HIF1A

Official Full Name

hypoxia inducible factor 1 subunit alpha

Organism

Homo sapiens

GeneID

3091

Background

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. [provided by RefSeq, Jul 2011]

Synonyms

HIF1; MOP1; PASD8; HIF-1A; bHLHe78; HIF-1alpha; HIF1-ALPHA; HIF-1-alpha;

Bio Chemical Class

mRNA target

Protein Sequence

MEGAGGANDKKKISSERRKEKSRDAARSRRSKESEVFYELAHQLPLPHNVSSHLDKASVMRLTISYLRVRKLLDAGDLDIEDDMKAQMNCFYLKALDGFVMVLTDDGDMIYISDNVNKYMGLTQFELTGHSVFDFTHPCDHEEMREMLTHRNGLVKKGKEQNTQRSFFLRMKCTLTSRGRTMNIKSATWKVLHCTGHIHVYDTNSNQPQCGYKKPPMTCLVLICEPIPHPSNIEIPLDSKTFLSRHSLDMKFSYCDERITELMGYEPEELLGRSIYEYYHALDSDHLTKTHHDMFTKGQVTTGQYRMLAKRGGYVWVETQATVIYNTKNSQPQCIVCVNYVVSGIIQHDLIFSLQQTECVLKPVESSDMKMTQLFTKVESEDTSSLFDKLKKEPDALTLLAPAAGDTIISLDFGSNDTETDDQQLEEVPLYNDVMLPSPNEKLQNINLAMSPLPTAETPKPLRSSADPALNQEVALKLEPNPESLELSFTMPQIQDQTPSPSDGSTRQSSPEPNSPSEYCFYVDSDMVNEFKLELVEKLFAEDTEAKNPFSTQDTDLDLEMLAPYIPMDDDFQLRSFDQLSPLESSSASPESASPQSTVTVFQQTQIQEPTANATTTTATTDELKTVTKDRMEDIKILIASPSPTHIHKETTSATSSPYRDTQSRTASPNRAGKGVIEQTEKSHPRSPNVLSVALSQRTTVPEEELNPKILALQNAQRKRKMEHDGSLFQAVGIGTLLQQPDDHAATTSLSWKRVKGCKSSEQNGMEQKTIILIPSDLACRLLGQSMDESGLPQLTSYDCEVNAPIQGSRNLLQGEELLRALDQVN

Open

Disease

Adrenomedullary hyperfunction, Brain cancer

Approved Drug

Clinical Trial Drug

7 +

Discontinued Drug

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Detailed Information

The response to low oxygen is mediated by hypoxia-inducible factors (HIFs), a family of transcription factors that are stabilized under hypoxic conditions in all mammalian cells and are thought to primarily upregulate a variety of pathways to adapt cells to low oxygen. HIFs are heterodimeric complexes composed of alpha and beta subunits. In the presence of oxygen, alpha subunits are hydroxylated by prolyl-hydroxylases, which allows recognition and ubiquitination by von Hippel Lindau (VHL), and rapid degradation by the proteasome. Under low oxygen conditions, alpha subunits escape hydroxylation, avoid degradation, and transfers to the nucleus to pair with constitutive beta subunits and regulate gene expression. It is reported that only 1-5 % of all human genes are expressed in response to hypoxia in more than one type of cell. HIF-1α regulates the expression of a large number of genes, including genes related to diseases and carcinogenesis; therefore, known targets involved in the regulation mechanisms can be applied to treatment.

Biological Functions of HIF1A

Transcription factor HIF1A mediates transcriptional responses to hypoxia for a large number of genes to control cellular oxygen supply and maintain cell viability during periods of low oxygen concentration. Analysis of 98 HIF1A target genes collected from 51 published studies revealed 20 related pathways. HIF1A was implicated in: metabolism and redox homeostasis (glucose catabolism, regulation of lipid metabolism), vascular responses in hypoxia (endothelial cells, ischemia-induced angiogenesis), inflammation (regulation in inflammatory cells, myeloid cell function, tumor-associated macrophages), cancer (tumorigenesis, metastasis, regulation by cancer metabolism, tumor angiogenesis, cancer stem cells), and also as part of a systemic response to hypoxia. Apart from regulating the expression of protein-coding genes, it has been shown that HIF1A also regulates noncoding RNA genes (ncRNA), including microRNAs (miRNAs) and transcribed-ultraconserved regions (T-UCRs).

HIF1A and Cancer

Hypoxia is an important factor in the pathology of many human diseases, including aging, diabetes, cancer, and stroke/ischemia. As a mechanism of drug resistance, low oxygen level is an important microenvironment condition that affects the activation status of signaling pathways. Of the 16 HIF1A SNPs associated with 40 different phenotypes, six SNPs have been associated with increased risk for 14 cancer types. These six SNPs were most frequently associated with lung, breast, prostate, colorectal (CRC), gastric, oral cancer and renal cell carcinoma (RCC). It is well known that solid tumors frequently have low levels of O₂, which can be a result of cancer cells growing faster than their supporting vascular network. Hypoxic stress might also be caused by a perfusion defect due to abnormal tumor blood vessel structure and function. Therefore, these events cause HIF1A levels to increase in solid tumors, but its levels can additionally be increased by HIF-independent pathways. Besides, HIF1A has the capability to directly reprogram the metabolic state in cells, which is very important in hypoxic settings such as cancer and vascular disease. Increased expression of HIF1A also often associates with poor clinical prognosis in many cancer types. However, in some malignancies, HIF1α accumulation is actually associated with lower cancer stage or decreased patient mortality, implicating opposing, context-dependent functions for HIF1α.

At present, targeting of hypoxia signaling has limitations in clinics with regard to changeable oxygen concentrations in solid tumor areas and HIF1A direct compounds do not show clinical efficiency. In fact, the identification of HIF1A target genes and deep insights into the mechanisms of HIF1A driven gene expression may provide novel risk factors to meliorate survival/therapeutic successes in high-risk cancer patients who lack precisely genomic causes.

References:

Gladek I, et al. HIF1A gene polymorphisms and human diseases: graphical review of 97 association studies. Genes, Chromosomes and Cancer, 2017, 56(6): 439-452.
Allan K C, et al. Non-canonical Targets of HIF1a Impair Oligodendrocyte Progenitor Cell Function. Cell stem cell, 2020.
Slemc L, Kunej T. Transcription factor HIF1A: downstream targets, associated pathways, polymorphic hypoxia response element (HRE) sites, and initiative for standardization of reporting in scientific literature. Tumor Biology, 2016, 37(11): 14851-14861.
Samardzija M, et al. Hif1a and Hif2a can be safely inactivated in cone photoreceptors. Scientific reports, 2019, 9(1): 1-14.
Lee K E, et al. Hif1a deletion reveals pro-neoplastic function of B cells in pancreatic neoplasia. Cancer discovery, 2016, 6(3): 256-269.
Cimmino F, et al. HIF-1 transcription activity: HIF1A driven response in normoxia and in hypoxia. BMC medical genetics, 2019, 20(1): 37.

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