EPAS1
From Wikipedia, the free encyclopedia
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]
Function
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
Mutations in this gene are associated with erythrocytosis familial type 4,[4] pulmonary hypertension and chronic mountain sickness.[6] There is also evidence that certain variants of this gene provide protection for people living at high altitude.[7] 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.[8]
Interactions
EPAS1 has been shown to interact with Aryl hydrocarbon receptor nuclear translocator[2] and ARNTL.[9]
References
- ↑ 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.
- ↑ 2.0 2.1 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.
- ↑ 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.
- ↑ 4.0 4.1 4.2 "Entrez Gene: EPAS1 endothelial PAS domain protein 1".
- ↑ 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.
- ↑ 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.
- ↑ http://www.ncbi.nlm.nih.gov/pubmed/20534544
- ↑ 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.
- ↑ 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
- Brahimi-Horn MC, Pouysségur J (2005). "The hypoxia-inducible factor and tumor progression along the angiogenic pathway.". Int. Rev. Cytol. 242: 157–213. doi:10.1016/S0074-7696(04)42004-X. PMID 15598469.
- Haase VH (2006). "Hypoxia-inducible factors in the kidney.". Am. J. Physiol. Renal Physiol. 291 (2): F271–81. doi:10.1152/ajprenal.00071.2006. PMID 16554418.
- Andersson B, Wentland MA, Ricafrente JY, et al. (1996). "A "double adaptor" method for improved shotgun library construction.". Anal. Biochem. 236 (1): 107–13. doi:10.1006/abio.1996.0138. PMID 8619474.
- Yu W, Andersson B, Worley KC, et al. (1997). "Large-scale concatenation cDNA sequencing.". Genome Res. 7 (4): 353–8. doi:10.1101/gr.7.4.353. PMC 139146. PMID 9110174.
- Ema M, Taya S, Yokotani N, et al. (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.". Proc. Natl. Acad. Sci. U.S.A. 94 (9): 4273–8. doi:10.1073/pnas.94.9.4273. PMC 20712. PMID 9113979.
- Hogenesch JB, Gu YZ, Jain S, Bradfield CA (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.
- Takahata S, Sogawa K, Kobayashi A, et al. (1998). "Transcriptionally active heterodimer formation of an Arnt-like PAS protein, Arnt3, with HIF-1a, HLF, and clock.". Biochem. Biophys. Res. Commun. 248 (3): 789–94. doi:10.1006/bbrc.1998.9012. PMID 9704006.
- Ema M, Hirota K, Mimura J, et al. (1999). "Molecular mechanisms of transcription activation by HLF and HIF1alpha in response to hypoxia: their stabilization and redox signal-induced interaction with CBP/p300.". EMBO J. 18 (7): 1905–14. doi:10.1093/emboj/18.7.1905. PMC 1171276. PMID 10202154.
- Cockman ME, Masson N, Mole DR, et al. (2000). "Hypoxia inducible factor-alpha binding and ubiquitylation by the von Hippel-Lindau tumor suppressor protein.". J. Biol. Chem. 275 (33): 25733–41. doi:10.1074/jbc.M002740200. PMID 10823831.
- Maemura K, de la Monte SM, Chin MT, et al. (2001). "CLIF, a novel cycle-like factor, regulates the circadian oscillation of plasminogen activator inhibitor-1 gene expression.". J. Biol. Chem. 275 (47): 36847–51. doi:10.1074/jbc.C000629200. PMID 11018023.
- Luo JC, Shibuya M (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. doi:10.1038/sj.onc.1204228. PMID 11313887.
- Woods SL, Whitelaw ML (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.". J. Biol. Chem. 277 (12): 10236–43. doi:10.1074/jbc.M110752200. PMID 11782478.
- Lando D, Peet DJ, Whelan DA, et al. (2002). "Asparagine hydroxylation of the HIF transactivation domain a hypoxic switch.". Science 295 (5556): 858–61. doi:10.1126/science.1068592. PMID 11823643.
- 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.". Adv. Enzyme Regul. 42: 333–47. doi:10.1016/S0065-2571(01)00037-1. PMID 12123724.
- Sivridis E, Giatromanolaki A, Gatter KC, et al. (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. doi:10.1002/cncr.10774. PMID 12209691.
- Elvert G, Kappel A, Heidenreich R, et al. (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).". J. Biol. Chem. 278 (9): 7520–30. doi:10.1074/jbc.M211298200. PMID 12464608.
- Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
- Sang N, Stiehl DP, Bohensky J, et al. (2003). "MAPK signaling up-regulates the activity of hypoxia-inducible factors by its effects on p300.". J. Biol. Chem. 278 (16): 14013–9. doi:10.1074/jbc.M209702200. PMID 12588875.
External links
- EPAS1 protein, human at the US 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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