HIF1A

This gene encodes the alpha subunit of transcription factor hypoxia-inducible factor-1 (HIF-1), which is a heterodimer composed of an alpha and a beta subunit. HIF-1 functions as a master regulator of cellular and systemic homeostatic response to hypoxia by activating transcription of many genes, including those involved in energy metabolism, angiogenesis, apoptosis, and other genes whose protein products increase oxygen delivery or facilitate metabolic adaptation to hypoxia. HIF-1 thus plays an essential role in embryonic vascularization, tumor angiogenesis and pathophysiology of ischemic disease. Alternatively spliced transcript variants encoding different isoforms have been identified for this gene.

hypoxia inducible factor 1 subunit alpha

Functions as a master transcriptional regulator of the adaptive response to hypoxia (PubMed:11292861, PubMed:11566883, PubMed:15465032, PubMed:16973622, PubMed:17610843, PubMed:18658046, PubMed:20624928, PubMed:22009797, PubMed:9887100, PubMed:30125331).

Under hypoxic conditions, activates the transcription of over 40 genes, including erythropoietin, glucose transporters, glycolytic enzymes, vascular endothelial growth factor, HILPDA, and other genes whose protein products increase oxygen delivery or facilitate metabolic adaptation to hypoxia (PubMed:11292861, PubMed:11566883, PubMed:15465032, PubMed:16973622, PubMed:17610843, PubMed:20624928, PubMed:22009797, PubMed:9887100, PubMed:30125331).

Plays an essential role in embryonic vascularization, tumor angiogenesis and pathophysiology of ischemic disease (PubMed:22009797).

Heterodimerizes with ARNT; heterodimer binds to core DNA sequence 5'-TACGTG-3' within the hypoxia response element (HRE) of target gene promoters (By similarity).

Activation requires recruitment of transcriptional coactivators such as CREBBP and EP300 (PubMed:9887100, PubMed:16543236).

Activity is enhanced by interaction with NCOA1 and/or NCOA2 (PubMed:10594042).

Interaction with redox regulatory protein APEX1 seems to activate CTAD and potentiates activation by NCOA1 and CREBBP (PubMed:10202154, PubMed:10594042).

Involved in the axonal distribution and transport of mitochondria in neurons during hypoxia (PubMed:19528298).

(Microbial infection) Upon infection by human coronavirus SARS-CoV-2, is required for induction of glycolysis in monocytes and the consequent proinflammatory state (PubMed:32697943).

In monocytes, induces expression of ACE2 and cytokines such as IL1B, TNF, IL6, and interferons (PubMed:32697943).

Promotes human coronavirus SARS-CoV-2 replication and monocyte inflammatory response (PubMed:32697943).

Angiogenesis Source: Ensembl
Axonal transport of mitochondrion Source: UniProtKB
B-1 B cell homeostasis Source: Ensembl
Cardiac ventricle morphogenesis Source: Ensembl
Cartilage development Source: Ensembl
Cellular glucose homeostasis Source: UniProtKB
Cellular iron ion homeostasis Source: Ensembl
Cellular response to hypoxia Source: UniProtKB
Cellular response to interleukin-1 Source: BHF-UCL
Cellular response to virus Source: UniProtKB
Cerebral cortex development Source: Ensembl
Collagen metabolic process Source: BHF-UCL
Connective tissue replacement involved in inflammatory response wound healing Source: BHF-UCL
Digestive tract morphogenesis Source: Ensembl
Dopaminergic neuron differentiation Source: Ensembl
Elastin metabolic process Source: BHF-UCL
Embryonic hemopoiesis Source: Ensembl
Embryonic placenta development Source: Ensembl
Epithelial cell differentiation involved in mammary gland alveolus development Source: Ensembl
Epithelial to mesenchymal transition Source: BHF-UCL
Heart looping Source: Ensembl
Hemoglobin biosynthetic process Source: Ensembl
Hypoxia-inducible factor-1alpha signaling pathway Source: Ensembl
Intestinal epithelial cell maturation Source: Ensembl
Iris morphogenesis Source: Ensembl
Lactate metabolic process Source: Ensembl
Lactation Source: Ensembl
Muscle cell cellular homeostasis Source: Ensembl
Negative regulation of bone mineralization Source: Ensembl
Negative regulation of gene expression Source: BHF-UCL
Negative regulation of growth Source: Ensembl
Negative regulation of mesenchymal cell apoptotic process Source: Ensembl
Negative regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway Source: ParkinsonsUK-UCL
Negative regulation of reactive oxygen species metabolic process Source: Ensembl
Negative regulation of thymocyte apoptotic process Source: Ensembl
Negative regulation of TOR signaling Source: Ensembl
Neural crest cell migration Source: Ensembl
Neural fold elevation formation Source: Ensembl
Outflow tract morphogenesis Source: Ensembl
Oxygen homeostasis Source: HGNC-UCL
Positive regulation of angiogenesis Source: UniProtKB
Positive regulation of autophagy of mitochondrion Source: Ensembl
Positive regulation of blood vessel endothelial cell migration Source: BHF-UCL
Positive regulation of chemokine-mediated signaling pathway Source: BHF-UCL
Positive regulation of chemokine production Source: BHF-UCL
Positive regulation of cytokine production involved in inflammatory response Source: UniProtKB
Positive regulation of endothelial cell proliferation Source: BHF-UCL
Positive regulation of epithelial cell migration Source: BHF-UCL
Positive regulation of erythrocyte differentiation Source: BHF-UCL
Positive regulation of gene expression Source: CAFA
Positive regulation of glycolytic process Source: BHF-UCL
Positive regulation of hormone biosynthetic process Source: BHF-UCL
Positive regulation of insulin secretion involved in cellular response to glucose stimulus Source: Ensembl
Positive regulation of macroautophagy Source: Ensembl
Positive regulation of neuroblast proliferation Source: Ensembl
Positive regulation of nitric-oxide synthase activity Source: BHF-UCL
Positive regulation of pri-miRNA transcription by RNA polymerase II Source: ARUK-UCL
Positive regulation of signaling receptor activity Source: BHF-UCL
Positive regulation of transcription, DNA-templated Source: UniProtKB
Positive regulation of transcription by RNA polymerase II Source: UniProtKB
Positive regulation of transcription from RNA polymerase II promoter in response to hypoxia Source: BHF-UCL
Positive regulation of vascular endothelial growth factor production Source: BHF-UCL
Positive regulation of vascular endothelial growth factor receptor signaling pathway Source: BHF-UCL
Regulation of aerobic respiration Source: Ensembl
Regulation of gene expression Source: UniProtKB
Regulation of glycolytic process Source: UniProtKB
Regulation of protein neddylation Source: UniProtKB
Regulation of transcription, DNA-templated Source: UniProtKB
Regulation of transcription by RNA polymerase II Source: GO_Central
Regulation of transcription from RNA polymerase II promoter in response to oxidative stress Source: BHF-UCL
Regulation of transforming growth factor beta2 production Source: BHF-UCL
Response to hypoxia Source: UniProtKB
Response to iron ion Source: UniProtKB
Response to muscle activity Source: Ensembl
Response to reactive oxygen species Source: UniProtKB
Retina vasculature development in camera-type eye Source: Ensembl
Signal transduction Source: BHF-UCL
Vascular endothelial growth factor production Source: BHF-UCL
Visual learning Source: Ensembl

Nucleus; Nucleus speckle; Cytoplasm. Colocalizes with HIF3A in the nucleus and speckles (By similarity). Cytoplasmic in normoxia, nuclear translocation in response to hypoxia (PubMed:9822602).

S-nitrosylation of Cys-800 may be responsible for increased recruitment of p300 coactivator necessary for transcriptional activity of HIF-1 complex.
Requires phosphorylation for DNA-binding. Phosphorylation at Ser-247 by CSNK1D/CK1 represses kinase activity and impairs ARNT binding (PubMed:20699359, PubMed:20889502). Phosphorylation by GSK3-beta and PLK3 promote degradation by the proteasome (By similarity).
Sumoylated; with SUMO1 under hypoxia (PubMed:15465032, PubMed:15776016, PubMed:17610843). Sumoylation is enhanced through interaction with RWDD3 (PubMed:17956732). Both sumoylation and desumoylation seem to be involved in the regulation of its stability during hypoxia (PubMed:15465032, PubMed:15776016, PubMed:17610843). Sumoylation can promote either its stabilization or its VHL-dependent degradation by promoting hydroxyproline-independent HIF1A-VHL complex binding, thus leading to HIF1A ubiquitination and proteasomal degradation (PubMed:15465032, PubMed:15776016, PubMed:17610843). Desumoylation by SENP1 increases its stability amd transcriptional activity (By similarity). There is a disaccord between various publications on the effect of sumoylation and desumoylation on its stability and transcriptional activity (Probable).
Acetylation of Lys-532 by ARD1 increases interaction with VHL and stimulates subsequent proteasomal degradation (PubMed:12464182). Deacetylation of Lys-709 by SIRT2 increases its interaction with and hydroxylation by EGLN1 thereby inactivating HIF1A activity by inducing its proteasomal degradation (PubMed:24681946).
Polyubiquitinated; in normoxia, following hydroxylation and interaction with VHL. Lys-532 appears to be the principal site of ubiquitination. Clioquinol, the Cu/Zn-chelator, inhibits ubiquitination through preventing hydroxylation at Asn-803. Ubiquitinated by a CUL2-based E3 ligase.
In normoxia, is hydroxylated on Pro-402 and Pro-564 in the oxygen-dependent degradation domain (ODD) by EGLN1/PHD2 and EGLN2/PHD1 (PubMed:11292861, PubMed:11566883, PubMed:12351678, PubMed:15776016, PubMed:25974097). EGLN3/PHD3 has also been shown to hydroxylate Pro-564 (PubMed:11292861, PubMed:11566883, PubMed:12351678, PubMed:15776016, PubMed:25974097). The hydroxylated prolines promote interaction with VHL, initiating rapid ubiquitination and subsequent proteasomal degradation (PubMed:11292861, PubMed:11566883, PubMed:12351678, PubMed:15776016, PubMed:25974097). Deubiquitinated by USP20 (PubMed:11292861, PubMed:11566883, PubMed:12351678, PubMed:15776016, PubMed:25974097). Under hypoxia, proline hydroxylation is impaired and ubiquitination is attenuated, resulting in stabilization (PubMed:11292861, PubMed:11566883, PubMed:12351678, PubMed:15776016, PubMed:25974097). In normoxia, is hydroxylated on Asn-803 by HIF1AN, thus abrogating interaction with CREBBP and EP300 and preventing transcriptional activation (PubMed:12080085). This hydroxylation is inhibited by the Cu/Zn-chelator, Clioquinol (PubMed:12080085). Repressed by iron ion, via Fe2+ prolyl hydroxylase (PHD) enzymes-mediated hydroxylation and subsequent proteasomal degradation (PubMed:28296633).
The iron and 2-oxoglutarate dependent 3-hydroxylation of asparagine is (S) stereospecific within HIF CTAD domains.
(Microbial infection) Glycosylated at Arg-18 by enteropathogenic E.coli protein NleB1: arginine GlcNAcylation enhances transcription factor activity and impairs glucose metabolism.