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Gene Review

Epas1  -  endothelial PAS domain protein 1

Mus musculus

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


High impact information on Epas1

  • We report that mice lacking the HIF family member HIF-2alpha (encoded by Epas1) have a syndrome of multiple-organ pathology, biochemical abnormalities and altered gene expression patterns [3].
  • Multiple organ pathology, metabolic abnormalities and impaired homeostasis of reactive oxygen species in Epas1-/- mice [3].
  • Prenatal or postnatal treatment of Epas1-/- mice with a superoxide dismutase (SOD) mimetic reversed several aspects of the null phenotype [3].
  • Transfection analyses showed that HIF-2alpha could efficiently transactivate the promoters of the primary AOEs [3].
  • Using a genetic "knock-in" strategy, we demonstrate that targeted replacement of the oxygen-regulated transcription factor HIF-1alpha with HIF-2alpha results in expanded expression of HIF-2alpha-specific target genes including Oct-4, a transcription factor essential for maintaining stem cell pluripotency [4].

Chemical compound and disease context of Epas1


Biological context of Epas1

  • Whole mount in situ hybridization experiments demonstrated that HLF mRNA was expressed in vascular endothelial cells at the middle stages (9.5 and 10.5 days postcoitus) of mouse embryo development, where HIF1alpha mRNA was almost undetectable [9].
  • The HIF1alpha-like factor (HLF) encoded by the isolated cDNA bound the hypoxia-response element (HRE) found in enhancers of genes for erythropoietin, vascular endothelial growth factor (VEGF), and various glycolytic enzymes, and activated transcription of a reporter gene harboring the HRE [9].
  • In lung development around parturition, HLF mRNA expression was markedly enhanced, whereas that of HIF1alpha mRNA remained apparently unchanged at a much lower level [9].
  • The deletion of the DNA binding and carboxyl-terminal transactivation domains of HIF-2alpha, respectively, created dominant negative mutants that suppressed transactivation by the wild type protein and failed to synergize with Ets-1 [10].
  • A tandem HIF-2alpha/Ets binding site was identified within the Flk-1 promoter that acted as a strong enhancer element [10].

Anatomical context of Epas1


Associations of Epas1 with chemical compounds

  • Transcriptionally active heterodimer formation of an Arnt-like PAS protein, Arnt3, with HIF-1a, HLF, and clock [13].
  • In addition, we engineered HEK293 cells to express stabilized forms of HIF-1alpha or HIF-2alpha via a tetracycline-regulated promoter [14].
  • Taken together, these results suggest that EPAS1 plays several supporting roles in maintaining specific aspects of adipogenesis and adipocyte function including regulation of glucose uptake followed by lipid synthesis [15].
  • Using pharmacological, molecular, and genetic approaches, we also observed that although progesterone primarily up-regulates uterine HIF-1alpha expression, estrogen transiently stimulates that of HIF-2alpha [16].
  • Here, employing a novel hydroxylation-specific antibody, we directly show that proline 564 of HIF-1alpha and proline 531 of HIF-2alpha are hydroxylated under normoxia [6].
  • Additional experiments indicate that the ETS transcription factor ELK is required for HIF-2alpha to activate specific target genes such as Cited-2, EPO, and PAI-1 [17].

Physical interactions of Epas1


Regulatory relationships of Epas1


Other interactions of Epas1

  • Treatment of EPAS1-null mice with exogenous erythropoietin reverses the hematopoietic and other defects [2].
  • These results suggest that the interaction between HIF-2alpha and endothelial Ets factors is required for the full transcriptional activation of Flk-1 in endothelial cells and may therefore represent a future target for the manipulation of angiogenesis [10].
  • Thus, HIMF and HIF-2alpha were temporally and spatially coexpressed in the developing lung [11].
  • The recent cloning of ARNT and HIF1(homologues (ARNT2 and HIF2 alpha) indicates that at least six distinct bHLH-PAS heterodimeric combinations can occur in response to a number of environmental stimuli [20].
  • In electrophoretic mobility studies, CHF1 inhibited the binding of the ARNT/EPAS1 heterodimer to its target site [21].
  • Under very stringent conditions, we ablate Hif-2alpha after birth and compare the effect of acute global deletion of Hif-2alpha and Hif-1alpha [22].

Analytical, diagnostic and therapeutic context of Epas1

  • Together with the results from intraperitoneal injection of Epo into HLF(kd/kd) mouse, this suggests that Epo is one of the target genes of HLF responsible for experimental ROP [1].
  • We have studied the role of the basic helix-loop-helix-PAS transcription factor EPAS-1/hypoxia-inducible factor 2alpha in vascular development by gene targeting [23].
  • To address this discrepancy, and to identify specific HIF-2alpha target genes, we used DNA microarray analysis to evaluate hypoxic gene induction in cells expressing HIF-2alpha but not HIF-1alpha [14].
  • Immunohistochemistry of newborn kidney demonstrated widespread expression of HIF-1beta protein in nuclei of glomeruli and all tubular segments, whereas HIF-2alpha protein expression was more restricted and localized chiefly to podocytes of developing glomeruli and developing tubules [24].
  • The expression of HIF-1alpha and HIF-2alpha mRNAs in newborn mouse kidney was confirmed by RT-PCR and Northern blot analysis [24].


  1. HLF/HIF-2alpha is a key factor in retinopathy of prematurity in association with erythropoietin. Morita, M., Ohneda, O., Yamashita, T., Takahashi, S., Suzuki, N., Nakajima, O., Kawauchi, S., Ema, M., Shibahara, S., Udono, T., Tomita, K., Tamai, M., Sogawa, K., Yamamoto, M., Fujii-Kuriyama, Y. EMBO J. (2003) [Pubmed]
  2. HIF-2alpha regulates murine hematopoietic development in an erythropoietin-dependent manner. Scortegagna, M., Ding, K., Zhang, Q., Oktay, Y., Bennett, M.J., Bennett, M., Shelton, J.M., Richardson, J.A., Moe, O., Garcia, J.A. Blood (2005) [Pubmed]
  3. Multiple organ pathology, metabolic abnormalities and impaired homeostasis of reactive oxygen species in Epas1-/- mice. Scortegagna, M., Ding, K., Oktay, Y., Gaur, A., Thurmond, F., Yan, L.J., Marck, B.T., Matsumoto, A.M., Shelton, J.M., Richardson, J.A., Bennett, M.J., Garcia, J.A. Nat. Genet. (2003) [Pubmed]
  4. HIF-2alpha regulates Oct-4: effects of hypoxia on stem cell function, embryonic development, and tumor growth. Covello, K.L., Kehler, J., Yu, H., Gordan, J.D., Arsham, A.M., Hu, C.J., Labosky, P.A., Simon, M.C., Keith, B. Genes Dev. (2006) [Pubmed]
  5. The transcriptional activation function of the HIF-like factor requires phosphorylation at a conserved threonine. Gradin, K., Takasaki, C., Fujii-Kuriyama, Y., Sogawa, K. J. Biol. Chem. (2002) [Pubmed]
  6. Role of prolyl hydroxylation in oncogenically stabilized hypoxia-inducible factor-1alpha. Chan, D.A., Sutphin, P.D., Denko, N.C., Giaccia, A.J. J. Biol. Chem. (2002) [Pubmed]
  7. Transcriptional regulation of the hypoxia inducible factor-2alpha (HIF-2alpha) gene during adipose differentiation in 3T3-L1 cells. Wada, T., Shimba, S., Tezuka, M. Biol. Pharm. Bull. (2006) [Pubmed]
  8. Mast cells and pulmonary fibrosis. Identification of a histamine releasing factor in bronchoalveolar lavage fluid. Broide, D.H., Smith, C.M., Wasserman, S.I. J. Immunol. (1990) [Pubmed]
  9. 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. Ema, M., Taya, S., Yokotani, N., Sogawa, K., Matsuda, Y., Fujii-Kuriyama, Y. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  10. 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). Elvert, G., Kappel, A., Heidenreich, R., Englmeier, U., Lanz, S., Acker, T., Rauter, M., Plate, K., Sieweke, M., Breier, G., Flamme, I. J. Biol. Chem. (2003) [Pubmed]
  11. Hypoxia-induced mitogenic factor has antiapoptotic action and is upregulated in the developing lung: coexpression with hypoxia-inducible factor-2alpha. Wagner, K.F., Hellberg, A.K., Balenger, S., Depping, R., Dodd-O, J., Johns, R.A., Li, D. Am. J. Respir. Cell Mol. Biol. (2004) [Pubmed]
  12. HRF, a putative basic helix-loop-helix-PAS-domain transcription factor is closely related to hypoxia-inducible factor-1 alpha and developmentally expressed in blood vessels. Flamme, I., Fröhlich, T., von Reutern, M., Kappel, A., Damert, A., Risau, W. Mech. Dev. (1997) [Pubmed]
  13. Transcriptionally active heterodimer formation of an Arnt-like PAS protein, Arnt3, with HIF-1a, HLF, and clock. Takahata, S., Sogawa, K., Kobayashi, A., Ema, M., Mimura, J., Ozaki, N., Fujii-Kuriyama, Y. Biochem. Biophys. Res. Commun. (1998) [Pubmed]
  14. Differential roles of hypoxia-inducible factor 1alpha (HIF-1alpha) and HIF-2alpha in hypoxic gene regulation. Hu, C.J., Wang, L.Y., Chodosh, L.A., Keith, B., Simon, M.C. Mol. Cell. Biol. (2003) [Pubmed]
  15. EPAS1 promotes adipose differentiation in 3T3-L1 cells. Shimba, S., Wada, T., Hara, S., Tezuka, M. J. Biol. Chem. (2004) [Pubmed]
  16. Expression of hypoxia-inducible factors in the peri-implantation mouse uterus is regulated in a cell-specific and ovarian steroid hormone-dependent manner. Evidence for differential function of HIFs during early pregnancy. Daikoku, T., Matsumoto, H., Gupta, R.A., Das, S.K., Gassmann, M., DuBois, R.N., Dey, S.K. J. Biol. Chem. (2003) [Pubmed]
  17. The N-terminal transactivation domain confers target gene specificity of hypoxia-inducible factors HIF-1alpha and HIF-2alpha. Hu, C.J., Sataur, A., Wang, L., Chen, H., Simon, M.C. Mol. Biol. Cell (2007) [Pubmed]
  18. Hypoxia-inducible transcription factor-2alpha in endothelial cells regulates tumor neovascularization through activation of ephrin A1. Yamashita, T., Ohneda, K., Nagano, M., Miyoshi, C., Kaneko, N., Miwa, Y., Yamamoto, M., Ohneda, O., Fujii-Kuriyama, Y. J. Biol. Chem. (2008) [Pubmed]
  19. Targeted replacement of hypoxia-inducible factor-1alpha by a hypoxia-inducible factor-2alpha knock-in allele promotes tumor growth. Covello, K.L., Simon, M.C., Keith, B. Cancer Res. (2005) [Pubmed]
  20. Expression of ARNT, ARNT2, HIF1 alpha, HIF2 alpha and Ah receptor mRNAs in the developing mouse. Jain, S., Maltepe, E., Lu, M.M., Simon, C., Bradfield, C.A. Mech. Dev. (1998) [Pubmed]
  21. Cardiovascular basic helix loop helix factor 1, a novel transcriptional repressor expressed preferentially in the developing and adult cardiovascular system. Chin, M.T., Maemura, K., Fukumoto, S., Jain, M.K., Layne, M.D., Watanabe, M., Hsieh, C.M., Lee, M.E. J. Biol. Chem. (2000) [Pubmed]
  22. Acute postnatal ablation of Hif-2alpha results in anemia. Gruber, M., Hu, C.J., Johnson, R.S., Brown, E.J., Keith, B., Simon, M.C. Proc. Natl. Acad. Sci. U.S.A. (2007) [Pubmed]
  23. The transcription factor EPAS-1/hypoxia-inducible factor 2alpha plays an important role in vascular remodeling. Peng, J., Zhang, L., Drysdale, L., Fong, G.H. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  24. Podocyte expression of hypoxia-inducible factor (HIF)-1 and HIF-2 during glomerular development. Freeburg, P.B., Robert, B., St John, P.L., Abrahamson, D.R. J. Am. Soc. Nephrol. (2003) [Pubmed]
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