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Endothelial PAS domain protein 1

PDB rendering based on 1p97.
Available structures
PDB Ortholog search: PDBe, RCSB
Symbols EPAS1 ; ECYT4; HIF2A; HLF; MOP2; PASD2; bHLHe73
External IDs OMIM603349 MGI109169 HomoloGene1095 ChEMBL: 1744522 GeneCards: EPAS1 Gene
RNA expression pattern
PBB GE EPAS1 200878 at tn.png
PBB GE EPAS1 200879 s at tn.png
More reference expression data
Species Human Mouse
Entrez 2034 13819
Ensembl ENSG00000116016 ENSMUSG00000024140
UniProt Q99814 P97481
RefSeq (mRNA) NM_001430 NM_010137
RefSeq (protein) NP_001421 NP_034267
Location (UCSC) Chr 2:
46.52 – 46.61 Mb
Chr 17:
86.75 – 86.83 Mb
PubMed search [1] [2]

Endothelial PAS domain-containing protein 1 (also known as Hypoxia-inducible factor-2alpha (HIF-2alpha)) is a protein that in humans is encoded by the EPAS1 gene.[1][2][3][4]


This gene encodes a half of a transcription factor involved in the induction of genes regulated by oxygen, which is induced as oxygen levels fall (hypoxia). 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. EPAS 1 is involved in the development of the embryonic heart and is expressed in the endothelial cells that line the walls of the blood vessels in the umbilical cord. It is essential in maintaining catecholamine homeostasis and protection against heart failure during early embryonic development.[4]

Catecholamines include epinephrine and norepinephrine. It is important for the production of catecholamines to remain in homeostatic conditions so that both the delicate fetal heart and the adult heart do not overexert themselves and induce heart failure. Catecholamine production in the embryo is related to control of cardiac output by increasing the fetal heart rate.[5]

Clinical significance[edit]

Mutations in EPAS1 gene are related to early onset of neuroendocrine tumors such as paragangliomas, somatostatinomas and/or pheochromocytomas. The mutations are commonly somatic missense mutations that locate in the primary hydroxylation site of HIF-2α, which disrupt the protein hydroxylation/degradation mechanism, and leads to protein stabilization and pseudohypoxic signalging. In addition, these neuroendocrine tumors release erythropoietin (EPO) into circulating blood, and lead to polycythemia.[6][7]

Mutations in this gene are associated with erythrocytosis familial type 4,[4] pulmonary hypertension and chronic mountain sickness.[8] There is also evidence that certain variants of this gene provide protection for people living at high altitude.[9] EPAS 1 is useful in high altitudes as a short term adaptive response. However, EPAS 1 can also cause excessive production of red blood cells leading to chronic mountain sickness that can lead to death and inhibited reproductive abilities. Some mutations that increase its expression are associated with increased hypertension and stroke at low altitude, with symptoms similar to mountain sickness. People permanently living at high altitudes might experience selection of EPAS 1 to reduce the fitness consequences of excessive red blood cell production.[9]


EPAS1 has been shown to interact with Aryl hydrocarbon receptor nuclear translocator[2] and ARNTL.[10]


  1. ^ Tian H, McKnight SL, Russell DW (Feb 1997). "Endothelial PAS domain protein 1 (EPAS1), a transcription factor selectively expressed in endothelial cells". Genes Dev 11 (1): 72–82. doi:10.1101/gad.11.1.72. PMID 9000051. 
  2. ^ a b Hogenesch JB, Chan WK, Jackiw VH, Brown RC, Gu YZ, Pray-Grant M, Perdew GH, Bradfield CA (May 1997). "Characterization of a subset of the basic helix-loop-helix-PAS superfamily that interacts with components of the dioxin signaling pathway". J Biol Chem 272 (13): 8581–93. doi:10.1074/jbc.272.13.8581. PMID 9079689. 
  3. ^ Percy MJ, Beer PA, Campbell G, Dekker AW, Green AR, Oscier D, Rainey MG, van Wijk R, Wood M, Lappin TR, McMullin MF, Lee FS (May 2008). "Novel exon 12 mutations in the HIF2A gene associated with erythrocytosis". Blood 111 (11): 5400–2. doi:10.1182/blood-2008-02-137703. PMC 2396730. PMID 18378852. 
  4. ^ a b c "Entrez Gene: EPAS1 endothelial PAS domain protein 1". 
  5. ^ Tian H, Hammer RE, Matsumoto AM, Russell DW, McKnight SL (November 1998). "The hypoxia-responsive transcription factor EPAS1 is essential for catecholamine homeostasis and protection against heart failure during embryonic development". Genes Dev. 12 (21): 3320–4. doi:10.1101/gad.12.21.3320. PMC 317225. PMID 9808618. 
  6. ^ Zhuang Z, Yang C, Lorenzo F, Merino M, Fojo T, Kebebew E, Popovic V, Stratakis CA, Prchal JT, Pacak K (September 2012). "Somatic HIF2A gain-of-function mutations in paraganglioma with polycythemia". N. Engl. J. Med. 367 (10): 922–30. doi:10.1056/NEJMoa1205119. PMC 3432945. PMID 22931260. 
  7. ^ Yang C, Sun MG, Matro J, Huynh TT, Rahimpour S, Prchal JT, Lechan R, Lonser R, Pacak K, Zhuang Z (March 2013). "Novel HIF2A mutations disrupt oxygen sensing, leading to polycythemia, paragangliomas, and somatostatinomas". Blood 121 (13): 2563–6. doi:10.1182/blood-2012-10-460972. PMID 23361906. 
  8. ^ Gale DP, Harten SK, Reid CD, Tuddenham EG, Maxwell PH (August 2008). "Autosomal dominant erythrocytosis and pulmonary arterial hypertension associated with an activating HIF2 alpha mutation". Blood 112 (3): 919–21. doi:10.1182/blood-2008-04-153718. PMID 18650473. 
  9. ^ a b Beall CM, Cavalleri GL, Deng L, Elston RC, Gao Y, Knight J, Li C, Li JC, Liang Y, McCormack M, Montgomery HE, Pan H, Robbins PA, Shianna KV, Tam SC, Tsering N, Veeramah KR, Wang W, Wangdui P, Weale ME, Xu Y, Xu Z, Yang L, Zaman MJ, Zeng C, Zhang L, Zhang X, Zhaxi P, Zheng YT (June 2010). "Natural selection on EPAS1 (HIF2alpha) associated with low hemoglobin concentration in Tibetan highlanders". Proc. Natl. Acad. Sci. U.S.A. 107 (25): 11459–64. doi:10.1073/pnas.1002443107. PMC 2895075. PMID 20534544. 
  10. ^ Hogenesch JB, Gu YZ, Jain S, Bradfield CA (May 1998). "The basic-helix-loop-helix-PAS orphan MOP3 forms transcriptionally active complexes with circadian and hypoxia factors". Proc. Natl. Acad. Sci. U.S.A. 95 (10): 5474–9. doi:10.1073/pnas.95.10.5474. PMC 20401. PMID 9576906. 

Further reading[edit]

External links[edit]

This article incorporates text from the United States National Library of Medicine, which is in the public domain.