Hypoxia-inducible Factor
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Hypoxia-inducible factors (HIFs) are
transcription factors In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The func ...
that respond to decreases in available
oxygen Oxygen is the chemical element with the symbol O and atomic number 8. It is a member of the chalcogen group in the periodic table, a highly reactive nonmetal, and an oxidizing agent that readily forms oxides with most elements as wel ...
in the cellular environment, or
hypoxia Hypoxia means a lower than normal level of oxygen, and may refer to: Reduced or insufficient oxygen * Hypoxia (environmental), abnormally low oxygen content of the specific environment * Hypoxia (medical), abnormally low level of oxygen in the tis ...
. They are only present in parahoxozoan animals.


Discovery

The HIF transcriptional complex was discovered in 1995 by Gregg L. Semenza and postdoctoral fellow Guang Wang. In 2016, William Kaelin Jr., Peter J. Ratcliffe and Gregg L. Semenza were presented the
Lasker Award The Lasker Awards have been awarded annually since 1945 to living persons who have made major contributions to medical science or who have performed public service on behalf of medicine. They are administered by the Lasker Foundation, which was f ...
for their work in elucidating the role of HIF-1 in oxygen sensing and its role in surviving low oxygen conditions. In 2019, the same three individuals were jointly awarded the
Nobel Prize in Physiology or Medicine The Nobel Prize in Physiology or Medicine is awarded yearly by the Nobel Assembly at the Karolinska Institute for outstanding discoveries in physiology or medicine. The Nobel Prize is not a single prize, but five separate prizes that, accord ...
for their work in elucidating how HIF senses and adapts cellular response to oxygen availability.


Structure

Most, if not all, oxygen-breathing species express the highly conserved transcriptional complex HIF-1, which is a
heterodimer In biochemistry, a protein dimer is a macromolecular complex formed by two protein monomers, or single proteins, which are usually non-covalently bound. Many macromolecules, such as proteins or nucleic acids, form dimers. The word ''dimer'' has ...
composed of an alpha and a beta subunit, the latter being a constitutively-expressed
aryl hydrocarbon receptor nuclear translocator The ARNT gene encodes the aryl hydrocarbon receptor nuclear translocator protein that forms a complex with ligand-bound aryl hydrocarbon receptor (AhR), and is required for receptor function. The encoded protein has also been identified as the be ...
(ARNT). HIF-1 belongs to the PER-ARNT-SIM (PAS) subfamily of the
basic helix-loop-helix BASIC (Beginners' All-purpose Symbolic Instruction Code) is a family of general-purpose, high-level programming languages designed for ease of use. The original version was created by John G. Kemeny and Thomas E. Kurtz at Dartmouth College ...
(bHLH) family of transcription factors. The alpha and beta subunit are similar in structure and both contain the following domains: *
N-terminus The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...
– a bHLH domain for DNA binding * central region – Per-ARNT-Sim (PAS) domain, which facilitates heterodimerization *
C-terminus The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...
– recruits transcriptional coregulatory proteins


Members

The following are members of the human HIF family:


Function

HIF1α expression in
haematopoietic stem cell Hematopoietic stem cells (HSCs) are the stem cells that give rise to other blood cells. This process is called haematopoiesis. In vertebrates, the very first definitive HSCs arise from the ventral endothelial wall of the embryonic aorta within t ...
s explains the quiescence nature of
stem cell In multicellular organisms, stem cells are undifferentiated or partially differentiated cells that can differentiate into various types of cells and proliferate indefinitely to produce more of the same stem cell. They are the earliest type o ...
s 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 The blood circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the entire body of a human or other vertebrate. It includes the cardiovascular system, or vascular system, tha ...
in
embryo An embryo is an initial stage of development of a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male spe ...
s and tumors. The hypoxia in
wound A wound is a rapid onset of injury that involves laceration, lacerated or puncture wound, punctured skin (an ''open'' wound), or a bruise, contusion (a ''closed'' wound) from blunt force physical trauma, trauma or compression. In pathology, a '' ...
s also promotes the migration of
keratinocyte Keratinocytes are the primary type of Cell (biology), cell found in the epidermis (skin), epidermis, the outermost layer of the skin. In humans, they constitute 90% of epidermal skin cells. Basal cells in the stratum basale, basal layer (''str ...
s and the restoration of the
epithelium Epithelium or epithelial tissue is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. It is a thin, continuous, protective layer of compactly packed cells with a little intercellul ...
. It is therefore not surprising that HIF-1 modulation was identified as a promising treatment paradigm in wound healing. In general, HIFs are 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 Chondrocytes (, from Greek χόνδρος, ''chondros'' = cartilage + κύτος, ''kytos'' = cell) are the only cells found in healthy cartilage. They produce and maintain the cartilaginous matrix, which consists mainly of collagen and proteog ...
survival, allowing the cells to adapt to low-oxygen conditions within the
growth plates The epiphyseal plate (or epiphysial plate, physis, or growth plate) is a hyaline cartilage plate in the metaphysis at each end of a long bone. It is the part of a long bone where new bone growth takes place; that is, the whole bone is alive, with ...
of
bone A bone is a Stiffness, rigid Organ (biology), organ that constitutes part of the skeleton in most vertebrate animals. Bones protect the various other organs of the body, produce red blood cell, red and white blood cells, store minerals, provid ...
s. HIF plays a central role in the regulation of human metabolism.


Mechanism

The alpha subunits of HIF are
hydroxylated In chemistry, hydroxylation can refer to: *(i) most commonly, hydroxylation describes a chemistry, chemical process that introduces a hydroxyl group () into an organic compound. *(ii) the ''degree of hydroxylation'' refers to the number of OH gr ...
at conserved
proline Proline (symbol Pro or P) is an organic acid classed as a proteinogenic amino acid (used in the biosynthesis of proteins), although it does not contain the amino group but is rather a secondary amine. The secondary amine nitrogen is in the prot ...
residues by
HIF prolyl-hydroxylase Hypoxia-inducible factor-proline dioxygenase (, ''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 r ...
s, allowing their recognition and
ubiquitination Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ''ubiquitously''. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 1980s. Fo ...
by the VHL
E3 ubiquitin ligase A ubiquitin ligase (also called an E3 ubiquitin ligase) is a protein that recruits an E2 ubiquitin-conjugating enzyme that has been loaded with ubiquitin, recognizes a protein substrate, and assists or directly catalyzes the transfer of ubiquitin ...
, which labels them for rapid degradation by the
proteasome Proteasomes are protein complexes which degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks peptide bonds. Enzymes that help such reactions are called proteases. Proteasomes are part of a major mechanism by w ...
. This occurs only in normoxic conditions. In hypoxic conditions, HIF prolyl-hydroxylase is inhibited, since it utilizes oxygen as a cosubstrate. Inhibition of electron transfer in the
succinate dehydrogenase Succinate dehydrogenase (SDH) or succinate-coenzyme Q reductase (SQR) or respiratory complex II is an enzyme complex, found in many bacterial cells and in the inner mitochondrial membrane of eukaryotes. It is the only enzyme that participates i ...
complex due to mutations in the
SDHB Succinate dehydrogenase biquinoneiron-sulfur subunit, mitochondrial (SDHB) also known as iron-sulfur subunit of complex II (Ip) is a protein that in humans is encoded by the ''SDHB'' gene. The succinate dehydrogenase (also called SDH or Complex ...
or
SDHD Succinate dehydrogenase biquinonecytochrome b small subunit, mitochondrial (CybS), also known as succinate dehydrogenase complex subunit D (SDHD), is a protein that in humans is encoded by the ''SDHD'' gene. Names previously used for SDHD were ...
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 Glycolysis is the metabolic pathway that converts glucose () into pyruvate (). The free energy released in this process is used to form the high-energy molecules adenosine triphosphate (ATP) and reduced nicotinamide adenine dinucleotide (NADH ...
enzymes, which allow ATP synthesis in an oxygen-independent manner, and
vascular endothelial growth factor Vascular endothelial growth factor (VEGF, ), originally known as vascular permeability factor (VPF), is a signal protein produced by many cells that stimulates the formation of blood vessels. To be specific, VEGF is a sub-family of growth factors, ...
(VEGF), which promotes
angiogenesis Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature by processes of sprouting and splitting ...
. HIF-1 acts by binding to Hypoxia-responsive elements (HREs) in promoters that contain the sequence NCGTG (where N is either A or G). Recent work from the laboratories of
Sónia Rocha Sónia Maria Campos Soares da Rocha, usually referred to as Professor Sónia Rocha, is a Portuguese cell biologist who holds a personal chair in biochemistry at the University of Liverpool, where she is the head of the Department of Biochemistry ...
and William Kaelin Jr. demonstrates that Hypoxia modulates
histone In biology, histones are highly basic proteins abundant in lysine and arginine residues that are found in eukaryotic cell nuclei. They act as spools around which DNA winds to create structural units called nucleosomes. Nucleosomes in turn are wr ...
methylation In the chemical sciences, methylation denotes the addition of a methyl group on a substrate, or the substitution of an atom (or group) by a methyl group. Methylation is a form of alkylation, with a methyl group replacing a hydrogen atom. These t ...
and reprograms
chromatin Chromatin is a complex of DNA and protein found in eukaryotic cells. The primary function is to package long DNA molecules into more compact, denser structures. This prevents the strands from becoming tangled and also plays important roles in r ...
This paper was published back-to-back with that of 2019
Nobel Prize in Physiology or Medicine The Nobel Prize in Physiology or Medicine is awarded yearly by the Nobel Assembly at the Karolinska Institute for outstanding discoveries in physiology or medicine. The Nobel Prize is not a single prize, but five separate prizes that, accord ...
winner for Medicine William Kaelin Jr. This work was highlighted in an independent editorial. 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. 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 Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a protein complex that controls transcription of DNA, cytokine production and cell survival. NF-κB is found in almost all animal cell types and is involved in cellular ...
-mediated HIF1 regulation under normoxic conditions. However, HIF-1α stabilization is also found in non-hypoxic conditions through an, until recently, unknown mechanism. It was shown that
NF-κB Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a protein complex that controls transcription of DNA, cytokine production and cell survival. NF-κB is found in almost all animal cell types and is involved in cellular ...
(nuclear factor κB) is a direct modulator of HIF-1α expression in the presence of normal oxygen pressure.
siRNA Small interfering RNA (siRNA), sometimes known as short interfering RNA or silencing RNA, is a class of double-stranded RNA at first non-coding RNA molecules, typically 20-24 (normally 21) base pairs in length, similar to miRNA, and operating wi ...
(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 Tumor necrosis factor (TNF, cachexin, or cachectin; formerly known as tumor necrosis factor alpha or TNF-α) is an adipokine and a cytokine. TNF is a member of the TNF superfamily, which consists of various transmembrane proteins with a homolog ...
(tumour necrosis factor α) treatment, HIF-1α levels also change in an NF-κB-dependent manner. HIF-1 and HIF-2 have different physiological roles. HIF-2 regulates
erythropoietin Erythropoietin (; EPO), also known as erythropoetin, haematopoietin, or haemopoietin, is a glycoprotein cytokine secreted mainly by the kidneys in response to cellular hypoxia; it stimulates red blood cell production (erythropoiesis) in the bo ...
production in adult life.


Repair, regeneration and rejuvenation

In normal circumstances after injury HIF-1a is degraded by
prolyl Proline (symbol Pro or P) is an organic acid classed as a proteinogenic amino acid (used in the biosynthesis of proteins), although it does not contain the amino group but is rather a secondary amine. The secondary amine nitrogen is in the prot ...
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. One such regenerative process in which HIF1A is involved is skin healing. Researchers at the
Stanford University School of Medicine Stanford University School of Medicine is the medical school of Stanford University and is located in Stanford, California. It traces its roots to the Medical Department of the University of the Pacific, founded in San Francisco in 1858. This ...
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. Additionally the regenerative effect of HIF-1A modulation on aged skin cells was described and a rejuvenating effect on aged facial skin was demonstrated in patients. HIF modulation has also been linked to a beneficial effect on hair loss. The biotech company Tomorrowlabs GmbH, founded in Vienna in 2016 by the physician
Dominik Duscher Dominic is a name common among Roman Catholics and other Latin-Romans as a male given name. Originally from the late Roman-Italic name "Dominicus", its translation means "Lordly", "Belonging to God" or "of the Master". Variations include: Domini ...
and pharmacologist
Dominik Thor Dominic is a name common among Roman Catholics and other Latin-Romans as a male given name. Originally from the late Roman-Italic name "Dominicus", its translation means "Lordly", "Belonging to God" or "of the Master". Variations include: Domini ...
, makes use of this mechanism. Based on the patent-pending HSF ("HIF strengthening factor") active ingredient, products have been developed that are supposed to promote skin and hair regeneration.


As a therapeutic target


Anemia

Recently, several drugs that act as selective
HIF prolyl-hydroxylase inhibitor Not to be confused with '' Factor Inhibiting HIF Asparaginyl Hydroxylase Inhibitors'' Hypoxia-inducible factor prolyl hydroxylase Inhibitors (HIF-PHIs) also known as hypoxia-inducible factor stabilizers (HIF stabilizers) are members of a mostl ...
s have been developed. The most notable compounds are:
Roxadustat 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 ...
(FG-4592);
Vadadustat Vadadustat, sold under the brand name Vafseo is a medication used for the treatment of symptomatic anemia associated with chronic kidney disease. Text was copied from this source which is copyright European Medicines Agency. Reproduction is au ...
(AKB-6548),
Daprodustat Daprodustat, sold under the brand name Duvroq among others, is a medication that is used for the treatment of anemia due to chronic kidney disease. It is a hypoxia-inducible factor prolyl hydroxylase inhibitor. It is taken by mouth. The most ...
(GSK1278863), Desidustat (ZYAN-1), and Molidustat (Bay 85-3934), all of which are intended as orally acting drugs for the treatment of
anemia Anemia or anaemia (British English) is a blood disorder in which the blood has a reduced ability to carry oxygen due to a lower than normal number of red blood cells, or a reduction in the amount of hemoglobin. When anemia comes on slowly, th ...
. Other significant compounds from this family, which are used in research but have not been developed for medical use in humans, include MK-8617, YC-1, IOX-2, 2-methoxyestradiol, GN-44028, AKB-4924, Bay 87-2243, FG-2216 and FG-4497. 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 Erythropoietin (; EPO), also known as erythropoetin, haematopoietin, or haemopoietin, is a glycoprotein cytokine secreted mainly by the kidneys in response to cellular hypoxia; it stimulates red blood cell production (erythropoiesis) in the bo ...
. 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 Hepatitis is inflammation of the liver tissue. Some people or animals with hepatitis have no symptoms, whereas others develop yellow discoloration of the skin and whites of the eyes (jaundice), poor appetite, vomiting, tiredness, abdominal pa ...
(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. Roxadustat, vadadustat, daprodustat and molidustat have now all progressed through to Phase III clinical trials for treatment of renal anemia.


Inflammation and cancer

In other scenarios and in contrast to the therapy outlined above, recent research suggests that HIF induction in normoxia is likely to have serious consequences in disease settings with a chronic inflammatory component. It has also been shown that chronic inflammation is self-perpetuating and that it distorts the microenvironment as a result of aberrantly active
transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The fu ...
s. 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 Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a protein complex that controls transcription of DNA, cytokine production and cell survival. NF-κB is found in almost all animal cell types and is involved in cellular ...
and HIF-1 are deregulated, including
rheumatoid arthritis Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and hands are involv ...
and cancer. 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. HIF activity is involved in
angiogenesis Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature by processes of sprouting and splitting ...
required for cancer tumor growth, so HIF inhibitors such as
phenethyl isothiocyanate Phenethyl isothiocyanate (PEITC) is a naturally occurring isothiocyanate whose precursor, gluconasturtiin is found in some cruciferous vegetables, especially watercress. PEITC has been studied for its potential for chemoprevention of cancers, ...
and
Acriflavine Acriflavine ( INN: acriflavinium chloride) is a topical antiseptic. It has the form of an orange or brown powder. It may be harmful in the eyes or if inhaled. It is a dye and it stains the skin and may irritate. The hydrochloride form is more irr ...
are (since 2006) under investigation for anti-cancer effects.


Neurology

Research conducted on mice suggests that stabilizing HIF using an
HIF prolyl-hydroxylase inhibitor Not to be confused with '' Factor Inhibiting HIF Asparaginyl Hydroxylase Inhibitors'' Hypoxia-inducible factor prolyl hydroxylase Inhibitors (HIF-PHIs) also known as hypoxia-inducible factor stabilizers (HIF stabilizers) are members of a mostl ...
enhances
hippocampal The hippocampus (via Latin from Greek , 'seahorse') is a major component of the brain of humans and other vertebrates. Humans and other mammals have two hippocampi, one in each side of the brain. The hippocampus is part of the limbic system, an ...
memory, likely by increasing
erythropoietin Erythropoietin (; EPO), also known as erythropoetin, haematopoietin, or haemopoietin, is a glycoprotein cytokine secreted mainly by the kidneys in response to cellular hypoxia; it stimulates red blood cell production (erythropoiesis) in the bo ...
expression. HIF pathway activators such as ML-228 may have neuroprotective effects and are of interest as potential treatments for
stroke A stroke is a medical condition in which poor blood flow to the brain causes cell death. There are two main types of stroke: ischemic, due to lack of blood flow, and hemorrhagic, due to bleeding. Both cause parts of the brain to stop functionin ...
and
spinal cord injury A spinal cord injury (SCI) is damage to the spinal cord that causes temporary or permanent changes in its function. Symptoms may include loss of muscle function, sensation, or autonomic function in the parts of the body served by the spinal cor ...
.


von Hippel–Lindau disease-associated renal cell carcinoma

Belzutifan is an hypoxia-inducible factor-2α inhibitor under investigation for the treatment of
von Hippel–Lindau disease Von Hippel–Lindau disease (VHL), also known as Von Hippel–Lindau syndrome, is a rare genetic disorder with multisystem involvement. It is characterized by visceral cysts and benign tumors with potential for subsequent malignant transformation ...
-associated
renal cell carcinoma Renal cell carcinoma (RCC) is a kidney cancer that originates in the lining of the proximal convoluted tubule, a part of the very small tubes in the kidney that transport primary urine. RCC is the most common type of kidney cancer in adults, resp ...
.


See also

* HIF-1α


References


External links

*
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 {{DEFAULTSORT:Hypoxia-Inducible Factors Developmental genes and proteins Transcription factors World Anti-Doping Agency prohibited substances