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Gene Review

EGLN1  -  egl-9 family hypoxia-inducible factor 1

Homo sapiens

Synonyms: C1orf12, ECYT3, Egl nine homolog 1, HALAH, HIF-PH2, ...
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Disease relevance of EGLN1


High impact information on EGLN1


Biological context of EGLN1


Anatomical context of EGLN1


Associations of EGLN1 with chemical compounds

  • The degradation requires formation of a multiprotein complex (VHLCBC) and hydroxylation of HIF1A proline residues via members of the egg-laying-defective nine (EGLN) family [10].
  • Utilizing modeling information from a recently resolved structure of human HIF-1alpha prolyl hydroxylase (EGLN1) and structure-based design, a novel series of imidazo[1,2-a]pyridine derivatives was prepared [14].
  • PHD2 crystallizes as a homotrimer and contains a double-stranded beta-helix core fold common to the Fe(II) and 2-oxoglutarate-dependant dioxygenase family, the residues of which are well conserved in the three human PHD enzymes (PHD 1-3) [8].
  • Furthermore, this polybasic region binds specifically to PI(3)P when fused to maltose-binding protein, PHD2, or as an isolated peptide, demonstrating that it is sufficient for specific PI binding [15].
  • The zinc chelator N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine augmented the activity of wild-type PHD2-F but not that of PHD2 lacking the MYND domain, confirming that the zinc finger domain is inhibitory [16].

Physical interactions of EGLN1


Regulatory relationships of EGLN1

  • Interestingly, EGLN1 and EGLN3 mRNAs were also triggered by EGLN inhibitors, suggesting the involvement of HIFalpha in the control of its transcription [1].
  • We found that SM-20 is down-regulated in ANG II-stimulated PC12 cells that express only AT2 receptors [18].

Other interactions of EGLN1

  • Phylogenetic analysis and domain organization show that EGLN1 represents the ancestral form of the gene family and that EGLN3 is the human orthologue of rat Sm-20 [3].
  • VEGF was also significantly related to the androgen receptor (P = 0.05), whereas PHD2 was inversely related to HIF-2a expression [19].
  • Induction of PHD2 by hypoxia was lost in pVHL-deficient RCC4 cells [12].
  • Structural analysis showed that the N-terminal region of PHD2 contains a Myeloid translocation protein 8, Nervy, and DEAF1 (MYND)-type zinc finger domain, whereas the catalytic domain is located in its C-terminal region [16].

Analytical, diagnostic and therapeutic context of EGLN1

  • In this work, we employed the yeast two-hybrid assay to study the sequence determinants required for the binding of EGLN1 and 3 to HIF1alpha in a cellular context [20].
  • Paradoxically, the expression of two family members (PHD2 and PHD3) is induced in hypoxic cell culture despite the reduced availability of the oxygen co-substrate, and it has been suggested that they become functionally relevant following re-oxygenation to rapidly terminate the HIF response [21].
  • In a model of myocardial infarction, in situ hybridization showed periischemic enhancement for PHD2 mRNA and PHD3 mRNA, but not PHD1 mRNA [22].


  1. The von Hippel Lindau/hypoxia-inducible factor (HIF) pathway regulates the transcription of the HIF-proline hydroxylase genes in response to low oxygen. del Peso, L., Castellanos, M.C., Temes, E., Martin-Puig, S., Cuevas, Y., Olmos, G., Landazuri, M.O. J. Biol. Chem. (2003) [Pubmed]
  2. Induction of human endometrial cancer cell senescence through modulation of HIF-1alpha activity by EGLN1. Kato, H., Inoue, T., Asanoma, K., Nishimura, C., Matsuda, T., Wake, N. Int. J. Cancer (2006) [Pubmed]
  3. Characterization and comparative analysis of the EGLN gene family. Taylor, M.S. Gene (2001) [Pubmed]
  4. Overexpression and nuclear translocation of hypoxia-inducible factor prolyl hydroxylase PHD2 in head and neck squamous cell carcinoma is associated with tumor aggressiveness. Jokilehto, T., Rantanen, K., Luukkaa, M., Heikkinen, P., Grenman, R., Minn, H., Kronqvist, P., Jaakkola, P.M. Clin. Cancer Res. (2006) [Pubmed]
  5. A novel erythrocytosis-associated PHD2 mutation suggests the location of a HIF binding groove. Percy, M.J., Furlow, P.W., Beer, P.A., Lappin, T.R., McMullin, M.F., Lee, F.S. Blood (2007) [Pubmed]
  6. The von Hippel-Lindau tumor suppressor protein: new insights into oxygen sensing and cancer. Kim, W., Kaelin, W.G. Curr. Opin. Genet. Dev. (2003) [Pubmed]
  7. HIF prolyl-hydroxylase 2 is the key oxygen sensor setting low steady-state levels of HIF-1alpha in normoxia. Berra, E., Benizri, E., Ginouvès, A., Volmat, V., Roux, D., Pouysségur, J. EMBO J. (2003) [Pubmed]
  8. Cellular oxygen sensing: Crystal structure of hypoxia-inducible factor prolyl hydroxylase (PHD2). McDonough, M.A., Li, V., Flashman, E., Chowdhury, R., Mohr, C., Liénard, B.M., Zondlo, J., Oldham, N.J., Clifton, I.J., Lewis, J., McNeill, L.A., Kurzeja, R.J., Hewitson, K.S., Yang, E., Jordan, S., Syed, R.S., Schofield, C.J. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  9. Suppression of hypoxia-inducible factor 1alpha (HIF-1alpha) transcriptional activity by the HIF prolyl hydroxylase EGLN1. To, K.K., Huang, L.E. J. Biol. Chem. (2005) [Pubmed]
  10. Dynamic HIF1A regulation during human placental development. Ietta, F., Wu, Y., Winter, J., Xu, J., Wang, J., Post, M., Caniggia, I. Biol. Reprod. (2006) [Pubmed]
  11. Hypoxia-inducible Factors in the First Trimester Human Lung. Groenman, F., Rutter, M., Caniggia, I., Tibboel, D., Post, M. J. Histochem. Cytochem. (2007) [Pubmed]
  12. Hypoxia-inducible factor-1 (HIF-1) promotes its degradation by induction of HIF-alpha-prolyl-4-hydroxylases. Marxsen, J.H., Stengel, P., Doege, K., Heikkinen, P., Jokilehto, T., Wagner, T., Jelkmann, W., Jaakkola, P., Metzen, E. Biochem. J. (2004) [Pubmed]
  13. Gene expression profiling of parkinsonian substantia nigra pars compacta; alterations in ubiquitin-proteasome, heat shock protein, iron and oxidative stress regulated proteins, cell adhesion/cellular matrix and vesicle trafficking genes. Grünblatt, E., Mandel, S., Jacob-Hirsch, J., Zeligson, S., Amariglo, N., Rechavi, G., Li, J., Ravid, R., Roggendorf, W., Riederer, P., Youdim, M.B. Journal of neural transmission (Vienna, Austria : 1996) (2004) [Pubmed]
  14. A novel series of imidazo[1,2-a]pyridine derivatives as HIF-1alpha prolyl hydroxylase inhibitors. Warshakoon, N.C., Wu, S., Boyer, A., Kawamoto, R., Sheville, J., Renock, S., Xu, K., Pokross, M., Evdokimov, A.G., Walter, R., Mekel, M. Bioorg. Med. Chem. Lett. (2006) [Pubmed]
  15. The polybasic region that follows the plant homeodomain zinc finger 1 of pf1 is necessary and sufficient for specific phosphoinositide binding. Kaadige, M.R., Ayer, D.E. J. Biol. Chem. (2006) [Pubmed]
  16. Inhibition of the catalytic activity of hypoxia-inducible factor-1alpha-prolyl-hydroxylase 2 by a MYND-type zinc finger. Choi, K.O., Lee, T., Lee, N., Kim, J.H., Yang, E.G., Yoon, J.M., Kim, J.H., Lee, T.G., Park, H. Mol. Pharmacol. (2005) [Pubmed]
  17. Regulation of the prolyl hydroxylase domain protein 2 (phd2/egln-1) gene: identification of a functional hypoxia-responsive element. Metzen, E., Stiehl, D.P., Doege, K., Marxsen, J.H., Hellwig-Bürgel, T., Jelkmann, W. Biochem. J. (2005) [Pubmed]
  18. Role of reactive oxygen species in angiotensin II-mediated renal growth, differentiation, and apoptosis. Wolf, G. Antioxid. Redox Signal. (2005) [Pubmed]
  19. The androgen receptor is significantly associated with vascular endothelial growth factor and hypoxia sensing via hypoxia-inducible factors HIF-1a, HIF-2a, and the prolyl hydroxylases in human prostate cancer. Boddy, J.L., Fox, S.B., Han, C., Campo, L., Turley, H., Kanga, S., Malone, P.R., Harris, A.L. Clin. Cancer Res. (2005) [Pubmed]
  20. Analysis of HIF-prolyl hydroxylases binding to substrates. Land??zuri, M.O., Vara-Vega, A., Vit??n, M., Cuevas, Y., del Peso, L. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  21. Increased prolyl 4-hydroxylase domain proteins compensate for decreased oxygen levels. Evidence for an autoregulatory oxygen-sensing system. Stiehl, D.P., Wirthner, R., Köditz, J., Spielmann, P., Camenisch, G., Wenger, R.H. J. Biol. Chem. (2006) [Pubmed]
  22. HIF prolyl hydroxylases in the rat; organ distribution and changes in expression following hypoxia and coronary artery ligation. William, C., Maxwell, P.H., Nichols, L., Lygate, C., Tian, Y.M., Bernhardt, W., Wiesener, M., Ratcliffe, P.J., Eckardt, K.U., Pugh, C.W. J. Mol. Cell. Cardiol. (2006) [Pubmed]
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