succinate dehydrogenase in complex 2 of the electron transport chain which is involved in making ATP, and as a signaling molecule reflecting the cellular metabolic state.

<span class="mw-page-title-main">Tumor hypoxia</span> Situation where tumor cells have been deprived of oxygen

Tumor hypoxia is the situation where tumor cells have been deprived of oxygen. As a tumor grows, it rapidly outgrows its blood supply, leaving portions of the tumor with regions where the oxygen concentration is significantly lower than in healthy tissues. Hypoxic microenvironments in solid tumors are a result of available oxygen being consumed within 70 to 150 μm of tumor vasculature by rapidly proliferating tumor cells thus limiting the amount of oxygen available to diffuse further into the tumor tissue. In order to support continuous growth and proliferation in challenging hypoxic environments, cancer cells are found to alter their metabolism. Furthermore, hypoxia is known to change cell behavior and is associated with extracellular matrix remodeling and increased migratory and metastatic behavior.

<span class="mw-page-title-main">Tumor metabolome</span>

The study of the tumor metabolism, also known as tumor metabolome describes the different characteristic metabolic changes in tumor cells. The characteristic attributes of the tumor metabolome are high glycolytic enzyme activities, the expression of the pyruvate kinase isoenzyme type M2, increased channeling of glucose carbons into synthetic processes, such as nucleic acid, amino acid and phospholipid synthesis, a high rate of pyrimidine and purine de novo synthesis, a low ratio of Adenosine triphosphate and Guanosine triphosphate to Cytidine triphosphate and Uridine triphosphate, low Adenosine monophosphate levels, high glutaminolytic capacities, release of immunosuppressive substances and dependency on methionine.

<span class="mw-page-title-main">Von Hippel–Lindau tumor suppressor</span> Mammalian protein found in humans

The Von Hippel–Lindau tumor suppressor also known as pVHL is a protein that, in humans, is encoded by the VHL gene. Mutations of the VHL gene are associated with Von Hippel–Lindau disease, which is characterized by hemangioblastomas of the brain, spinal cord and retina. It is also associated with kidney and pancreatic lesions.

<span class="mw-page-title-main">HIF1A</span> Protein-coding gene in the species Homo sapiens

Hypoxia-inducible factor 1-alpha, also known as HIF-1-alpha, is a subunit of a heterodimeric transcription factor hypoxia-inducible factor 1 (HIF-1) that is encoded by the HIF1A gene. The Nobel Prize in Physiology or Medicine 2019 was awarded for the discovery of HIF.

<span class="mw-page-title-main">Procollagen-proline dioxygenase</span> Enzyme

Procollagen-proline dioxygenase, commonly known as prolyl hydroxylase, is a member of the class of enzymes known as alpha-ketoglutarate-dependent hydroxylases. These enzymes catalyze the incorporation of oxygen into organic substrates through a mechanism that requires alpha-Ketoglutaric acid, Fe2+, and ascorbate. This particular enzyme catalyzes the formation of (2S, 4R)-4-hydroxyproline, a compound that represents the most prevalent post-translational modification in the human proteome.

<span class="mw-page-title-main">EGLN2</span> Protein-coding gene in the species Homo sapiens

Egl nine homolog 2 is a protein that in humans is encoded by the EGLN2 gene. ELGN2 is an alpha-ketoglutarate-dependent hydroxylase, a superfamily of non-haem iron-containing proteins.

<span class="mw-page-title-main">EGLN1</span> Protein-coding gene in the species Homo sapiens

Hypoxia-inducible factor prolyl hydroxylase 2 (HIF-PH2), or prolyl hydroxylase domain-containing protein 2 (PHD2), is an enzyme encoded by the EGLN1 gene. It is also known as Egl nine homolog 1. PHD2 is a α-ketoglutarate/2-oxoglutarate-dependent hydroxylase, a superfamily non-haem iron-containing proteins. In humans, PHD2 is one of the three isoforms of hypoxia-inducible factor-proline dioxygenase, which is also known as HIF prolyl-hydroxylase.

<span class="mw-page-title-main">EGLN3</span> Protein-coding gene in the species Homo sapiens

Egl nine homolog 3 is a protein that in humans is encoded by the EGLN3 gene. ELGN3 is a member of the superfamily of alpha-ketoglutarate-dependent hydroxylases, which are non-haem iron-containing proteins.

<span class="mw-page-title-main">HIF1AN</span> Protein-coding gene in the species Homo sapiens

Hypoxia-inducible factor 1-alpha inhibitor (FIH) is a protein that in humans is encoded by the HIF1AN gene.

<span class="mw-page-title-main">HIF prolyl-hydroxylase inhibitor</span> Drug class

Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are a novel class of oral medications developed for the treatment of anemia in chronic kidney disease (CKD). These drugs work by inhibiting hypoxia-inducible factor-proline dioxygenase, which are responsible for the degradation of hypoxia-inducible factor (HIF) under normal oxygen conditions. By stabilizing HIF, these inhibitors mimic the body's natural response to hypoxia, leading to increased endogenous erythropoietin production and improved iron metabolism. HIF-PHIs have shown efficacy in correcting and maintaining hemoglobin levels in both dialysis-dependent and non-dialysis-dependent CKD patients, offering an alternative to traditional erythropoiesis-stimulating agents (ESAs).

Hypoxia-inducible factor-proline dioxygenase (EC 1.14.11.29, HIF hydroxylase) is an enzyme with systematic name hypoxia-inducible factor-L-proline, 2-oxoglutarate:oxygen oxidoreductase (4-hydroxylating). This enzyme catalyses the following chemical reaction

Hypoxia-inducible factor-asparagine dioxygenase (EC 1.14.11.30, HIF hydroxylase) is an enzyme with systematic name hypoxia-inducible factor-L-asparagine, 2-oxoglutarate:oxygen oxidoreductase (4-hydroxylating). This enzyme catalyses the following chemical reaction:

hypoxia-inducible factor-L-asparagine + 2-oxoglutarate + O2 hypoxia-inducible factor-(3S)-3-hydroxy-L-asparagine + succinate + CO2

Alpha-ketoglutarate-dependent hydroxylases are a major class of non-heme iron proteins that catalyse a wide range of reactions. These reactions include hydroxylation reactions, demethylations, ring expansions, ring closures, and desaturations. Functionally, the αKG-dependent hydroxylases are comparable to cytochrome P450 enzymes. Both use O2 and reducing equivalents as cosubstrates and both generate water.

Christopher Joseph Schofield is a Professor of Chemistry at the University of Oxford and a Fellow of the Royal Society. Chris Schofield is a professor of organic chemistry at the University of Oxford, Department of Chemistry and a Fellow of Hertford College. Schofield studied functional, structural and mechanistic understanding of enzymes that employ oxygen and 2-oxoglutarate as a co-substrate. His work has opened up new possibilities in antibiotic research, oxygen sensing, and gene regulation.

<span class="mw-page-title-main">Gregg L. Semenza</span> American physician (born 1956)

Gregg Leonard Semenza is an American pediatrician and Professor of Genetic Medicine at the Johns Hopkins School of Medicine. He serves as the director of the vascular program at the Institute for Cell Engineering. He is a 2016 recipient of the Albert Lasker Award for Basic Medical Research. He is known for his discovery of HIF-1, which allows cancer cells to adapt to oxygen-poor environments. He shared the 2019 Nobel Prize in Physiology or Medicine for "discoveries of how cells sense and adapt to oxygen availability" with William Kaelin Jr. and Peter J. Ratcliffe. Semenza has had thirteen research papers retracted due to falsified data.

<span class="mw-page-title-main">P4HTM</span> Protein-coding gene in the species Homo sapiens

Prolyl 4-hydroxylase, transmembrane is a protein that in humans is encoded by the P4HTM gene.

<span class="mw-page-title-main">Roxadustat</span> Anti-anemia medication

Roxadustat, sold under the brand name Evrenzo, is an anti-anemia medication. Roxadustat is a HIF prolyl-hydroxylase inhibitor that increases endogenous production of erythropoietin and stimulates production of hemoglobin and red blood cells. It was investigated in clinical trials for the treatment of anemia caused by chronic kidney disease (CKD). It is taken by mouth. The drug was developed by FibroGen, in partnership with AstraZeneca.

<span class="mw-page-title-main">Molidustat</span> Chemical compound

Molidustat is a drug which acts as an HIF prolyl-hydroxylase inhibitor and thereby increases endogenous production of erythropoietin, which stimulates production of hemoglobin and red blood cells. It is in Phase III clinical trials for the treatment of anemia caused by chronic kidney disease. Due to its potential applications in athletic doping, it has also been incorporated into screens for performance-enhancing drugs.

Factor Inhibiting HIF (FIH) Asparaginyl Hydroxylase Inhibitors inhibit the FIH pathway also catalyzed by Asparaginyl Hydroxylase inhibition. Before 2010s thought to be identical to HIF prolyl-hydroxylase pathway, studies have shown FIH to be the master regulator that controls HIF transcriptional activity in an oxygen-dependent manner. and that HIF prolyl-hydroxylase inhibitors may only minimally inhibit FIH. Skeletal muscle expresses 50-fold higher levels of FIH than other tissues.

References

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  2. ↑ Wilkins SE, Abboud MI, Hancock RL, Schofield CJ (April 2016). "Targeting Protein-Protein Interactions in the HIF System". ChemMedChem. 11 (8): 773–86. doi:10.1002/cmdc.201600012. PMC   4848768 . PMID   26997519.
  3. ↑ Rl S, Ja Z (2013). "HIF1-α-mediated gene expression induced by vitamin B1 deficiency". International Journal for Vitamin and Nutrition Research. 83 (3): 188–197. doi:10.1024/0300-9831/a000159. ISSN   0300-9831. PMID   24846908.
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  6. 1 2 Wang GL, Jiang BH, Rue EA, Semenza GL (June 1995). "Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension". Proceedings of the National Academy of Sciences of the United States of America. 92 (12): 5510–4. Bibcode:1995PNAS...92.5510W. doi: 10.1073/pnas.92.12.5510 . PMC   41725 . PMID   7539918.
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