EGLN1

Summary

Gene Symbol: EGLN1
Description: egl-9 family hypoxia inducible factor 1
Alias: C1orf12, ECYT3, HALAH, HIF-PH2, HIFPH2, HPH-2, HPH2, PHD2, SM20, ZMYND6, egl nine homolog 1, HIF-prolyl hydroxylase 2, egl nine-like protein 1, hypoxia-inducible factor prolyl hydroxylase 2, prolyl hydroxylase domain-containing protein 2, zinc finger MYND domain-containing protein 6
Species: human
Products:     EGLN1

Top Publications

  1. Pappalardi M, Martin J, Jiang Y, Burns M, Zhao H, Ho T, et al. Biochemical characterization of human prolyl hydroxylase domain protein 2 variants associated with erythrocytosis. Biochemistry. 2008;47:11165-7 pubmed publisher
    ..Herein, we examine the biochemical characterization of PHD2 variants, Arg371His and Pro317Arg, identified from patients with familial erythrocytosis...
  2. Lee K, Lynd J, O Reilly S, Kiupel M, McCormick J, LaPres J. The biphasic role of the hypoxia-inducible factor prolyl-4-hydroxylase, PHD2, in modulating tumor-forming potential. Mol Cancer Res. 2008;6:829-42 pubmed publisher
    ..We found that PHD2 is the primary functional isoform in these cells and its levels are inversely correlated to tumor-forming potential...
  3. Baek J, Mahon P, Oh J, Kelly B, Krishnamachary B, Pearson M, et al. OS-9 interacts with hypoxia-inducible factor 1alpha and prolyl hydroxylases to promote oxygen-dependent degradation of HIF-1alpha. Mol Cell. 2005;17:503-12 pubmed
    ..These data indicate that OS-9 is an essential component of a multiprotein complex that regulates HIF-1alpha levels in an O2-dependent manner. ..
  4. Xu W, Yang H, Liu Y, Yang Y, Wang P, Kim S, et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of ?-ketoglutarate-dependent dioxygenases. Cancer Cell. 2011;19:17-30 pubmed publisher
    ..Hence, tumor-derived IDH1 and IDH2 mutations reduce ?-KG and accumulate an ?-KG antagonist, 2-HG, leading to genome-wide histone and DNA methylation alterations. ..
  5. Wottawa M, Leisering P, Ahlen M, Schnelle M, Vogel S, Malz C, et al. Knockdown of prolyl-4-hydroxylase domain 2 inhibits tumor growth of human breast cancer MDA-MB-231 cells by affecting TGF-?1 processing. Int J Cancer. 2013;132:2787-98 pubmed publisher
    ..b>PHD2 is the main isoform regulating HIF-1? hydroxylation and thus stability in normoxia...
  6. Metzen E, Stiehl D, Doege K, Marxsen J, Hellwig Burgel T, Jelkmann W. Regulation of the prolyl hydroxylase domain protein 2 (phd2/egln-1) gene: identification of a functional hypoxia-responsive element. Biochem J. 2005;387:711-7 pubmed
    ..RNA interference directed against PHD2, but not PHD1 or PHD3, is sufficient to stabilize HIF-1alpha in normoxia...
  7. McMahon S, Charbonneau M, Grandmont S, Richard D, Dubois C. Transforming growth factor beta1 induces hypoxia-inducible factor-1 stabilization through selective inhibition of PHD2 expression. J Biol Chem. 2006;281:24171-81 pubmed
    ..and specifically decreases both mRNA and protein levels of a HIF-1alpha-associated prolyl hydroxylase (PHD), PHD2, through the Smad signaling pathway...
  8. Appelhoff R, Tian Y, Raval R, Turley H, Harris A, Pugh C, et al. Differential function of the prolyl hydroxylases PHD1, PHD2, and PHD3 in the regulation of hypoxia-inducible factor. J Biol Chem. 2004;279:38458-65 pubmed
    ..Although three HIF prolyl hydroxylases, PHD1, PHD2, and PHD3, have been identified that have the potential to catalyze this reaction, the contribution of each isoform ..
  9. Percy M, Zhao Q, Flores A, Harrison C, Lappin T, Maxwell P, et al. A family with erythrocytosis establishes a role for prolyl hydroxylase domain protein 2 in oxygen homeostasis. Proc Natl Acad Sci U S A. 2006;103:654-9 pubmed
    ..Here we describe an inherited mutation in a mammalian PHD enzyme. We show that this mutation in PHD2 results in a marked decrease in enzyme activity and is associated with familial erythrocytosis, identifying a ..

More Information

Publications80

  1. Bordoli M, Stiehl D, Borsig L, Kristiansen G, Hausladen S, Schraml P, et al. Prolyl-4-hydroxylase PHD2- and hypoxia-inducible factor 2-dependent regulation of amphiregulin contributes to breast tumorigenesis. Oncogene. 2011;30:548-60 pubmed publisher
    ..and bad prognosis, the function of the HIF-? protein stability regulating prolyl-4-hydroxylase domain enzyme PHD2 in carcinogenesis is less well understood...
  2. Epstein A, Gleadle J, McNeill L, Hewitson K, O ROURKE J, Mole D, et al. C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell. 2001;107:43-54 pubmed
  3. Percy M, Furlow P, Beer P, Lappin T, McMullin M, Lee F. A novel erythrocytosis-associated PHD2 mutation suggests the location of a HIF binding groove. Blood. 2007;110:2193-6 pubmed
    ..Several mutations in VHL have been reported in erythrocytosis, but only 1 mutation in the HIF prolyl hydroxylase PHD2 (prolyl hydroxylase domain protein 2) has been described...
  4. Huang K, Mikeska T, Dobrovic A, Fox S. DNA methylation analysis of the HIF-1? prolyl hydroxylase domain genes PHD1, PHD2, PHD3 and the factor inhibiting HIF gene FIH in invasive breast carcinomas. Histopathology. 2010;57:451-60 pubmed publisher
    Hypoxia-inducible factor-1 (HIF-1) activity is regulated by prolyl hydroxylase (PHD1, PHD2, PHD3) and factor inhibiting HIF-1 (FIH) that target the ? subunit of HIF-1 (HIF-1?) for proteosomal degradation...
  5. Ivan M, Haberberger T, Gervasi D, Michelson K, Gunzler V, Kondo K, et al. Biochemical purification and pharmacological inhibition of a mammalian prolyl hydroxylase acting on hypoxia-inducible factor. Proc Natl Acad Sci U S A. 2002;99:13459-64 pubmed
    ..A model compound of this series stabilized HIF in a variety of cells, leading to the increased production of its downstream target, vascular endothelial growth factor. ..
  6. Xiang K, Ouzhuluobu -, Peng Y, Yang Z, Zhang X, Cui C, et al. Identification of a Tibetan-specific mutation in the hypoxic gene EGLN1 and its contribution to high-altitude adaptation. Mol Biol Evol. 2013;30:1889-98 pubmed publisher
    ..Here we conducted resequencing of the entire genomic region (59.4 kb) of the hypoxic gene EGLN1 (one of the top candidates from the genome-wide scans) in Tibetans and identified 185 sequence variations, ..
  7. Hatzimichael E, Dasoula A, Shah R, Syed N, Papoudou Bai A, Coley H, et al. The prolyl-hydroxylase EGLN3 and not EGLN1 is inactivated by methylation in plasma cell neoplasia. Eur J Haematol. 2010;84:47-51 pubmed publisher
    b>EGLN1 and EGLN3 are members of the egg-laying-defective 9 (EglN) prolyl-hydroxylases which during normoxia catalyse hydroxylation of the hypoxia-inducible factor (HIF)-1alpha, thereby promoting its ubiquitination by a complex containing ..
  8. Chan D, Kawahara T, Sutphin P, Chang H, Chi J, Giaccia A. Tumor vasculature is regulated by PHD2-mediated angiogenesis and bone marrow-derived cell recruitment. Cancer Cell. 2009;15:527-38 pubmed publisher
    ..These two factors are regulated by PHD2 in a HIF-independent but NF-kappaB-dependent manner...
  9. Henze A, Riedel J, Diem T, Wenner J, Flamme I, Pouyseggur J, et al. Prolyl hydroxylases 2 and 3 act in gliomas as protective negative feedback regulators of hypoxia-inducible factors. Cancer Res. 2010;70:357-66 pubmed publisher
    ..Hypoxia induces expression of the PHD2 and PHD3 proteins in tumors but the pathobiological significance of these events is uncertain...
  10. Bruick R, McKnight S. A conserved family of prolyl-4-hydroxylases that modify HIF. Science. 2001;294:1337-40 pubmed
    ..These findings indicate that HPH is an essential component of the pathway through which cells sense oxygen. ..
  11. Metzen E, Berchner Pfannschmidt U, Stengel P, Marxsen J, Stolze I, Klinger M, et al. Intracellular localisation of human HIF-1 alpha hydroxylases: implications for oxygen sensing. J Cell Sci. 2003;116:1319-26 pubmed
    ..Three human oxygen-dependent HIF-1 alpha prolyl hydroxylases (PHD1, PHD2, and PHD3) function as oxygen sensors in vivo...
  12. Peurala E, Koivunen P, Bloigu R, Haapasaari K, Jukkola Vuorinen A. Expressions of individual PHDs associate with good prognostic factors and increased proliferation in breast cancer patients. Breast Cancer Res Treat. 2012;133:179-88 pubmed publisher
    ..for increased breast cancer-specific survival and longer disease-free survival among patients with high tumor PHD2 expression. Surprisingly, PHD1-3 expression did not correlate with HIF-1? or HIF-2? downregulation...
  13. Andersen S, Donnem T, Stenvold H, Al Saad S, Al Shibli K, Busund L, et al. Overexpression of the HIF hydroxylases PHD1, PHD2, PHD3 and FIH are individually and collectively unfavorable prognosticators for NSCLC survival. PLoS ONE. 2011;6:e23847 pubmed publisher
    ..023), PHD2 (P?=?0.013), PHD3 (P?=?0.018) and FIH (P?=?0.033)...
  14. Ginouves A, Ilc K, Macías N, Pouyssegur J, Berra E. PHDs overactivation during chronic hypoxia "desensitizes" HIFalpha and protects cells from necrosis. Proc Natl Acad Sci U S A. 2008;105:4745-50 pubmed publisher
    ..Hence, PHDs serve as dual enzymes, for which inactivation and later overactivation is necessary for cell survival in acute or chronic hypoxia, respectively. ..
  15. Thoms B, Murphy C. Inhibition of hypoxia-inducible factor-targeting prolyl hydroxylase domain-containing protein 2 (PHD2) enhances matrix synthesis by human chondrocytes. J Biol Chem. 2010;285:20472-80 pubmed publisher
    ..Here, we have identified PHD2 as the dominant isoenzyme regulating HIF-2alpha stability in human chondrocytes...
  16. Xie G, Zheng L, Ou J, Huang H, He J, Li J, et al. Low expression of prolyl hydroxylase 2 is associated with tumor grade and poor prognosis in patients with colorectal cancer. Exp Biol Med (Maywood). 2012;237:860-6 pubmed publisher
    ..Expressions of PHD1, PHD2, PHD3 and hypoxia-inducible factor (HIF)-1? were detected using immunohistochemistry in an independent CRC cohort ..
  17. Astuti D, Ricketts C, Chowdhury R, McDonough M, Gentle D, Kirby G, et al. Mutation analysis of HIF prolyl hydroxylases (PHD/EGLN) in individuals with features of phaeochromocytoma and renal cell carcinoma susceptibility. Endocr Relat Cancer. 2011;18:73-83 pubmed publisher
    ..The 2-oxoglutarate-dependent prolyl hydroxylase enzymes PHD1 (EGLN2), PHD2 (EGLN1) and PHD3 (EGLN3) have a key role in regulating the stability of HIF-α subunits (and hence expression of the HIF-..
  18. Kato H, Inoue T, Asanoma K, Nishimura C, Matsuda T, Wake N. Induction of human endometrial cancer cell senescence through modulation of HIF-1alpha activity by EGLN1. Int J Cancer. 2006;118:1144-53 pubmed
    ..Among them, EGLN1, that is a member of prolyl hydroxylase and can facilitate HIF-1 degradation by ubiquitination through the ..
  19. Oehme F, Ellinghaus P, Kolkhof P, Smith T, Ramakrishnan S, Hütter J, et al. Overexpression of PH-4, a novel putative proline 4-hydroxylase, modulates activity of hypoxia-inducible transcription factors. Biochem Biophys Res Commun. 2002;296:343-9 pubmed
    ..the oxygen-dependent degradation domain (ODDD) are hydroxylated by oxoglutarate-dependent proline 4-hydroxylases EGLN1-3...
  20. Chowdhury R, McDonough M, Mecinovic J, Loenarz C, Flashman E, Hewitson K, et al. Structural basis for binding of hypoxia-inducible factor to the oxygen-sensing prolyl hydroxylases. Structure. 2009;17:981-9 pubmed publisher
    ..We report crystal structures of the catalytic domain of PHD2, the most important of the human PHDs, in complex with the C-terminal oxygen-dependent degradation domain of HIF-..
  21. Song D, Li L, Arsenault P, Tan Q, Bigham A, Heaton Johnson K, et al. Defective Tibetan PHD2 binding to p23 links high altitude adaption to altered oxygen sensing. J Biol Chem. 2014;289:14656-65 pubmed publisher
    ..Tibetans bear a genetic signature in the prolyl hydroxylase domain protein 2 (PHD2/EGLN1) gene, which encodes for the central oxygen sensor of the hypoxia-inducible factor (HIF) pathway...
  22. Xu S, Li S, Yang Y, Tan J, Lou H, Jin W, et al. A genome-wide search for signals of high-altitude adaptation in Tibetans. Mol Biol Evol. 2011;28:1003-11 pubmed publisher
    ..We discovered the most differentiated variants between TBN and HAN at chromosome 1q42.2 and 2p21. EGLN1 (or HIFPH2, MIM 606425) and EPAS1 (or HIF2A, MIM 603349), both related to hypoxia-inducible factor, were found most ..
  23. Nakayama K, Gazdoiu S, Abraham R, Pan Z, RONAI Z. Hypoxia-induced assembly of prolyl hydroxylase PHD3 into complexes: implications for its activity and susceptibility for degradation by the E3 ligase Siah2. Biochem J. 2007;401:217-26 pubmed
    ..Firstly, PHD3 lacks an N-terminal extension found in PHD1 and PHD2; deletion of this domain from PHD1 and PHD2 renders them susceptible to degradation by Siah2...
  24. Jokilehto T, Högel H, Heikkinen P, Rantanen K, Elenius K, Sundström J, et al. Retention of prolyl hydroxylase PHD2 in the cytoplasm prevents PHD2-induced anchorage-independent carcinoma cell growth. Exp Cell Res. 2010;316:1169-78 pubmed publisher
    ..The PHD2 isoform is considered as the main downregulator of HIF in normoxia...
  25. Jokilehto T, Rantanen K, Luukkaa M, Heikkinen P, Grenman R, Minn H, et al. Overexpression and nuclear translocation of hypoxia-inducible factor prolyl hydroxylase PHD2 in head and neck squamous cell carcinoma is associated with tumor aggressiveness. Clin Cancer Res. 2006;12:1080-7 pubmed
    ..HIFs in turn are negatively regulated by a family of prolyl hydroxylases (PHD1-3). The PHD2 isoform is the main down-regulator of HIFs in normoxia and mild hypoxia...
  26. Aprelikova O, Chandramouli G, Wood M, Vasselli J, Riss J, Maranchie J, et al. Regulation of HIF prolyl hydroxylases by hypoxia-inducible factors. J Cell Biochem. 2004;92:491-501 pubmed
    ..In contrast, we demonstrate that PHD2 is not affected by overexpression or downregulation of HIF-2alpha...
  27. Foxler D, Bridge K, James V, Webb T, Mee M, Wong S, et al. The LIMD1 protein bridges an association between the prolyl hydroxylases and VHL to repress HIF-1 activity. Nat Cell Biol. 2012;14:201-8 pubmed publisher
    ..LIMD1 family member proteins Ajuba and WTIP also bind to VHL and PHDs 1 and 3, indicating that these LIM domain-containing proteins represent a previously unrecognized group of hypoxic regulators. ..
  28. Ozer A, Wu L, Bruick R. The candidate tumor suppressor ING4 represses activation of the hypoxia inducible factor (HIF). Proc Natl Acad Sci U S A. 2005;102:7481-6 pubmed
    ..These data support a model in which, in addition to regulating HIF stability, HIF prolyl hydroxylases can modulate HIF function through the recruitment of ING4, a likely component of a chromatin-remodeling complex. ..
  29. Barth S, Edlich F, Berchner Pfannschmidt U, Gneuss S, Jahreis G, Hasgall P, et al. Hypoxia-inducible factor prolyl-4-hydroxylase PHD2 protein abundance depends on integral membrane anchoring of FKBP38. J Biol Chem. 2009;284:23046-58 pubmed publisher
    ..protein regulation of the main oxygen sensor responsible for hypoxia-inducible factor alpha regulation, PHD2, remained unknown...
  30. Berchner Pfannschmidt U, Tug S, Trinidad B, Oehme F, Yamac H, Wotzlaw C, et al. Nuclear oxygen sensing: induction of endogenous prolyl-hydroxylase 2 activity by hypoxia and nitric oxide. J Biol Chem. 2008;283:31745-53 pubmed publisher
    ..in both compartments, knockdown experiments for each isoenzyme revealed that nuclear PHD activity was only due to PHD2. Maximal PHD2 activity was found between 120 and 210 microm O2...
  31. Mikhaylova O, Ignacak M, Barankiewicz T, Harbaugh S, Yi Y, Maxwell P, et al. The von Hippel-Lindau tumor suppressor protein and Egl-9-Type proline hydroxylases regulate the large subunit of RNA polymerase II in response to oxidative stress. Mol Cell Biol. 2008;28:2701-17 pubmed publisher
    ..Egln-9-type prolyl hydroxylases, PHD1 and PHD2, coimmunoprecipitated with Rpb1 in the chromatin fraction of VHL(+) RCC cells in response to oxidative stress, and ..
  32. Berra E, Benizri E, Ginouves A, Volmat V, Roux D, Pouyssegur J. HIF prolyl-hydroxylase 2 is the key oxygen sensor setting low steady-state levels of HIF-1alpha in normoxia. EMBO J. 2003;22:4082-90 pubmed
    ..Here we show that specific 'silencing' of PHD2 with short interfering RNAs is sufficient to stabilize and activate HIF-1alpha in normoxia in all the human cells ..
  33. Berchner Pfannschmidt U, Yamac H, Trinidad B, Fandrey J. Nitric oxide modulates oxygen sensing by hypoxia-inducible factor 1-dependent induction of prolyl hydroxylase 2. J Biol Chem. 2007;282:1788-96 pubmed
    ..NO induces expression of PHD2 and -3 mRNA and protein under normoxia and hypoxia in a strictly HIF-1-dependent manner...
  34. McDonough M, Li V, Flashman E, Chowdhury R, Mohr C, Lienard B, et al. Cellular oxygen sensing: Crystal structure of hypoxia-inducible factor prolyl hydroxylase (PHD2). Proc Natl Acad Sci U S A. 2006;103:9814-9 pubmed
    ..We describe crystal structures of the catalytic domain of human PHD2, an important prolyl-4-hydroxylase in the human hypoxic response in normal cells, in complex with Fe(II) and an ..
  35. Tseng C, Kuo W, Chan S, Chan H, Chang K, Wang L. Transketolase Regulates the Metabolic Switch to Control Breast Cancer Cell Metastasis via the ?-Ketoglutarate Signaling Pathway. Cancer Res. 2018;78:2799-2812 pubmed publisher
    ..and fumarate hydratase (FH), decreasing oncometabolites succinate and fumarate, and further stabilizing HIF prolyl hydroxylase 2 (PHD2) and decreasing HIF1?, ultimately suppressing breast cancer metastasis...
  36. Souma T, Nezu M, Nakano D, Yamazaki S, Hirano I, Sekine H, et al. Erythropoietin Synthesis in Renal Myofibroblasts Is Restored by Activation of Hypoxia Signaling. J Am Soc Nephrol. 2016;27:428-38 pubmed publisher
    ..activation of hypoxia-inducible factors (HIFs) by genetic inactivation of HIF-prolyl hydroxylases (PHD1, PHD2, and PHD3) selectively in Epo-producing cells reactivated Epo production in MF-REPs...
  37. Huo Z, Ye J, Chen J, Lin X, Zhou Z, Xu X, et al. Prolyl hydroxylase domain protein 2 regulates the intracellular cyclic AMP level in cardiomyocytes through its interaction with phosphodiesterase 4D. Biochem Biophys Res Commun. 2012;427:73-9 pubmed publisher
    ..Through the overexpression/knockdown of the PHD gene and the measurement of the cAMP content, we found that PHD2, but not PHD1 or PHD3, acts as a regulator of intracellular cAMP...
  38. Ryou M, Choudhury G, Li W, Winters A, Yuan F, Liu R, et al. Methylene blue-induced neuronal protective mechanism against hypoxia-reoxygenation stress. Neuroscience. 2015;301:193-203 pubmed publisher
    ..Protein content changes were measured by immunoblot: HIF-1α, prolyl hydroxylase 2 (PHD2), erythropoietin (EPO), Akt, mTOR, and PIP5K...
  39. Cheng S, Aghajanian P, Pourteymoor S, Alarcon C, Mohan S. Prolyl Hydroxylase Domain-Containing Protein 2 (Phd2) Regulates Chondrocyte Differentiation and Secondary Ossification in Mice. Sci Rep. 2016;6:35748 pubmed publisher
    ..We recently demonstrated that Prolyl Hydroxylase Domain-containing Protein 2 (Phd2) is a key mediator of vitamin C effects on bone...
  40. Zhang E, Zhang J, Jin J, Qin J, Li H, Huang L. Variants of the low oxygen sensors EGLN1 and HIF-1AN associated with acute mountain sickness. Int J Mol Sci. 2014;15:21777-87 pubmed publisher
    Two low oxygen sensors, Egl nine homolog 1 (EGLN1) and hypoxia-inducible factor 1-α inhibitor (HIF-1AN), play pivotal roles in the regulation of HIF-1α, and high altitude adaption may be involved in the pathology of acute mountain ..
  41. Abboud M, McAllister T, Leung I, Chowdhury R, Jorgensen C, Domene C, et al. 2-Oxoglutarate regulates binding of hydroxylated hypoxia-inducible factor to prolyl hydroxylase domain 2. Chem Commun (Camb). 2018;54:3130-3133 pubmed publisher
    ..We report that binding of prolyl-hydroxylated HIF-α to PHD2 is ∼50 fold hindered by prior 2OG binding; thus, when 2OG is limiting, HIF-α degradation might be inhibited by ..
  42. Tcholakov I, Grimshaw C, Shi L, Kiryanov A, Murphy S, Larson C, et al. Time-dependent inhibition of PHD2. Biosci Rep. 2017;37: pubmed publisher
    ..Most of these compounds are pan PHD inhibitors and exhibit a time-dependent inhibition (TDI) mechanism due to an extremely slow dissociation rate constant, koff, and a long residence time. ..
  43. Devine R, Bicer S, Reiser P, Wold L. Increased hypoxia-inducible factor-1? in striated muscle of tumor-bearing mice. Am J Physiol Heart Circ Physiol. 2017;312:H1154-H1162 pubmed publisher
    ..heart, whereas there were no changes in its regulatory proteins, prolyl hydroxylase domain-containing protein 2 (PHD2) and von Hippel-Lindau protein (VHL)...
  44. Di Conza G, Trusso Cafarello S, Zheng X, Zhang Q, Mazzone M. PHD2 Targeting Overcomes Breast Cancer Cell Death upon Glucose Starvation in a PP2A/B55α-Mediated Manner. Cell Rep. 2017;18:2836-2844 pubmed publisher
    ..have recently found that B55α-associated PP2A promotes partial deactivation of the HIF-prolyl-hydroxylase enzyme PHD2. Here, we show that, in turn, PHD2 triggers degradation of B55α by hydroxylating it at proline 319...
  45. Hirayama Y, Koizumi S. Hypoxia-independent mechanisms of HIF-1α expression in astrocytes after ischemic preconditioning. Glia. 2017;65:523-530 pubmed publisher
    ..The neuronal HIF-1α increase was dependent on inhibition of PHD2, an oxygen-dependent HIF-1α degrading enzyme, whereas astrocytic one was independent of PHD2...
  46. Arsenault P, Song D, Bergkamp M, Ravaschiere A, Navalsky B, Lieberman P, et al. Identification of Small-Molecule PHD2 Zinc Finger Inhibitors that Activate Hypoxia Inducible Factor. Chembiochem. 2016;17:2316-2323 pubmed publisher
    ..In mammals, there are three PHD paralogues, and PHD2 has emerged as a particularly critical one for regulating HIF target genes such as erythropoietin (EPO), which ..
  47. Singh M, Devi U, Roy S, Gupta P, Saraf S, Kaithwas G. Prolyl hydroxylase mediated inhibition of fatty acid synthase to combat tumor growth in mammary gland carcinoma. Breast Cancer. 2016;23:820-829 pubmed
    ..Considering the above, it is hypothesized that chemical activation of Phd-2 can curtail down HIF-1α and subsequently fatty acid synthase expression. ..
  48. Metikala S, Neuhaus H, Hollemann T. Suppression of vascular network formation by chronic hypoxia and prolyl-hydroxylase 2 (phd2) deficiency during vertebrate development. Angiogenesis. 2016;19:119-31 pubmed publisher
    ..Interestingly, suppression of Phd2 function using specific antisense morpholinos or a chemical inhibitor resulted in mostly overlapping vascular ..
  49. Bakirtzi K, Law I, Xue X, Iliopoulos D, Shah Y, Pothoulakis C. Neurotensin Promotes the Development of Colitis and Intestinal Angiogenesis via Hif-1α-miR-210 Signaling. J Immunol. 2016;196:4311-21 pubmed publisher
    Neurotensin (NT) via its receptor 1 (NTR1) modulates the development of colitis, decreases HIF-1α/PHD2 interaction, stabilizes and increases HIF-1α transcriptional activity, and promotes intestinal angiogenesis...
  50. Arsenault P, Song D, Chung Y, Khurana T, Lee F. The Zinc Finger of Prolyl Hydroxylase Domain Protein 2 Is Essential for Efficient Hydroxylation of Hypoxia-Inducible Factor α. Mol Cell Biol. 2016;36:2328-43 pubmed publisher
    Prolyl hydroxylase domain protein 2 (PHD2) (also known as EGLN1) is a key oxygen sensor in mammals that posttranslationally modifies hypoxia-inducible factor α (HIF-α) and targets it for degradation...
  51. Harnoss J, Platzer L, Burhenne J, Radhakrishnan P, Cai J, Strowitzki M, et al. Prolyl Hydroxylase Inhibition Enhances Liver Regeneration Without Induction of Tumor Growth. Ann Surg. 2017;265:782-791 pubmed publisher
    ..pharmacological inhibition of hypoxia-inducible transcription factor (HIF)-prolyl hydroxylase enzymes (PHD1, PHD2, and PHD3) is a suitable strategy to stimulate liver regeneration after partial hepatectomy for colorectal liver ..
  52. Hulley P, Bishop T, Vernet A, Schneider J, Edwards J, Athanasou N, et al. Hypoxia-inducible factor 1-alpha does not regulate osteoclastogenesis but enhances bone resorption activity via prolyl-4-hydroxylase 2. J Pathol. 2017;242:322-333 pubmed publisher
    ..b>Phd2+/- murine osteoclasts also exhibited enhanced bone resorption, associated with increased expression of ..
  53. Yi Y, Mikhaylova O, Mamedova A, Bastola P, Biesiada J, Alshaikh E, et al. von Hippel-Lindau-dependent patterns of RNA polymerase II hydroxylation in human renal clear cell carcinomas. Clin Cancer Res. 2010;16:5142-52 pubmed publisher
    ..Rpb1 hydroxylated on P1465 [Rpb1(OH)], Rpb1 phosphorylated on Ser5 [Rpb1(S5P)], and proline hydroxylases PHD1, PHD2, and PHD3. Results from RCC tumors were categorized according to the status of VHL gene...
  54. Jeong C, Alkorta Aranburu G, Basnyat B, Neupane M, Witonsky D, Pritchard J, et al. Admixture facilitates genetic adaptations to high altitude in Tibet. Nat Commun. 2014;5:3281 pubmed publisher
    ..Studies of Tibetans revealed candidates for high-altitude adaptations in the EGLN1 and EPAS1 genes, associated with lower haemoglobin concentration...
  55. Di Conza G, Trusso Cafarello S, Loroch S, Mennerich D, Deschoemaeker S, Di Matteo M, et al. The mTOR and PP2A Pathways Regulate PHD2 Phosphorylation to Fine-Tune HIF1α Levels and Colorectal Cancer Cell Survival under Hypoxia. Cell Rep. 2017;18:1699-1712 pubmed publisher
    Oxygen-dependent HIF1α hydroxylation and degradation are strictly controlled by PHD2. In hypoxia, HIF1α partly escapes degradation because of low oxygen availability...
  56. Zhu Y, Wang J, Meng X, Xie H, Tan J, Guo X, et al. A positive feedback loop promotes HIF-1? stability through miR-210-mediated suppression of RUNX3 in paraquat-induced EMT. J Cell Mol Med. 2017;21:3529-3539 pubmed publisher
    ..RUNX3 increased the hydroxylation ability of prolyl hydroxylase domain-containing protein 2 (PHD2), a key enzyme that promotes HIF-1? degradation...
  57. Flashman E, Hoffart L, Hamed R, Bollinger J, Krebs C, Schofield C. Evidence for the slow reaction of hypoxia-inducible factor prolyl hydroxylase 2 with oxygen. FEBS J. 2010;277:4089-99 pubmed publisher
  58. Yasumoto K, Kowata Y, Yoshida A, Torii S, Sogawa K. Role of the intracellular localization of HIF-prolyl hydroxylases. Biochim Biophys Acta. 2009;1793:792-7 pubmed publisher
    ..In mammalian cells, HIF-1 protein levels are regulated by three HIF-prolyl hydroxylases, termed PHD1, PHD2 and PHD3...
  59. Pientka F, Hu J, Schindler S, Brix B, Thiel A, Jöhren O, et al. Oxygen sensing by the prolyl-4-hydroxylase PHD2 within the nuclear compartment and the influence of compartmentalisation on HIF-1 signalling. J Cell Sci. 2012;125:5168-76 pubmed publisher
    ..the HIF-? subunit is hydroxylated by members of a family of prolyl-4-hydroxylase domain (PHD) proteins, PHD1, PHD2 and PHD3, resulting in recognition by von-Hippel-Lindau protein, ubiquitylation and proteasomal degradation...
  60. Steinhoff A, Pientka F, Möckel S, Kettelhake A, Hartmann E, Kohler M, et al. Cellular oxygen sensing: Importins and exportins are mediators of intracellular localisation of prolyl-4-hydroxylases PHD1 and PHD2. Biochem Biophys Res Commun. 2009;387:705-11 pubmed publisher
    ..Inhibition of prolyl hydroxylation of HIF-alpha subunits by prolyl-hydroxylases (PHD1, PHD2 and PHD3) leads to transcription of a greater number of hypoxia responsive genes...
  61. Song D, Li L, Heaton Johnson K, Arsenault P, Master S, Lee F. Prolyl hydroxylase domain protein 2 (PHD2) binds a Pro-Xaa-Leu-Glu motif, linking it to the heat shock protein 90 pathway. J Biol Chem. 2013;288:9662-74 pubmed publisher
    Prolyl hydroxylase domain protein 2 (PHD2, also known as Egg Laying Defective Nine homolog 1) is a key oxygen-sensing protein in metazoans...
  62. Yang C, Zhuang Z, Fliedner S, Shankavaram U, Sun M, Bullova P, et al. Germ-line PHD1 and PHD2 mutations detected in patients with pheochromocytoma/paraganglioma-polycythemia. J Mol Med (Berl). 2015;93:93-104 pubmed publisher
    ..We have found for the first time a germ-line mutation in PHD1 in one patient and a novel germ-line PHD2 mutation in a second patient...
  63. An X, Xu G, Yang L, Wang Y, Li Y, McHepange U, et al. Expression of hypoxia-inducible factor-1?, vascular endothelial growth factor and prolyl hydroxylase domain protein 2 in cutaneous squamous cell carcinoma and precursor lesions and their relationship with histological stages and clinical features. J Dermatol. 2014;41:76-83 pubmed publisher
    ..vascular endothelial growth factor (VEGF) and the HIF negative regulator, prolyl hydroxylase domain protein 2 (PHD2), in cutaneous SCC, Bowen's disease, seborrheic keratosis (SK) and normal skin by immunohistochemistry and in situ ..
  64. Chen C, Li H, Jiang J, Zhang Q, Yan F. Inhibiting PHD2 in bone marrow mesenchymal stem cells via lentiviral vector-mediated RNA interference facilitates the repair of periodontal tissue defects in SD rats. Oncotarget. 2017;8:72676-72699 pubmed publisher
    ..Prolyl hydroxylase domain-containing protein 2 (PHD2) is the main catabolic enzyme for HIF-1?, and it can accelerate its degradation under normoxic conditions...
  65. Deppe J, Popp T, Egea V, Steinritz D, Schmidt A, Thiermann H, et al. Impairment of hypoxia-induced HIF-1α signaling in keratinocytes and fibroblasts by sulfur mustard is counteracted by a selective PHD-2 inhibitor. Arch Toxicol. 2016;90:1141-50 pubmed publisher
  66. Vogel S, Wottawa M, Farhat K, Zieseniss A, Schnelle M, Le Huu S, et al. Prolyl hydroxylase domain (PHD) 2 affects cell migration and F-actin formation via RhoA/rho-associated kinase-dependent cofilin phosphorylation. J Biol Chem. 2010;285:33756-63 pubmed publisher
    ..To gain further insight into PHD function, we generated knockdown cell models for the PHD2 isoform, which is the main isoform regulating HIF-1? hydroxylation and thus stability in normoxia...
  67. Tarhonskaya H, Hardy A, Howe E, Loik N, Kramer H, McCullagh J, et al. Kinetic Investigations of the Role of Factor Inhibiting Hypoxia-inducible Factor (FIH) as an Oxygen Sensor. J Biol Chem. 2015;290:19726-42 pubmed publisher
    ..In humans, they comprise three prolyl hydroxylases (PHD1-3 or EGLN1-3) and factor inhibiting HIF (FIH)...
  68. Miyake T, Nakamura S, Meng Z, Hamano S, Inoue K, Numata T, et al. Distinct Mechanism of Cysteine Oxidation-Dependent Activation and Cold Sensitization of Human Transient Receptor Potential Ankyrin 1 Channel by High and Low Oxaliplatin. Front Physiol. 2017;8:878 pubmed publisher
    ..Ca2+ concentration but did confer cold sensitivity on hTRPA1-expressing cells, and this was inhibited by PHD2 co-overexpression...
  69. Nangaku M, Izuhara Y, Takizawa S, Yamashita T, Fujii Kuriyama Y, Ohneda O, et al. A novel class of prolyl hydroxylase inhibitors induces angiogenesis and exerts organ protection against ischemia. Arterioscler Thromb Vasc Biol. 2007;27:2548-54 pubmed
    ..Our docking simulation studies based on the 3-dimensional structure of human PHD2 disclosed that they preferentially bind to the active site of PHD...
  70. Huang J, Song D, Flores A, Zhao Q, Mooney S, Shaw L, et al. IOP1, a novel hydrogenase-like protein that modulates hypoxia-inducible factor-1alpha activity. Biochem J. 2007;401:341-52 pubmed
    ..The results collectively provide evidence that IOP1 is a component of the protein network that regulates HIF-1alpha in mammalian cells. ..
  71. Peng Y, Yang Z, Zhang H, Cui C, Qi X, Luo X, et al. Genetic variations in Tibetan populations and high-altitude adaptation at the Himalayas. Mol Biol Evol. 2011;28:1075-81 pubmed publisher
    ..with the reported data, we identified strong signals of selective sweep in two hypoxia-related genes, EPAS1 and EGLN1. For these two genes, Tibetans show unusually high divergence from the non-Tibetan lowlanders (Han Chinese and ..