EPAS1

Official Full Name

endothelial PAS domain protein 1

Organism

Homo sapiens

GeneID

2034

Background

This gene encodes a transcription factor involved in the induction of genes regulated by oxygen, which is induced as oxygen levels fall. The encoded protein contains a basic-helix-loop-helix domain protein dimerization domain as well as a domain found in proteins in signal transduction pathways which respond to oxygen levels. Mutations in this gene are associated with erythrocytosis familial type 4. [provided by RefSeq, Nov 2009]

Synonyms

HLF; MOP2; ECYT4; HIF2A; PASD2; bHLHe73;

Protein Sequence

MTADKEKKRSSSERRKEKSRDAARCRRSKETEVFYELAHELPLPHSVSSHLDKASIMRLAISFLRTHKLLSSVCSENESEAEADQQMDNLYLKALEGFIAVVTQDGDMIFLSENISKFMGLTQVELTGHSIFDFTHPCDHEEIRENLSLKNGSGFGKKSKDMSTERDFFMRMKCTVTNRGRTVNLKSATWKVLHCTGQVKVYNNCPPHNSLCGYKEPLLSCLIIMCEPIQHPSHMDIPLDSKTFLSRHSMDMKFTYCDDRITELIGYHPEELLGRSAYEFYHALDSENMTKSHQNLCTKGQVVSGQYRMLAKHGGYVWLETQGTVIYNPRNLQPQCIMCVNYVLSEIEKNDVVFSMDQTESLFKPHLMAMNSIFDSSGKGAVSEKSNFLFTKLKEEPEELAQLAPTPGDAIISLDFGNQNFEESSAYGKAILPPSQPWATELRSHSTQSEAGSLPAFTVPQAAAPGSTTPSATSSSSSCSTPNSPEDYYTSLDNDLKIEVIEKLFAMDTEAKDQCSTQTDFNELDLETLAPYIPMDGEDFQLSPICPEERLLAENPQSTPQHCFSAMTNIFQPLAPVAPHSPFLLDKFQQQLESKKTEPEHRPMSSIFFDAGSKASLPPCCGQASTPLSSMGGRSNTQWPPDPPLHFGPTKWAVGDQRTEFLGAAPLGPPVSPPHVSTFKTRSAKGFGARGPDVLSPAMVALSNKLKLKRQLEYEEQAFQDLSGGDPPGGSTSHLMWKRMKNLRGGSCPLMPDKPLSANVPNDKFTQNPMRGLGHPLRHLPLPQPPSAISPGENSKSRFPPQCYATQYQDYSLSSAHKVSGMASRLLGPSFESYLLPELTRYDCEVNVPVLGSSTLLQGGDLLRALDQAT

Open

Disease

Adrenomedullary hyperfunction, Brain cancer, Renal cell carcinoma, Solid tumour/cancer

Approved Drug

1 +

Clinical Trial Drug

2 +

Discontinued Drug

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Detailed Information

Endothelial PAS domain-containing protein 1 (EPAS1), also known as Hypoxia inducible factor 2 (HIF-2α). It is a major transcription factor for cells and tissues to respond to hypoxia and plays an important role in the changes of enzymes or factors caused by hypoxia. EPAS1 is expressed primarily in the placenta, heart, lung and endothelial cells. It induces expression in hypoxic regions and regulates the expression of genes necessary for tumor to adapt to hypoxic state, such as encoding VEGF, EPO, Glut and glycolytic enzyme, thus playing an important role in angiogenesis, bone marrow hematopoiesis, energy metabolism and tumor development. In the case of normoxia (21% O2), EPAS1 degrades. In the absence of oxygen (1% O2), EPAS1 promotes the expression of genes that mediate cellular responses to hypoxic conditions via the HIF complex.

Figure 1. Oxygen sensing by VHL complex. (M Janeš, et al. 2017)

EPAS1 Gene Polymorphism

The EPAS1 gene plays an important role in oxygen sensing and oxygen metabolism. Studies have found that mutations in the EPAS1 gene in the plain population can also lead to erythrocyte proliferation. Studies have shown that the EPAS1 gene polymorphism site plays a key role in regulating red blood cell (RBC) production and hemoglobin (Hb) concentration. The study found that the rs13419896 and rs1868092 mutations in the EPAS1 gene regulatory region were not only different between the Tibetan population and the Han population, but also correlated with Tibetan low Hb levels. Studies have shown that the A allele of rs6756667 locus of EPAS1 gene may be a favorable factor for plateau hypoxia adaptation in Tibetan population, and GG genotype may be an unfavorable factor for Tibetan athletes to adapt to plateau hypoxia. The EPAS1 gene plays a key role in the plateau hypoxia adaptation process in the Tibetan population.

EPAS1 and Tumor

EPAS1 is widely present in the human body under hypoxic conditions, and can promote the production of angiogenic factors such as vascular endothelial growth factor, thereby promoting tumor neovascularization, which leads to enhanced malignant behavior of tumor cells and anti-radiation therapy. EPAS1 is low or no expression in normal tissues, but can be expressed in a variety of tumor tissues or cells and regulate its biological behavior. Studies have shown that in endometrial carcinonma (EC), the expression of EPAS1 m RNA is increased, which is more than twice that of normal endometrial tissue. The expression of EPAS1 protein is significantly increased, which is 4 times that of normal endometrial tissue. Moreover, the later the EC staging, the deeper the infiltration depth, the higher the positive expression rate of EPAS1.

In a study by Raspaglio et al., it was found in the A2780 cell line that silencing of EPAS1 inhibited the proliferation of ovarian cancer (OC) cancer cells and increased the sensitivity of OC cancer cells to paclitaxel and cisplatin. The small interfering RNA (si RNA) experiment targeting EPAS1 by OC cell line showed that EPAS1 was inhibited at both mRNA level and protein expression level, and the growth curve of OC cells tended to be stable. This result showed that the malignant biological behavior of OC cells is effectively controlled. By analyzing the expression of EPAS1 in patients with OC, it was found that patients with low expression of EPAS1 gene had longer survival time and better prognosis.

References:

M Janeš, M Zorc, VČ Čurik, P Dovč, M Janeš, et al. POPULATION VARIABILITY OF TIBETAN TERRIER, Colloquium of Genetics 2017.
Liu, W., Wang, S. J., & Lin, Q. D. (2014). Study on the expressions of phd and hif in placentas from normal pregnant women and patients with preeclampsia. International Journal of Biological Sciences, 10(3), 278-84.
Raspaglio, G., Petrillo, M., Martinelli, E., Li, P. D., Mariani, M., & De, D. M., et al. (2014). Sox9 and hif-2α regulate tubb3 gene expression and affect ovarian cancer aggressiveness. Gene, 542(2), 173-181.

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