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Gene Review

EGLN3  -  egl-9 family hypoxia-inducible factor 3

Homo sapiens

Synonyms: Egl nine homolog 3, HIF-PH3, HIF-prolyl hydroxylase 3, HIFP4H3, HIFPH3, ...
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Disease relevance of EGLN3


High impact information on EGLN3

  • Siah2 null fibroblasts exhibit prolonged PHD3 half-life, resulting in lower levels of HIF1alpha expression during hypoxia [6].
  • Significantly, hypoxia-induced HIF1alpha expression was completely inhibited in Siah1a/2 null cells, yet could be rescued upon inhibition of PHD3 by RNAi [6].
  • In these domain-swapping experiments, prolyl hydroxylase domain 1 (PHD1) and PHD2 preferentially hydroxylated the proline located in the site of the original 564 ODD, while PHD3 preferred the proline 564 sequence, regardless of its location [7].
  • 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 [8].
  • The RING finger ubiquitin ligase Siah2 controls the stability of various substrates involved in stress and hypoxia responses, including the PHD3, which controls the stability of HIF-1alpha [9].

Biological context of EGLN3


Anatomical context of EGLN3

  • In agreement with this possibility, pVHL-deficient cell lines, which present high HIF activity under normoxia, also showed dramatically increased normoxic levels of EGLN3 [1].
  • Immunoreactivity for PHD1, PHD3, and seven in absentia homolog (SIAH)1 was noted in the pulmonary epithelium [13].
  • In the present study, we report that human PHD2 and PHD3 are induced by hypoxia in primary and transformed cell lines [2].
  • PHD2 mRNA was induced by hypoxia in the liver and PHD3 mRNA in liver, testis and heart [3].
  • We also demonstrate that prolyl-hydroxylases 2 and 3 (PHD2, PHD3), one of the major factors coordinating HIF degradation under normoxic but not hypoxic conditions, are induced in osteoblasts under hypoxic conditions [14].

Associations of EGLN3 with chemical compounds


Regulatory relationships of EGLN3

  • Interestingly, EGLN1 and EGLN3 mRNAs were also triggered by EGLN inhibitors, suggesting the involvement of HIFalpha in the control of its transcription [1].
  • We further tested the regulation of these genes by HIF-1 and HIF-2 and found that siRNA targeted degradation of HIF-1alpha and HIF-2alpha results in decreased hypoxia-induced PHD3 expression [17].

Other interactions of EGLN3

  • 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 [18].
  • Ectopic overexpression of HIF-2alpha in two different cell lines provided a much better induction of PHD3 gene than HIF-1alpha [17].
  • In the present study we determined the role of Siah2 phosphorylation in the regulation of its activity toward PHD3 [9].
  • Phospho-mutant forms of Siah2 (S29A or T24A/S29A) exhibit impaired degradation of PHD3, particularly after hypoxia [9].


  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. 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]
  3. 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]
  4. Inconsistent effects of acidosis on HIF-alpha protein and its target genes. Willam, C., Warnecke, C., Schefold, J.C., Kügler, J., Koehne, P., Frei, U., Wiesener, M., Eckardt, K.U. Pflugers Arch. (2006) [Pubmed]
  5. Genetic association analysis of chronic mountain sickness in an Andean high-altitude population. Mejía, O.M., Prchal, J.T., León-Velarde, F., Hurtado, A., Stockton, D.W. Haematologica (2005) [Pubmed]
  6. Siah2 regulates stability of prolyl-hydroxylases, controls HIF1alpha abundance, and modulates physiological responses to hypoxia. Nakayama, K., Frew, I.J., Hagensen, M., Skals, M., Habelhah, H., Bhoumik, A., Kadoya, T., Erdjument-Bromage, H., Tempst, P., Frappell, P.B., Bowtell, D.D., Ronai, Z. Cell (2004) [Pubmed]
  7. Coordinate regulation of the oxygen-dependent degradation domains of hypoxia-inducible factor 1 alpha. Chan, D.A., Sutphin, P.D., Yen, S.E., Giaccia, A.J. Mol. Cell. Biol. (2005) [Pubmed]
  8. 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]
  9. Regulation of the Ring Finger E3 Ligase Siah2 by p38 MAPK. Khurana, A., Nakayama, K., Williams, S., Davis, R.J., Mustelin, T., Ronai, Z. J. Biol. Chem. (2006) [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. Identification of a functional hypoxia-responsive element that regulates the expression of the egl nine homologue 3 (egln3/phd3) gene. Pescador, N., Cuevas, Y., Naranjo, S., Alcaide, M., Villar, D., Landázuri, M.O., Del Peso, L. Biochem. J. (2005) [Pubmed]
  12. Sequence determinants in hypoxia-inducible factor-1alpha for hydroxylation by the prolyl hydroxylases PHD1, PHD2, and PHD3. Huang, J., Zhao, Q., Mooney, S.M., Lee, F.S. J. Biol. Chem. (2002) [Pubmed]
  13. Hypoxia-inducible Factors in the First Trimester Human Lung. Groenman, F., Rutter, M., Caniggia, I., Tibboel, D., Post, M. J. Histochem. Cytochem. (2007) [Pubmed]
  14. Prolyl-hydroxylase inhibition and HIF activation in osteoblasts promotes an adipocytic phenotype. Irwin, R., Lapres, J.J., Kinser, S., McCabe, L.R. J. Cell. Biochem. (2007) [Pubmed]
  15. A common pathway for genetic events leading to pheochromocytoma. Maxwell, P.H. Cancer Cell (2005) [Pubmed]
  16. Mammalian gene expression program resiliency: the roles of multiple coactivator mechanisms in hypoxia-responsive transcription. Kasper, L.H., Brindle, P.K. Cell Cycle (2006) [Pubmed]
  17. Regulation of HIF prolyl hydroxylases by hypoxia-inducible factors. Aprelikova, O., Chandramouli, G.V., Wood, M., Vasselli, J.R., Riss, J., Maranchie, J.K., Linehan, W.M., Barrett, J.C. J. Cell. Biochem. (2004) [Pubmed]
  18. Characterization and comparative analysis of the EGLN gene family. Taylor, M.S. Gene (2001) [Pubmed]
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