EPAS1
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| Location (UCSC) | Chr 2: 46.29 – 46.39 Mb | Chr 17: 87.06 – 87.14 Mb | |||||||
| PubMed search | [3] | [4] | |||||||
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Endothelial PAS domain-containing protein 1 (EPAS1, also known as hypoxia-inducible factor-2alpha (HIF-2α)) is a
transcription factors involved in the physiological response to oxygen concentration.[5][6][7][8] The gene is active under hypoxic conditions. It is also important in the development of the heart, and for maintaining the catecholamine balance required for protection of the heart. Mutation often leads to neuroendocrine tumors
.
However, several characterized alleles of EPAS1 contribute to high-altitude adaptation in humans.[9][10] One such allele, which has been inherited from Denisovan archaic hominins, is known to confer increased athletic performance in some people, and has therefore been referred to as the "super athlete gene".[11]
Function
The EPAS1 gene encodes one subunit of a
blood vessels in the umbilical cord
.
EPAS1 is also essential for the maintenance of
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.[12]
Alleles
A high percentage of
hybridization.[13]
The
Tibetan mastiff[15] have inherited an altitude-adaptive allele of the gene from interbreeding with a ghost population of an unknown wolf-like canid. The EPAS1 allele is known to confer an adaptive advantage to animals living at high-altitudes.[14]
Clinical significance
Mutations in the EPAS1 gene are related to early-onset 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 signaling. In addition, these neuroendocrine tumors release erythropoietin (EPO) into circulating blood, and lead to polycythemia.[16][17]
Mutations in this gene are associated with erythrocytosis familial type 4,[8] pulmonary hypertension, and chronic mountain sickness.[18] There is also evidence that certain variants of this gene provide protection for people living at high altitude such as in Tibet.[9][10][19] The effect is most profound among the Tibetans living in the Himalayas at an altitude of about 4,000 metres above sea level, the environment of which is intolerable to other human populations due to 40% less atmospheric oxygen.
A study by
haemoglobin) sufficient for less oxygen, more elaborate blood vessels,[21] have lower infant mortality,[22] and are heavier at birth.[23]
EPAS1 is useful in high altitudes as a short term adaptive response. However, EPAS1 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. Populations living permanently at high altitudes experience selection on EPAS1 for mutations which reduce the negative fitness consequences of excessive red blood cell production.[19]
Interactions
EPAS1 has been shown to
ARNTL.[25]
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000116016 - Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000024140 - Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- PMID 9000051.
- PMID 9079689.
- PMID 18378852.
- ^ a b c "Entrez Gene: EPAS1 endothelial PAS domain protein 1".
- ^ PMID 20595611.
- ^ PMID 23227185.
- ^ Algar J (1 July 2014). "Tibetan 'super athlete' gene courtesy of an extinct human species". Tech Times. Retrieved 22 July 2014.
- PMID 9808618.
- PMID 24513612.
- ^ PMID 32384152.
- S2CID 47507546.
- PMID 22931260.
- PMID 23361906.
- PMID 18650473.
- ^ PMID 20534544.
- ^ Schaffer G (24 April 2014). "Five myths about Mount Everest". Washington Post. Retrieved 18 May 2019. – cites Sanders, Robert (July 1, 2010) Tibetans adapted to high altitude in less than 3,000 years, Mind & body, Research, Science & environment, Berkeley News
- PMID 21672719.
- PMID 15353580.
- PMID 17494744.
- PMID 9079689.
- PMID 9576906.
Further reading
- Brahimi-Horn MC, Pouysségur J (2005). "The hypoxia-inducible factor and tumor progression along the angiogenic pathway". International Review of Cytology. 242: 157–213. PMID 15598469.
- Haase VH (August 2006). "Hypoxia-inducible factors in the kidney". American Journal of Physiology. Renal Physiology. 291 (2): F271-81. PMID 16554418.
- Andersson B, Wentland MA, Ricafrente JY, Liu W, Gibbs RA (April 1996). "A "double adaptor" method for improved shotgun library construction". Analytical Biochemistry. 236 (1): 107–13. PMID 8619474.
- Yu W, Andersson B, Worley KC, Muzny DM, Ding Y, Liu W, Ricafrente JY, Wentland MA, Lennon G, Gibbs RA (April 1997). "Large-scale concatenation cDNA sequencing". Genome Research. 7 (4): 353–8. PMID 9110174.
- Ema M, Taya S, Yokotani N, Sogawa K, Matsuda Y, Fujii-Kuriyama Y (April 1997). "A novel bHLH-PAS factor with close sequence similarity to hypoxia-inducible factor 1alpha regulates the VEGF expression and is potentially involved in lung and vascular development". Proceedings of the National Academy of Sciences of the United States of America. 94 (9): 4273–8. PMID 9113979.
- 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". Proceedings of the National Academy of Sciences of the United States of America. 95 (10): 5474–9. PMID 9576906.
- Takahata S, Sogawa K, Kobayashi A, Ema M, Mimura J, Ozaki N, Fujii-Kuriyama Y (July 1998). "Transcriptionally active heterodimer formation of an Arnt-like PAS protein, Arnt3, with HIF-1a, HLF, and clock". Biochemical and Biophysical Research Communications. 248 (3): 789–94. PMID 9704006.
- Ema M, Hirota K, Mimura J, Abe H, Yodoi J, Sogawa K, Poellinger L, Fujii-Kuriyama Y (April 1999). "Molecular mechanisms of transcription activation by HLF and HIF1alpha in response to hypoxia: their stabilization and redox signal-induced interaction with CBP/p300". The EMBO Journal. 18 (7): 1905–14. PMID 10202154.
- Cockman ME, Masson N, Mole DR, Jaakkola P, Chang GW, Clifford SC, Maher ER, Pugh CW, Ratcliffe PJ, Maxwell PH (August 2000). "Hypoxia inducible factor-alpha binding and ubiquitylation by the von Hippel-Lindau tumor suppressor protein". The Journal of Biological Chemistry. 275 (33): 25733–41. PMID 10823831.
- Maemura K, de la Monte SM, Chin MT, Layne MD, Hsieh CM, Yet SF, Perrella MA, Lee ME (November 2000). "CLIF, a novel cycle-like factor, regulates the circadian oscillation of plasminogen activator inhibitor-1 gene expression". The Journal of Biological Chemistry. 275 (47): 36847–51. PMID 11018023.
- Luo JC, Shibuya M (March 2001). "A variant of nuclear localization signal of bipartite-type is required for the nuclear translocation of hypoxia inducible factors (1alpha, 2alpha and 3alpha)". Oncogene. 20 (12): 1435–44. S2CID 40330235.
- Woods SL, Whitelaw ML (March 2002). "Differential activities of murine single minded 1 (SIM1) and SIM2 on a hypoxic response element. Cross-talk between basic helix-loop-helix/per-Arnt-Sim homology transcription factors". The Journal of Biological Chemistry. 277 (12): 10236–43. PMID 11782478.
- Lando D, Peet DJ, Whelan DA, Gorman JJ, Whitelaw ML (February 2002). "Asparagine hydroxylation of the HIF transactivation domain a hypoxic switch". Science. 295 (5556): 858–61. S2CID 24045310.
- Mole DR, Pugh CW, Ratcliffe PJ, Maxwell PH (2002). "Regulation of the HIF pathway: enzymatic hydroxylation of a conserved prolyl residue in hypoxia-inducible factor alpha subunits governs capture by the pVHL E3 ubiquitin ligase complex". Advances in Enzyme Regulation. 42: 333–47. PMID 12123724.
- Sivridis E, Giatromanolaki A, Gatter KC, Harris AL, Koukourakis MI (September 2002). "Association of hypoxia-inducible factors 1alpha and 2alpha with activated angiogenic pathways and prognosis in patients with endometrial carcinoma". Cancer. 95 (5): 1055–63. S2CID 72624677.
- Elvert G, Kappel A, Heidenreich R, Englmeier U, Lanz S, Acker T, Rauter M, Plate K, Sieweke M, Breier G, Flamme I (February 2003). "Cooperative interaction of hypoxia-inducible factor-2alpha (HIF-2alpha ) and Ets-1 in the transcriptional activation of vascular endothelial growth factor receptor-2 (Flk-1)". The Journal of Biological Chemistry. 278 (9): 7520–30. PMID 12464608.
- Sang N, Stiehl DP, Bohensky J, Leshchinsky I, Srinivas V, Caro J (April 2003). "MAPK signaling up-regulates the activity of hypoxia-inducible factors by its effects on p300". The Journal of Biological Chemistry. 278 (16): 14013–9. PMID 12588875.
External links
- EPAS1+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
This article incorporates text from the United States National Library of Medicine, which is in the public domain.
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