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词条 EPAS1
释义

  1. Function

  2. Alleles

  3. Clinical significance

  4. Interactions

  5. References

  6. Further reading

  7. External links

{{Infobox_gene}}

Endothelial PAS domain-containing protein 1 (EPAS1, also known as hypoxia-inducible factor-2alpha (HIF-2alpha)) is a protein that is encoded by the EPAS1 gene in humans. It is a type of hypoxia-inducible factor, a group of transcription factors involved in the physiological response to oxygen concentration.[1][2][3][4] 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.[5][6] 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".[7]

Function

The EPAS1 gene encodes one subunit of a transcription factor involved in the induction of genes regulated by oxygen, and which is induced as oxygen concentration falls (hypoxia). The protein contains a basic helix-loop-helix protein dimerization domain as well as a domain found in signal transduction proteins which respond to oxygen levels. EPAS1 is involved in the development of the embryonic heart and is expressed in endothelial cells that line the walls of blood vessels in the umbilical cord.

EPAS1 is also essential for the maintenance of catecholamine homeostasis and protection against heart failure during early embryonic development.[4] Catecholamines regulated by EPAS1 include epinephrine and norepinephrine. It is critical that the production of catecholamines 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.[8]

Alleles

A high percentage of Tibetans carry an allele of EPAS1 that improves oxygen transport. The beneficial allele is also found in the extinct Denisovan genome, suggesting that it arose in them and entered the modern human population through hybridization.[9]

Additionally, the Tibetan Mastiff has inherited an altitude-adaptive allele of the gene from interbreeding with the native Tibetan wolf.[10]

Clinical significance

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 signaling. In addition, these neuroendocrine tumors release erythropoietin (EPO) into circulating blood, and lead to polycythemia.[11][12]

Mutations in this gene are associated with erythrocytosis familial type 4,[4] pulmonary hypertension and chronic mountain sickness.[13] There is also evidence that certain variants of this gene provide protection for people living at high altitude such as in Tibet.[5][6][14] 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. The Tibetans suffer no health problems associated with altitude sickness, but instead produce low levels of blood pigment (haemoglobin) sufficient for less oxygen, more elaborate blood vessels,[15] have lower infant mortality,[16] and are heavier at birth.[17]

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.[14]

Interactions

EPAS1 has been shown to interact with aryl hydrocarbon receptor nuclear translocator[18] and ARNTL.[19]

References

1. ^{{cite journal | vauthors = Tian H, McKnight SL, Russell DW | title = Endothelial PAS domain protein 1 (EPAS1), a transcription factor selectively expressed in endothelial cells | journal = Genes & Development | volume = 11 | issue = 1 | pages = 72–82 | date = January 1997 | pmid = 9000051 | doi = 10.1101/gad.11.1.72 }}
2. ^{{cite journal | vauthors = Hogenesch JB, Chan WK, Jackiw VH, Brown RC, Gu YZ, Pray-Grant M, Perdew GH, Bradfield CA | title = Characterization of a subset of the basic-helix-loop-helix-PAS superfamily that interacts with components of the dioxin signaling pathway | journal = The Journal of Biological Chemistry | volume = 272 | issue = 13 | pages = 8581–93 | date = March 1997 | pmid = 9079689 | pmc = | doi = 10.1074/jbc.272.13.8581 }}
3. ^{{cite journal | vauthors = 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 | title = Novel exon 12 mutations in the HIF2A gene associated with erythrocytosis | journal = Blood | volume = 111 | issue = 11 | pages = 5400–2 | date = June 2008 | pmid = 18378852 | pmc = 2396730 | doi = 10.1182/blood-2008-02-137703 }}
4. ^1 2 {{cite web | title = Entrez Gene: EPAS1 endothelial PAS domain protein 1| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2034| accessdate = }}
5. ^1 {{cite journal | vauthors = Yi X, Liang Y, Huerta-Sanchez E, Jin X, Cuo ZX, Pool JE, Xu X, Jiang H, Vinckenbosch N, Korneliussen TS, Zheng H, Liu T, He W, Li K, Luo R, Nie X, Wu H, Zhao M, Cao H, Zou J, Shan Y, Li S, Yang Q, Ni P, Tian G, Xu J, Liu X, Jiang T, Wu R, Zhou G, Tang M, Qin J, Wang T, Feng S, Li G, Luosang J, Wang W, Chen F, Wang Y, Zheng X, Li Z, Bianba Z, Yang G, Wang X, Tang S, Gao G, Chen Y, Luo Z, Gusang L, Cao Z, Zhang Q, Ouyang W, Ren X, Liang H, Zheng H, Huang Y, Li J, Bolund L, Kristiansen K, Li Y, Zhang Y, Zhang X, Li R, Li S, Yang H, Nielsen R, Wang J, Wang J | title = Sequencing of 50 human exomes reveals adaptation to high altitude | journal = Science | volume = 329 | issue = 5987 | pages = 75–8 | date = July 2010 | pmid = 20595611 | pmc = 3711608 | doi = 10.1126/science.1190371 }}
6. ^1 {{cite journal | vauthors = Hanaoka M, Droma Y, Basnyat B, Ito M, Kobayashi N, Katsuyama Y, Kubo K, Ota M | title = Genetic variants in EPAS1 contribute to adaptation to high-altitude hypoxia in Sherpas | journal = PLoS One | volume = 7 | issue = 12 | pages = e50566 | year = 2012 | pmid = 23227185 | pmc = 3515610 | doi = 10.1371/journal.pone.0050566 }}
7. ^{{cite news|last1=Algar|first1=Jim|title=Tibetan 'super athlete' gene courtesy of an extinct human species|url=http://www.techtimes.com/articles/9659/20140703/tibetan-super-athlete-gene-came-from-extinct-human-species.htm|accessdate=22 July 2014|work=Tech Times|date=1 July 2014}}
8. ^{{cite journal | vauthors = Tian H, Hammer RE, Matsumoto AM, Russell DW, McKnight SL | title = The hypoxia-responsive transcription factor EPAS1 is essential for catecholamine homeostasis and protection against heart failure during embryonic development | journal = Genes & Development | volume = 12 | issue = 21 | pages = 3320–4 | date = November 1998 | pmid = 9808618 | pmc = 317225 | doi = 10.1101/gad.12.21.3320 }}
9. ^{{cite journal | vauthors = Jeong C, Alkorta-Aranburu G, Basnyat B, Neupane M, Witonsky DB, Pritchard JK, Beall CM, Di Rienzo A | title = Admixture facilitates genetic adaptations to high altitude in Tibet | journal = Nature Communications | volume = 5 | pages = 3281 | date = 2014-02-10 | pmid = 24513612 | doi = 10.1038/ncomms4281 | url = http://www.nature.com/ncomms/2014/140210/ncomms4281/full/ncomms4281.html }}
10. ^{{cite journal | vauthors = Miao B, Wang Z, Li Y | title = Genomic Analysis Reveals Hypoxia Adaptation in the Tibetan Mastiff by Introgression of the Grey Wolf from the Tibetan Plateau | journal = Molecular Biology and Evolution | pages = msw274 | date = December 2016 | pmid = 27927792 | doi = 10.1093/molbev/msw274 }}
11. ^{{cite journal | vauthors = Zhuang Z, Yang C, Lorenzo F, Merino M, Fojo T, Kebebew E, Popovic V, Stratakis CA, Prchal JT, Pacak K | title = Somatic HIF2A gain-of-function mutations in paraganglioma with polycythemia | journal = The New England Journal of Medicine | volume = 367 | issue = 10 | pages = 922–30 | date = September 2012 | pmid = 22931260 | pmc = 3432945 | doi = 10.1056/NEJMoa1205119 }}
12. ^{{cite journal | vauthors = Yang C, Sun MG, Matro J, Huynh TT, Rahimpour S, Prchal JT, Lechan R, Lonser R, Pacak K, Zhuang Z | title = Novel HIF2A mutations disrupt oxygen sensing, leading to polycythemia, paragangliomas, and somatostatinomas | journal = Blood | volume = 121 | issue = 13 | pages = 2563–6 | date = March 2013 | pmid = 23361906 | pmc = 3612863 | doi = 10.1182/blood-2012-10-460972 }}
13. ^{{cite journal | vauthors = Gale DP, Harten SK, Reid CD, Tuddenham EG, Maxwell PH | title = Autosomal dominant erythrocytosis and pulmonary arterial hypertension associated with an activating HIF2 alpha mutation | journal = Blood | volume = 112 | issue = 3 | pages = 919–21 | date = August 2008 | pmid = 18650473 | doi = 10.1182/blood-2008-04-153718 }}
14. ^1 {{cite journal | vauthors = 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 | title = Natural selection on EPAS1 (HIF2alpha) associated with low hemoglobin concentration in Tibetan highlanders | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 107 | issue = 25 | pages = 11459–64 | date = June 2010 | pmid = 20534544 | pmc = 2895075 | doi = 10.1073/pnas.1002443107 }}
15. ^{{cite journal | vauthors = Beall CM | title = Andean, Tibetan, and Ethiopian patterns of adaptation to high-altitude hypoxia | journal = Integrative and Comparative Biology | volume = 46 | issue = 1 | pages = 18–24 | date = February 2006 | pmid = 21672719 | doi = 10.1093/icb/icj004 | citeseerx = 10.1.1.595.7464 }}
16. ^{{cite journal | vauthors = Beall CM, Song K, Elston RC, Goldstein MC | title = Higher offspring survival among Tibetan women with high oxygen saturation genotypes residing at 4,000 m | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 101 | issue = 39 | pages = 14300–4 | date = September 2004 | pmid = 15353580 | pmc = 521103 | doi = 10.1073/pnas.0405949101 }}
17. ^{{cite journal | vauthors = Beall CM | title = Two routes to functional adaptation: Tibetan and Andean high-altitude natives | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 104 Suppl 1 | issue = | pages = 8655–60 | date = May 2007 | pmid = 17494744 | pmc = 1876443 | doi = 10.1073/pnas.0701985104 }}
18. ^{{cite journal | vauthors = Hogenesch JB, Chan WK, Jackiw VH, Brown RC, Gu YZ, Pray-Grant M, Perdew GH, Bradfield CA | title = Characterization of a subset of the basic-helix-loop-helix-PAS superfamily that interacts with components of the dioxin signaling pathway | journal = The Journal of Biological Chemistry | volume = 272 | issue = 13 | pages = 8581–93 | date = March 1997 | pmid = 9079689 | doi = 10.1074/jbc.272.13.8581 }}
19. ^{{cite journal | vauthors = Hogenesch JB, Gu YZ, Jain S, Bradfield CA | title = The basic-helix-loop-helix-PAS orphan MOP3 forms transcriptionally active complexes with circadian and hypoxia factors | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 95 | issue = 10 | pages = 5474–9 | date = May 1998 | pmid = 9576906 | pmc = 20401 | doi = 10.1073/pnas.95.10.5474 }}

Further reading

{{refbegin|35em}}
  • {{cite journal | vauthors = Brahimi-Horn MC, Pouysségur J | title = The hypoxia-inducible factor and tumor progression along the angiogenic pathway | journal = International Review of Cytology | volume = 242 | issue = | pages = 157–213 | year = 2005 | pmid = 15598469 | doi = 10.1016/S0074-7696(04)42004-X | isbn = 9780123646460 }}
  • {{cite journal | vauthors = Haase VH | title = Hypoxia-inducible factors in the kidney | journal = American Journal of Physiology. Renal Physiology | volume = 291 | issue = 2 | pages = F271-81 | date = August 2006 | pmid = 16554418 | doi = 10.1152/ajprenal.00071.2006 | pmc = 4232221 }}
  • {{cite journal | vauthors = Andersson B, Wentland MA, Ricafrente JY, Liu W, Gibbs RA | title = A "double adaptor" method for improved shotgun library construction | journal = Analytical Biochemistry | volume = 236 | issue = 1 | pages = 107–13 | date = April 1996 | pmid = 8619474 | doi = 10.1006/abio.1996.0138 }}
  • {{cite journal | vauthors = Yu W, Andersson B, Worley KC, Muzny DM, Ding Y, Liu W, Ricafrente JY, Wentland MA, Lennon G, Gibbs RA | title = Large-scale concatenation cDNA sequencing | journal = Genome Research | volume = 7 | issue = 4 | pages = 353–8 | date = April 1997 | pmid = 9110174 | pmc = 139146 | doi = 10.1101/gr.7.4.353 }}
  • {{cite journal | vauthors = Ema M, Taya S, Yokotani N, Sogawa K, Matsuda Y, Fujii-Kuriyama Y | title = 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 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 94 | issue = 9 | pages = 4273–8 | date = April 1997 | pmid = 9113979 | pmc = 20712 | doi = 10.1073/pnas.94.9.4273 }}
  • {{cite journal | vauthors = Hogenesch JB, Gu YZ, Jain S, Bradfield CA | title = The basic-helix-loop-helix-PAS orphan MOP3 forms transcriptionally active complexes with circadian and hypoxia factors | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 95 | issue = 10 | pages = 5474–9 | date = May 1998 | pmid = 9576906 | pmc = 20401 | doi = 10.1073/pnas.95.10.5474 }}
  • {{cite journal | vauthors = Takahata S, Sogawa K, Kobayashi A, Ema M, Mimura J, Ozaki N, Fujii-Kuriyama Y | title = Transcriptionally active heterodimer formation of an Arnt-like PAS protein, Arnt3, with HIF-1a, HLF, and clock | journal = Biochemical and Biophysical Research Communications | volume = 248 | issue = 3 | pages = 789–94 | date = July 1998 | pmid = 9704006 | doi = 10.1006/bbrc.1998.9012 }}
  • {{cite journal | vauthors = Ema M, Hirota K, Mimura J, Abe H, Yodoi J, Sogawa K, Poellinger L, Fujii-Kuriyama Y | title = Molecular mechanisms of transcription activation by HLF and HIF1alpha in response to hypoxia: their stabilization and redox signal-induced interaction with CBP/p300 | journal = The EMBO Journal | volume = 18 | issue = 7 | pages = 1905–14 | date = April 1999 | pmid = 10202154 | pmc = 1171276 | doi = 10.1093/emboj/18.7.1905 }}
  • {{cite journal | vauthors = Cockman ME, Masson N, Mole DR, Jaakkola P, Chang GW, Clifford SC, Maher ER, Pugh CW, Ratcliffe PJ, Maxwell PH | title = Hypoxia inducible factor-alpha binding and ubiquitylation by the von Hippel-Lindau tumor suppressor protein | journal = The Journal of Biological Chemistry | volume = 275 | issue = 33 | pages = 25733–41 | date = August 2000 | pmid = 10823831 | doi = 10.1074/jbc.M002740200 }}
  • {{cite journal | vauthors = Maemura K, de la Monte SM, Chin MT, Layne MD, Hsieh CM, Yet SF, Perrella MA, Lee ME | title = CLIF, a novel cycle-like factor, regulates the circadian oscillation of plasminogen activator inhibitor-1 gene expression | journal = The Journal of Biological Chemistry | volume = 275 | issue = 47 | pages = 36847–51 | date = November 2000 | pmid = 11018023 | doi = 10.1074/jbc.C000629200 }}
  • {{cite journal | vauthors = Luo JC, Shibuya M | title = A variant of nuclear localization signal of bipartite-type is required for the nuclear translocation of hypoxia inducible factors (1alpha, 2alpha and 3alpha) | journal = Oncogene | volume = 20 | issue = 12 | pages = 1435–44 | date = March 2001 | pmid = 11313887 | doi = 10.1038/sj.onc.1204228 }}
  • {{cite journal | vauthors = Woods SL, Whitelaw ML | title = 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 | journal = The Journal of Biological Chemistry | volume = 277 | issue = 12 | pages = 10236–43 | date = March 2002 | pmid = 11782478 | doi = 10.1074/jbc.M110752200 }}
  • {{cite journal | vauthors = Lando D, Peet DJ, Whelan DA, Gorman JJ, Whitelaw ML | title = Asparagine hydroxylation of the HIF transactivation domain a hypoxic switch | journal = Science | volume = 295 | issue = 5556 | pages = 858–61 | date = February 2002 | pmid = 11823643 | doi = 10.1126/science.1068592 }}
  • {{cite journal | vauthors = Mole DR, Pugh CW, Ratcliffe PJ, Maxwell PH | title = 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 | journal = Advances in Enzyme Regulation | volume = 42 | issue = | pages = 333–47 | year = 2002 | pmid = 12123724 | doi = 10.1016/S0065-2571(01)00037-1 }}
  • {{cite journal | vauthors = Sivridis E, Giatromanolaki A, Gatter KC, Harris AL, Koukourakis MI | title = Association of hypoxia-inducible factors 1alpha and 2alpha with activated angiogenic pathways and prognosis in patients with endometrial carcinoma | journal = Cancer | volume = 95 | issue = 5 | pages = 1055–63 | date = September 2002 | pmid = 12209691 | doi = 10.1002/cncr.10774 }}
  • {{cite journal | vauthors = Elvert G, Kappel A, Heidenreich R, Englmeier U, Lanz S, Acker T, Rauter M, Plate K, Sieweke M, Breier G, Flamme I | title = 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) | journal = The Journal of Biological Chemistry | volume = 278 | issue = 9 | pages = 7520–30 | date = February 2003 | pmid = 12464608 | doi = 10.1074/jbc.M211298200 }}
  • {{cite journal | vauthors = Sang N, Stiehl DP, Bohensky J, Leshchinsky I, Srinivas V, Caro J | title = MAPK signaling up-regulates the activity of hypoxia-inducible factors by its effects on p300 | journal = The Journal of Biological Chemistry | volume = 278 | issue = 16 | pages = 14013–9 | date = April 2003 | pmid = 12588875 | doi = 10.1074/jbc.M209702200 | pmc = 4518846 }}
{{refend}}

External links

  • {{MeshName|EPAS1+protein,+human}}
{{NLM content}}{{PDB Gallery|geneid=2034}}{{Transcription factors|g1}}

2 : Transcription factors|PAS-domain-containing proteins
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