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Gene Review

Epas1  -  endothelial PAS domain protein 1

Rattus norvegicus

Synonyms: EPAS-1, Endothelial PAS domain-containing protein 1, HIF-2-alpha, HIF2-alpha, HLF, ...
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Disease relevance of Epas1


High impact information on Epas1


Chemical compound and disease context of Epas1

  • HIF-1 alpha and HLF/EPAS are two basic helix-loop-helix/PAS domain transcription factors that bind to hypoxia sensitive elements in the promoters /enhancers of hypoxia sensitive genes such as vascular endothelial growth factor (VEGF) [4].

Biological context of Epas1

  • Transient transfection assays using the site-specific mutation of the AM promoter showed that EPAS1 overexpression increases the transcriptional activity through a sequence similar to the consensus HRE (hypoxia responsive element) [3].
  • Since IL-1beta has been implicated in the pathogenesis of heart failure and AM can ameliorate the cardiac function, our results suggest that EPAS1 plays a role in the adaptation of the cardiac myocytes during heart failure as well as in the regulation of gene expression by hypoxia [3].
  • Deletion analysis and the use of single site reporter constructs demonstrate that sites II and IV are highly responsive to transactivation by DBP and HLF [5].
  • The proteins binding to site IV are elevated in this line, suggesting that upregulation of DBP expression in response to inappropriate HLF activity may be mediated through this site [5].

Anatomical context of Epas1


Associations of Epas1 with chemical compounds

  • NGF treatment did not increase HIF-hydroxylase gene expression or activity, and the reduction of the HIF-2 alpha protein level upon stimulation was observed even in the presence of HIF-hydroxylase inhibitors such as deferoxamine or dimethyloxoglutarate [2].
  • Cardiac expressions of HIF-1 alpha and HLF/EPAS, two basic loop helix/PAS domain transcription factors involved in adaptative responses to hypoxic stresses [4].
  • These compounds are 5'-methylethyl(5'adenosyl) sulfonium chloride (MEAS), 5'-methylpropyl-(5'adenosyl)sulfonium chloride (MPAS), and 5'-ethylpropyl(5'-adenosyl)sulfonium chloride (EPAS) They were prepared by reacting an alkyl iodide with the appropriate alkyladenosyl thioether [6].
  • Such an induction of EPAS1 by IL-1beta was efficiently inhibited by the pretreatment of the cells with Src kinase inhibitors, such as herbimycin A and PP1 [3].
  • The isolated rat heart subjected to HLF was used as model of global ischaemia, and sarcolemmal permeability assessed by release of LDH from and influx of lanthanum and Ca2+ into myocardial tissue [7].

Other interactions of Epas1

  • To date, virtually nothing is known about the signaling pathways that lead to either EPAS1 or HIF1-alpha activation [1].
  • We further show that hypoxia-induced trans-activation of EPAS1 is independent of Ras [1].

Analytical, diagnostic and therapeutic context of Epas1

  • Mechanical function as well as tissue high energy phosphates were significantly depressed during both HLF and reperfusion [7].
  • Palmitate (0.5 mM conjugated to 0.1 mM albumin) or substrate-free perfusion caused ultrastructural damage and loss of normal sarcolemmal integrity during both normoxia and HLF [7].


  1. EPAS1 trans-activation during hypoxia requires p42/p44 MAPK. Conrad, P.W., Freeman, T.L., Beitner-Johnson, D., Millhorn, D.E. J. Biol. Chem. (1999) [Pubmed]
  2. Down-regulation of hypoxia-inducible factor-2 in PC12 cells by nerve growth factor stimulation. Naranjo-Suárez, S., Castellanos, M.C., Alvarez-Tejado, M., Vara, A., Landázuri, M.O., del Peso, L. J. Biol. Chem. (2003) [Pubmed]
  3. Endothelial PAS domain protein 1 (EPAS1) induces adrenomedullin gene expression in cardiac myocytes: role of EPAS1 in an inflammatory response in cardiac myocytes. Tanaka, T., Akiyama, H., Kanai, H., Sato, M., Takeda, S., Sekiguchi, K., Yokoyama, T., Kurabayashi, M. J. Mol. Cell. Cardiol. (2002) [Pubmed]
  4. Cardiac expressions of HIF-1 alpha and HLF/EPAS, two basic loop helix/PAS domain transcription factors involved in adaptative responses to hypoxic stresses. Ladoux, A., Frelin, C. Biochem. Biophys. Res. Commun. (1997) [Pubmed]
  5. Regulation of the DBP promoter by PAR proteins and in leukemic cells bearing an E2A/HLF translocation. Newcombe, K., Glassco, T., Mueller, C. Biochem. Biophys. Res. Commun. (1998) [Pubmed]
  6. Inhibitors of tRNA methyltransferases. S-Adenosylsulfonium salts. Gnegy, M.E., Lotspeich, F.J. J. Med. Chem. (1976) [Pubmed]
  7. Substrate effects on sarcolemmal permeability in the normoxic and hypoxic perfused rat heart. Lochner, A., Pentz, A., Williams, K., Tromp, E., Harper, I.S. Basic Res. Cardiol. (1996) [Pubmed]
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