HIF1A

GeneName

HIF1A

Summary

HIF1A, also known as HIF-1 alpha or hypoxia inducible factor 1 alpha, is a 93kDa transcription factor that plays a pivotal role in cellular responses to hypoxia. It is primarily expressed in the nucleus and cytoplasm and is involved in the regulation of genes that control angiogenesis, metabolism, and cell survival under low oxygen conditions. HIF1A functions by binding to specific DNA sequences in the regulatory regions of target genes, modulating their transcription in response to oxygen levels. It interacts with various proteins, including p53 and histone deacetylases, to exert its regulatory effects, and is crucial for processes such as erythropoiesis and vascular development.

Importance

HIF1A is relevant to: - Cancer biology, as it is implicated in tumor growth and metastasis through its role in angiogenesis and metabolic adaptation to hypoxic environments. - Cardiovascular research, given its involvement in cardiac ventricle morphogenesis and response to ischemic conditions. - Metabolic disorders, due to its regulation of glucose homeostasis and insulin secretion in response to hypoxia. - Neurobiology, as it influences neuronal survival and differentiation under oxidative stress conditions.

Top Products

For researchers investigating HIF1A, we recommend two outstanding primary antibodies. The first is the highly regarded Anti-HIF-1 alpha antibody [H1alpha67] (ab1), a well-cited monoclonal antibody with 246 citations. It has demonstrated excellent performance in Western blotting (WB), immunocytochemistry (ICC), immunoprecipitation (IP), and flow cytometry (FC), making it a reliable choice for various applications. Importantly, this antibody has also been validated in knockout models, ensuring its effectiveness in specific experimental contexts.Additionally, we offer the recombinant antibody Anti-HIF-1 alpha antibody [EP1215Y] (ab51608), which has garnered even more attention with 429 citations. This recombinant product is suitable for a wide range of applications, including WB, immunohistochemistry (IHC), ICC, IP, and FC. Like the top-cited product, it has also been validated in knockout models, providing researchers with confidence in its performance. The availability of both these antibodies allows for flexibility and consistency in HIF1A research. The Recombinant Human HIF-1 alpha protein ELISA Kit (ab154478), supported by 9 citations, is an excellent option for researchers looking to accurately measure HIF-1 alpha levels in their studies.

Abcam Product Citation Summary

The data indicates a significant focus on the role of HIF1A in various human cancers, particularly in studies involving hepatocellular carcinoma, renal cell carcinoma, and endometrial cancer. Additionally, there is notable research on the effects of hypoxia and its regulatory mechanisms in both human and mouse models, highlighting the importance of HIF1A in cellular responses to oxygen levels. The use of multiple applications, including Western blotting and immunohistochemistry, underscores the versatility of the antibodies in studying HIF1A across different biological contexts.

Abcam Product Citation Table

Domain

Contains two independent C-terminal transactivation domains, NTAD and CTAD, which function synergistically. Their transcriptional activity is repressed by an intervening inhibitory domain (ID).

Function

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:30125331, PubMed:9887100). 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:30125331, PubMed:9887100). 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:16543236, PubMed:9887100). 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 pro-inflammatory 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).

Post-translational modifications

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 E3 ligase VHL (PubMed:25615526). Deubiquitinated by UCHL1 (PubMed:25615526).

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 Fe(2+) 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.

Tissue Specificity

Expressed in most tissues with highest levels in kidney and heart. Overexpressed in the majority of common human cancers and their metastases, due to the presence of intratumoral hypoxia and as a result of mutations in genes encoding oncoproteins and tumor suppressors. A higher level expression seen in pituitary tumors as compared to the pituitary gland.

Cellular localization

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

Alternative names

BHLHE78, MOP1, PASD8, HIF1A, Hypoxia-inducible factor 1-alpha, HIF-1-alpha, HIF1-alpha, ARNT-interacting protein, Basic-helix-loop-helix-PAS protein MOP1, Class E basic helix-loop-helix protein 78, Member of PAS protein 1, PAS domain-containing protein 8, bHLHe78

Database links

swissprot:Q16665 omim:603348 entrezGene:3091

Other research areas

• Immunology & Infectious Disease
• Oncology