Egln1

Summary

Gene Symbol: Egln1
Description: egl-9 family hypoxia-inducible factor 1
Alias: AI503754, C1orf12, HIF-PH2, HPH-2, Hif-p4h-2, ORF13, Phd2, SM-20, egl nine homolog 1, HIF-prolyl hydroxylase 2, hypoxia-inducible factor prolyl hydroxylase 2, prolyl hydroxylase domain-containing protein 2
Species: mouse
Products:     Egln1

Top Publications

  1. Spinella F, Rosanò L, Del Duca M, Di Castro V, Nicotra M, Natali P, et al. Endothelin-1 inhibits prolyl hydroxylase domain 2 to activate hypoxia-inducible factor-1alpha in melanoma cells. PLoS ONE. 2010;5:e11241 pubmed publisher
    ..In particular, ETs through ET(B)R markedly decrease PHD2 mRNA and protein levels and promoter activity...
  2. 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. ..
  3. Chang E, Loh S, Ceradini D, Chang E, Lin S, Bastidas N, et al. Age decreases endothelial progenitor cell recruitment through decreases in hypoxia-inducible factor 1alpha stabilization during ischemia. Circulation. 2007;116:2818-29 pubmed
    ..Aging impairs EPC trafficking to sites of ischemia through a failure of aged tissues to normally activate the hypoxia-inducible factor 1alpha-mediated hypoxia response. ..
  4. Takeda K, Aguila H, Parikh N, Li X, Lamothe K, Duan L, et al. Regulation of adult erythropoiesis by prolyl hydroxylase domain proteins. Blood. 2008;111:3229-35 pubmed
    ..HIF-2alpha, which is known to activate Epo expression, accumulated in the liver. In adult mice deficient for PHD2, the prototypic Epo transcriptional activator HIF-1alpha accumulated in both the kidney and liver...
  5. Wu S, Nishiyama N, Kano M, Morishita Y, Miyazono K, Itaka K, et al. Enhancement of angiogenesis through stabilization of hypoxia-inducible factor-1 by silencing prolyl hydroxylase domain-2 gene. Mol Ther. 2008;16:1227-34 pubmed publisher
    ..Prolyl hydroxylase domain-2 (PHD2) protein induces the degradation of HIF-1 by hydroxylating specific prolyl residues...
  6. Huang M, Chan D, Jia F, Xie X, Li Z, Hoyt G, et al. Short hairpin RNA interference therapy for ischemic heart disease. Circulation. 2008;118:S226-33 pubmed publisher
    ..However, hypoxia inducible factor-1 alpha is naturally degraded by prolyl hydroxylase-2 (PHD2) protein...
  7. Bishop T, Gallagher D, Pascual A, Lygate C, de Bono J, Nicholls L, et al. Abnormal sympathoadrenal development and systemic hypotension in PHD3-/- mice. Mol Cell Biol. 2008;28:3386-400 pubmed publisher
    ..Perturbation of this interface between developmental and adaptive signaling by hypoxic, metabolic, or other stresses could have important effects on key sympathoadrenal functions, such as blood pressure regulation. ..
  8. Takeda Y, Costa S, Delamarre E, Roncal C, Leite De Oliveira R, Squadrito M, et al. Macrophage skewing by Phd2 haplodeficiency prevents ischaemia by inducing arteriogenesis. Nature. 2011;479:122-6 pubmed publisher
    ..We show that Phd2 (also known as Egln1) haplodeficient (Phd2(+/-)) mice displayed preformed collateral arteries that preserved limb perfusion and ..
  9. Matsuura H, Ichiki T, Inoue E, Nomura M, Miyazaki R, Hashimoto T, et al. Prolyl hydroxylase domain protein 2 plays a critical role in diet-induced obesity and glucose intolerance. Circulation. 2013;127:2078-87 pubmed publisher
    ..We examined whether deletion of PHD2, the main oxygen sensor, in adipocytes affects diet-induced obesity and associated metabolic abnormalities...

More Information

Publications86

  1. Hölscher M, Silter M, Krull S, von Ahlen M, Hesse A, Schwartz P, et al. Cardiomyocyte-specific prolyl-4-hydroxylase domain 2 knock out protects from acute myocardial ischemic injury. J Biol Chem. 2011;286:11185-94 pubmed publisher
    ..We have disrupted PHD2 in cardiomyocytes (cPhd (-/-)) using Phd2(flox/flox) mice in combination with MLCvCre mice, which resulted in HIF-1?..
  2. Taniguchi C, Finger E, Krieg A, Wu C, Diep A, LaGory E, et al. Cross-talk between hypoxia and insulin signaling through Phd3 regulates hepatic glucose and lipid metabolism and ameliorates diabetes. Nat Med. 2013;19:1325-30 pubmed publisher
    ..alpha (Hif-1?) and Hif-2? is regulated by three prolyl hydroxylase domain-containing protein isoforms (Phd1, Phd2 and Phd3)...
  3. Mazzone M, Dettori D, de Oliveira R, Loges S, Schmidt T, Jonckx B, et al. Heterozygous deficiency of PHD2 restores tumor oxygenation and inhibits metastasis via endothelial normalization. Cell. 2009;136:839-851 pubmed publisher
    ..We therefore studied the role of endothelial PHD2 in vessel shaping by implanting tumors in PHD2(+/-) mice...
  4. Aragones J, Schneider M, van Geyte K, Fraisl P, Dresselaers T, Mazzone M, et al. Deficiency or inhibition of oxygen sensor Phd1 induces hypoxia tolerance by reprogramming basal metabolism. Nat Genet. 2008;40:170-80 pubmed publisher
    ..Hypoxia tolerance relies primarily on Hif-2alpha and was not observed in heterozygous Phd2-deficient or homozygous Phd3-deficient mice...
  5. Takeda K, Cowan A, Fong G. Essential role for prolyl hydroxylase domain protein 2 in oxygen homeostasis of the adult vascular system. Circulation. 2007;116:774-81 pubmed
    Prolyl hydroxylase domain (PHD) proteins, including PHD1, PHD2, and PHD3, mediate oxygen-dependent degradation of hypoxia-inducible factor (HIF)-alpha subunits...
  6. Kiss J, Mollenhauer M, Walmsley S, Kirchberg J, Radhakrishnan P, Niemietz T, et al. Loss of the oxygen sensor PHD3 enhances the innate immune response to abdominal sepsis. J Immunol. 2012;189:1955-65 pubmed publisher
    ..The HIF prolyl hydroxylase enzymes PHD1, PHD2 and PHD3 regulate the mammalian adaptive response to hypoxia; however, their significance in the innate immune ..
  7. Sadiku P, Willson J, Dickinson R, Murphy F, Harris A, Lewis A, et al. Prolyl hydroxylase 2 inactivation enhances glycogen storage and promotes excessive neutrophilic responses. J Clin Invest. 2017;127:3407-3420 pubmed publisher
    ..Here, we have identified a critical role for the prolyl hydroxylase enzyme Phd2 in maintaining the balance between appropriate, predominantly neutrophil-mediated pathogen clearance and resolution ..
  8. Mamlouk S, Kalucka J, Singh R, Franke K, Muschter A, Langer A, et al. Loss of prolyl hydroxylase-2 in myeloid cells and T-lymphocytes impairs tumor development. Int J Cancer. 2014;134:849-58 pubmed publisher
    ..Recently, we demonstrated that the oxygen sensor HIF-prolyl hydroxylase-2 (PHD2) plays a detrimental role in tumor cells, stimulating systemic growth and metastasis in mice...
  9. Singh R, Franke K, Kalucka J, Mamlouk S, Muschter A, Gembarska A, et al. HIF prolyl hydroxylase 2 (PHD2) is a critical regulator of hematopoietic stem cell maintenance during steady-state and stress. Blood. 2013;121:5158-66 pubmed publisher
    ..Here, we describe a mouse line with conditional loss of HIF prolyl hydroxylase 2 (PHD2) in very early hematopoietic precursors that results in self-renewal of multipotent progenitors ..
  10. Urrutia A, Afzal A, Nelson J, Davidoff O, Gross K, Haase V. Prolyl-4-hydroxylase 2 and 3 coregulate murine erythropoietin in brain pericytes. Blood. 2016;128:2550-2560 pubmed
    ..We furthermore determined that Epo transcription in brain pericytes was HIF-2 dependent and cocontrolled by PHD2 and PHD3, oxygen- and 2-oxoglutarate-dependent prolyl-4-hydroxylases that regulate HIF activity...
  11. Clever D, Roychoudhuri R, Constantinides M, Askenase M, Sukumar M, Klebanoff C, et al. Oxygen Sensing by T Cells Establishes an Immunologically Tolerant Metastatic Niche. Cell. 2016;166:1117-1131.e14 pubmed publisher
    ..Collectively, PHD proteins function in T cells to coordinate distinct immunoregulatory programs within the lung that are permissive to cancer metastasis. PAPERCLIP. ..
  12. Wu S, Zhang J, Huang C, Jia H, Wang Y, Xu Z, et al. Prolyl hydroxylase domain-2 silencing induced by hydrodynamic limb vein injection enhances vascular regeneration in critical limb ischemia mice through activation of multiple genes. Curr Gene Ther. 2015;15:313-25 pubmed
    ..injection, the hydrodynamic limb vein (HLV) injection of naked short-hairpin RNA expression plasmid targeting PHD2 (shPHD2) into critical himblimb ischemia mice could increase not only the expressions of HIF-dependent and HIF-..
  13. Rankin E, Wu C, Khatri R, Wilson T, Andersen R, Araldi E, et al. The HIF signaling pathway in osteoblasts directly modulates erythropoiesis through the production of EPO. Cell. 2012;149:63-74 pubmed publisher
    ..Furthermore, these studies demonstrate a molecular role for osteoblastic PHD/VHL/HIF signaling that can be targeted to elevate both HSCs and erythroid progenitors in the local hematopoietic microenvironment. ..
  14. Taniguchi C, Miao Y, Diep A, Wu C, Rankin E, Atwood T, et al. PHD inhibition mitigates and protects against radiation-induced gastrointestinal toxicity via HIF2. Sci Transl Med. 2014;6:236ra64 pubmed publisher
    ..Thus, prolyl hydroxylase inhibition represents a treatment strategy to protect against and mitigate GI toxicity from both therapeutic radiation and potentially lethal radiation exposures. ..
  15. Jiao X, Xu X, Fang Y, Zhang H, Liang M, Teng J, et al. miR-21 contributes to renal protection by targeting prolyl hydroxylase domain protein 2 in delayed ischaemic preconditioning. Nephrology (Carlton). 2017;22:366-373 pubmed publisher
    ..Hypoxic induction of HIF-1? is mediated by inhibition of prolyl hydroxylase domain protein 2 (PHD2) .We hypothesized that miR-21 regulated HIF-1? by targeting PHD2 in the renal IPC...
  16. Terkhorn S, Bohensky J, Shapiro I, Koyama E, Srinivas V. Expression of HIF prolyl hydroxylase isozymes in growth plate chondrocytes: relationship between maturation and apoptotic sensitivity. J Cell Physiol. 2007;210:257-65 pubmed
    ..This loss of protective activity together with the changes mediated by HIF would be expected to generate conditions that would favor the induction of chondrocyte apoptosis. ..
  17. Aggarwal S, Gheware A, Agrawal A, Ghosh S, Prasher B, Mukerji M. Combined genetic effects of EGLN1 and VWF modulate thrombotic outcome in hypoxia revealed by Ayurgenomics approach. J Transl Med. 2015;13:184 pubmed publisher
    ..Our earlier genetic study has revealed differences in EGLN1, key modulator of hypoxia axis between Prakriti types...
  18. 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...
  19. Kapitsinou P, Sano H, Michael M, Kobayashi H, Davidoff O, Bian A, et al. Endothelial HIF-2 mediates protection and recovery from ischemic kidney injury. J Clin Invest. 2014;124:2396-409 pubmed publisher
    ..Taken together, our data indicate that endothelial HIF-2 protects from hypoxia-induced renal damage and represents a potential therapeutic target for renoprotection and prevention of fibrosis following acute ischemic injury. ..
  20. Wang S, Zeng H, Xie X, Tao Y, He X, Roman R, et al. Loss of prolyl hydroxylase domain protein 2 in vascular endothelium increases pericyte coverage and promotes pulmonary arterial remodeling. Oncotarget. 2016;7:58848-58861 pubmed publisher
    ..The present study examined the role of endothelial cell specific prolyl hydroxylase-2 (PHD2) in the development of PAH and pulmonary vascular remodeling...
  21. Ko S, Nauta A, Morrison S, Hu M, Zimmermann A, Chung M, et al. PHD-2 Suppression in Mesenchymal Stromal Cells Enhances Wound Healing. Plast Reconstr Surg. 2018;141:55e-67e pubmed publisher
    ..This effect appears to be mediated by overexpression of HIF family transcription factors and up-regulation of multiple downstream angiogenic factors. ..
  22. Moschella M, Menzies K, Tsao L, Lieb M, Kohtz J, Kohtz D, et al. SM-20 is a novel growth factor-responsive gene regulated during skeletal muscle development and differentiation. Gene Expr. 1999;8:59-66 pubmed
    ..SM-20 thus represents a novel intracellular protein that is regulated during skeletal muscle differentiation and development. ..
  23. Scholz C, Cavadas M, Tambuwala M, Hams E, Rodriguez J, von Kriegsheim A, et al. Regulation of IL-1?-induced NF-?B by hydroxylases links key hypoxic and inflammatory signaling pathways. Proc Natl Acad Sci U S A. 2013;110:18490-5 pubmed publisher
    ..Thus, we hypothesize that hydroxylases regulate IL-1? signaling and subsequent inflammatory gene expression. Furthermore, hydroxylase inhibition represents a unique approach to the inhibition of IL-1?-dependent inflammatory signaling. ..
  24. Segura I, Lange C, Knevels E, Moskalyuk A, Pulizzi R, Eelen G, et al. The Oxygen Sensor PHD2 Controls Dendritic Spines and Synapses via Modification of Filamin A. Cell Rep. 2016;14:2653-67 pubmed publisher
    ..that hypoxia, chemical inhibition of the oxygen-sensing prolyl hydroxylase domain proteins (PHDs), and silencing of Phd2 induce immature filopodium-like dendritic protrusions, promote spine regression, reduce synaptic density, and ..
  25. Heindryckx F, Kuchnio A, Casteleyn C, Coulon S, Olievier K, Colle I, et al. Effect of prolyl hydroxylase domain-2 haplodeficiency on the hepatocarcinogenesis in mice. J Hepatol. 2012;57:61-8 pubmed publisher
    ..Furthermore, PHD2 deficiency and the accompanying continuous HIF activation, selected for a more metastatic tumor phenotype...
  26. Van Welden S, De Vos M, Wielockx B, Tavernier S, Dullaers M, Neyt S, et al. Haematopoietic prolyl hydroxylase-1 deficiency promotes M2 macrophage polarization and is both necessary and sufficient to protect against experimental colitis. J Pathol. 2017;241:547-558 pubmed publisher
    ..epithelial erosions, immune cell infiltration, and colonic microvascular dysfunction, whereas the response of Phd2f/+ Tie2:cre and Phd3f/f Tie2:cre mice to DSS was similar to that of their ..
  27. Chen R, Nagel S, Papadakis M, Bishop T, Pollard P, Ratcliffe P, et al. Roles of individual prolyl-4-hydroxylase isoforms in the first 24 hours following transient focal cerebral ischaemia: insights from genetically modified mice. J Physiol. 2012;590:4079-91 pubmed publisher
    ..Male, 8- to 12-week old PHD1?/?, PHD2+/? and PHD3?/? mice and their wild-type (WT) littermate were subjected to 45 min of middle cerebral artery ..
  28. Zeng H, Chen J. Conditional knockout of prolyl hydroxylase domain protein 2 attenuates high fat-diet-induced cardiac dysfunction in mice. PLoS ONE. 2014;9:e115974 pubmed publisher
    ..This study was designed to investigate the direct role of PHD2 in high fat-diet (HFD)-induced cardiac dysfunction...
  29. Nytko K, Maeda N, Schlafli P, Spielmann P, Wenger R, Stiehl D. Vitamin C is dispensable for oxygen sensing in vivo. Blood. 2011;117:5485-93 pubmed publisher
    ..A Cys201Ser mutation in PHD2 increased basal hydroxylation rates and conferred resistance to oxidative damage in vitro, suggesting that this ..
  30. 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 ..
  31. Xie L, Pi X, Townley Tilson W, Li N, Wehrens X, Entman M, et al. PHD2/3-dependent hydroxylation tunes cardiac response to β-adrenergic stress via phospholamban. J Clin Invest. 2015;125:2759-71 pubmed publisher
    ..Both PHD2 and PHD3 are highly expressed in the heart, yet their functional roles in modulating contractile function remain ..
  32. Shin J, Nunomiya A, Kitajima Y, Dan T, Miyata T, Nagatomi R. Prolyl hydroxylase domain 2 deficiency promotes skeletal muscle fiber-type transition via a calcineurin/NFATc1-dependent pathway. Skelet Muscle. 2016;6:5 pubmed publisher
    ..The purpose of this study was therefore to examine the effect of HIF-1α stabilization in PHD2 conditional knockout mouse on skeletal muscle fiber-type transition and to elucidate the involvement of calcineurin ..
  33. Murphy D, Xu J, Waller S. Transgenic studies in rats and mice on the osmotic regulation of vasopressin gene expression. Exp Physiol. 2000;85 Spec No:211S-222S pubmed
  34. Ikeda J, Ichiki T, Matsuura H, Inoue E, Kishimoto J, Watanabe A, et al. Deletion of phd2 in myeloid lineage attenuates hypertensive cardiovascular remodeling. J Am Heart Assoc. 2013;2:e000178 pubmed publisher
    ..We recently reported that inhibition of prolyl hydroxylase domain protein 2 (PHD2), which hydroxylates the proline residues of hypoxia-inducible factor-? (HIF-?) and thereby induces HIF-? ..
  35. Minamishima Y, Moslehi J, Bardeesy N, Cullen D, Bronson R, Kaelin W. Somatic inactivation of the PHD2 prolyl hydroxylase causes polycythemia and congestive heart failure. Blood. 2008;111:3236-44 pubmed
    ..PHD1, PHD2, and PHD3) capable of catalyzing this reaction have been identified, although PHD2 (also called Egln1) appears to be the primary HIF prolyl hydroxylase in cell culture experiments...
  36. Querbes W, Bogorad R, Moslehi J, Wong J, Chan A, Bulgakova E, et al. Treatment of erythropoietin deficiency in mice with systemically administered siRNA. Blood. 2012;120:1916-22 pubmed publisher
  37. Bishop T, Talbot N, Turner P, Nicholls L, Pascual A, Hodson E, et al. Carotid body hyperplasia and enhanced ventilatory responses to hypoxia in mice with heterozygous deficiency of PHD2. J Physiol. 2013;591:3565-77 pubmed publisher
    ..8 ± 0.3 versus 4.1 ± 0.7 ml min(-1) g(-1) in controls; P < 0.01). HVR was similarly exaggerated in PHD2(+/-) animals compared to littermate controls (8.4 ± 0.7 versus 5.0 ± 0.8 ml min(-1) g(-1); P < 0.01)...
  38. Suhara T, Hishiki T, Kasahara M, Hayakawa N, Oyaizu T, Nakanishi T, et al. Inhibition of the oxygen sensor PHD2 in the liver improves survival in lactic acidosis by activating the Cori cycle. Proc Natl Acad Sci U S A. 2015;112:11642-7 pubmed publisher
    Loss of prolyl hydroxylase 2 (PHD2) activates the hypoxia-inducible factor-dependent hypoxic response, including anaerobic glycolysis, which causes large amounts of lactate to be released from cells into the circulation...
  39. Kapitsinou P, Jaffe J, Michael M, Swan C, Duffy K, Erickson Miller C, et al. Preischemic targeting of HIF prolyl hydroxylation inhibits fibrosis associated with acute kidney injury. Am J Physiol Renal Physiol. 2012;302:F1172-9 pubmed publisher
    ..Therefore, preischemic targeting of the PHD/HIF pathway represents an effective therapeutic strategy for the prevention of CKD resulting from AKI, and it warrants further investigation in clinical trials. ..
  40. 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...
  41. Gomes A, Price N, Ling A, Moslehi J, Montgomery M, Rajman L, et al. Declining NAD(+) induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging. Cell. 2013;155:1624-38 pubmed publisher
    ..Thus, a pseudohypoxic state that disrupts PGC-1?/?-independent nuclear-mitochondrial communication contributes to the decline in mitochondrial function with age, a process that is apparently reversible. ..
  42. Thienpont B, Steinbacher J, Zhao H, D Anna F, Kuchnio A, Ploumakis A, et al. Tumour hypoxia causes DNA hypermethylation by reducing TET activity. Nature. 2016;537:63-68 pubmed publisher
    ..Accordingly, increased hypoxia in mouse breast tumours increases hypermethylation, while restoration of tumour oxygenation abrogates this effect. Tumour hypoxia therefore acts as a novel regulator of DNA methylation. ..
  43. Kobayashi H, Liu Q, Binns T, Urrutia A, Davidoff O, Kapitsinou P, et al. Distinct subpopulations of FOXD1 stroma-derived cells regulate renal erythropoietin. J Clin Invest. 2016;126:1926-38 pubmed publisher
    ..EPO synthesis in the kidney and liver and is regulated by prolyl-4-hydroxylase domain (PHD) dioxygenases PHD1, PHD2, and PHD3, which function as cellular oxygen sensors...
  44. Kalucka J, Ettinger A, Franke K, Mamlouk S, Singh R, Farhat K, et al. Loss of epithelial hypoxia-inducible factor prolyl hydroxylase 2 accelerates skin wound healing in mice. Mol Cell Biol. 2013;33:3426-38 pubmed publisher
    ..Hypoxia-inducible factor (HIF) prolyl hydroxylase 2 (PHD2) serves as a crucial oxygen sensor and may therefore play an important role during reepithelialization...
  45. Wang S, Zeng H, Chen S, Zhou L, Xie X, He X, et al. Ablation of endothelial prolyl hydroxylase domain protein-2 promotes renal vascular remodelling and fibrosis in mice. J Cell Mol Med. 2017;21:1967-1978 pubmed publisher
    ..Using an endothelial-specific prolyl hydroxylase domain protein-2 (PHD2) knockout (PHD2EC KO) mouse model, this study investigates the regulatory role of endothelial HIF-? ..
  46. Nunomiya A, Shin J, Kitajima Y, Dan T, Miyata T, Nagatomi R. Activation of the hypoxia-inducible factor pathway induced by prolyl hydroxylase domain 2 deficiency enhances the effect of running training in mice. Acta Physiol (Oxf). 2017;220:99-112 pubmed publisher
    ..of HIF activation to running training without exposure to atmospheric hypoxia, we used prolyl hydroxylase domain 2 (PHD2) conditional knockout mice (cKO), which exhibit HIF activation independent of oxygen concentration, and we examined ..
  47. Olenchock B, Moslehi J, Baik A, Davidson S, Williams J, Gibson W, et al. EGLN1 Inhibition and Rerouting of α-Ketoglutarate Suffice for Remote Ischemic Protection. Cell. 2016;164:884-95 pubmed publisher
    ..We created mouse models to ask if inhibition of the alpha-ketoglutarate (αKG)-dependent dioxygenase Egln1, which senses oxygen and regulates the hypoxia-inducible factor (HIF) transcription factor, could suffice to ..
  48. Quaegebeur A, Segura I, Schmieder R, Verdegem D, Decimo I, Bifari F, et al. Deletion or Inhibition of the Oxygen Sensor PHD1 Protects against Ischemic Stroke via Reprogramming of Neuronal Metabolism. Cell Metab. 2016;23:280-91 pubmed publisher
    ..These data identify PHD1 as a regulator of neuronal metabolism and a potential therapeutic target in ischemic stroke. ..
  49. Rahtu Korpela L, Karsikas S, Horkko S, Blanco Sequeiros R, Lammentausta E, Mäkelä K, et al. HIF prolyl 4-hydroxylase-2 inhibition improves glucose and lipid metabolism and protects against obesity and metabolic dysfunction. Diabetes. 2014;63:3324-33 pubmed publisher
    ..HIF-P4H-2 inhibition may be a novel therapy that not only protects against the development of obesity and its consequences but also reverses these conditions. ..
  50. Guentsch A, Beneke A, Swain L, Farhat K, Nagarajan S, Wielockx B, et al. PHD2 Is a Regulator for Glycolytic Reprogramming in Macrophages. Mol Cell Biol. 2017;37: pubmed
    ..We hypothesized that macrophage metabolism and function can be controlled via manipulation of PHD2. We characterized the metabolic phenotypes of PHD2-deficient RAW cells and primary PHD2 knockout bone marrow-..
  51. Li X, Sutherland S, Takeda K, Fong G, Lee F. Integrity of the prolyl hydroxylase domain protein 2:erythropoietin pathway in aging mice. Blood Cells Mol Dis. 2010;45:9-19 pubmed publisher
    ..Recent studies have identified PHD2 as the critical PHD isoform regulating the EPO gene...
  52. Zhu K, Jiao H, Li S, Cao H, Galson D, Zhao Z, et al. ATF4 promotes bone angiogenesis by increasing VEGF expression and release in the bone environment. J Bone Miner Res. 2013;28:1870-1884 pubmed publisher
    ..Thus, ATF4 is a new key regulator of the HIF/VEGF axis in osteoblasts in response to hypoxia and of VEGF release from bone matrix, two critical steps for bone angiogenesis. ..
  53. Kapitsinou P, Rajendran G, Astleford L, Michael M, Schonfeld M, Fields T, et al. The Endothelial Prolyl-4-Hydroxylase Domain 2/Hypoxia-Inducible Factor 2 Axis Regulates Pulmonary Artery Pressure in Mice. Mol Cell Biol. 2016;36:1584-94 pubmed publisher
    ..HIFs are regulated in response to oxygen availability by prolyl-4-hydroxylase domain (PHD) proteins, with PHD2 being the main oxygen sensor that controls HIF activity under normoxia...
  54. Rahtu Korpela L, Määttä J, Dimova E, Hörkkö S, Gylling H, Walkinshaw G, et al. Hypoxia-Inducible Factor Prolyl 4-Hydroxylase-2 Inhibition Protects Against Development of Atherosclerosis. Arterioscler Thromb Vasc Biol. 2016;36:608-17 pubmed publisher
    ..HIF-P4H-2 (also known as PHD2 or EglN1) inhibition improves glucose and lipid metabolism and protects against obesity and metabolic dysfunction...
  55. Laitala A, Aro E, Walkinshaw G, Maki J, Rossi M, Heikkilä M, et al. Transmembrane prolyl 4-hydroxylase is a fourth prolyl 4-hydroxylase regulating EPO production and erythropoiesis. Blood. 2012;120:3336-44 pubmed publisher
    ..Our data thus indicate that P4H-TM plays a role in the regulation of EPO production, hepcidin expression, and erythropoiesis. ..
  56. Matsushima S, Kuroda J, Ago T, Zhai P, Ikeda Y, Oka S, et al. Broad suppression of NADPH oxidase activity exacerbates ischemia/reperfusion injury through inadvertent downregulation of hypoxia-inducible factor-1? and upregulation of peroxisome proliferator-activated receptor-?. Circ Res. 2013;112:1135-49 pubmed publisher
  57. Franke K, Kalucka J, Mamlouk S, Singh R, Muschter A, Weidemann A, et al. HIF-1? is a protective factor in conditional PHD2-deficient mice suffering from severe HIF-2?-induced excessive erythropoiesis. Blood. 2013;121:1436-45 pubmed publisher
    ..Here, we describe a novel mouse line with conditional PHD2 inactivation (cKO P2) in renal EPO producing cells, neurons, and astrocytes that displayed excessive erythrocytosis ..
  58. Leite De Oliveira R, Deschoemaeker S, Henze A, Debackere K, Finisguerra V, Takeda Y, et al. Gene-targeting of Phd2 improves tumor response to chemotherapy and prevents side-toxicity. Cancer Cell. 2012;22:263-77 pubmed publisher
    ..Prolyl hydroxylase domain protein 2 (PHD2) is an oxygen/redox-sensitive enzyme that induces cellular adaptations to stress conditions...
  59. Moslehi J, Minamishima Y, Shi J, Neuberg D, Charytan D, Padera R, et al. Loss of hypoxia-inducible factor prolyl hydroxylase activity in cardiomyocytes phenocopies ischemic cardiomyopathy. Circulation. 2010;122:1004-16 pubmed publisher
  60. Ozolins T, Fisher T, Nadeau D, Stock J, Klein A, Milici A, et al. Defects in embryonic development of EGLN1/PHD2 knockdown transgenic mice are associated with induction of Igfbp in the placenta. Biochem Biophys Res Commun. 2009;390:372-6 pubmed publisher
    ..Progeny with demonstrated EGLN1 inhibition had elevated EPO production and erythropoiesis in vivo...
  61. Duan L, Takeda K, Fong G. Prolyl hydroxylase domain protein 2 (PHD2) mediates oxygen-induced retinopathy in neonatal mice. Am J Pathol. 2011;178:1881-90 pubmed publisher
    ..Here we show that prolyl hydroxylase domain protein 2 (PHD2), an enzyme mostly responsible for oxygen-induced degradation of HIF-? proteins, plays a major role in oxygen-..
  62. Michailidou Z, Morton N, Moreno Navarrete J, West C, Stewart K, Fernández Real J, et al. Adipocyte pseudohypoxia suppresses lipolysis and facilitates benign adipose tissue expansion. Diabetes. 2015;64:733-45 pubmed publisher
    ..In this study, we demonstrate that adipose PHD2 inhibition plays a key role in the suppression of adipocyte lipolysis...
  63. Dai Z, Li M, Wharton J, Zhu M, Zhao Y. Prolyl-4 Hydroxylase 2 (PHD2) Deficiency in Endothelial Cells and Hematopoietic Cells Induces Obliterative Vascular Remodeling and Severe Pulmonary Arterial Hypertension in Mice and Humans Through Hypoxia-Inducible Factor-2?. Circulation. 2016;133:2447-58 pubmed publisher
    ..Mice with Tie2Cre-mediated disruption of Egln1 (encoding prolyl-4 hydroxylase 2 [PHD2]; Egln1(Tie2)) in endothelial cells and hematopoietic cells exhibited ..
  64. Takeda K, Duan L, Takeda H, Fong G. Improved vascular survival and growth in the mouse model of hindlimb ischemia by a remote signaling mechanism. Am J Pathol. 2014;184:686-96 pubmed publisher
    ..We generated mice that carry a keratinocyte-specific Phd2 knockout (kPhd2KO) and performed femoral artery ligation...
  65. Kerkela R, Karsikas S, Szabo Z, Serpi R, Magga J, Gao E, et al. Activation of hypoxia response in endothelial cells contributes to ischemic cardioprotection. Mol Cell Biol. 2013;33:3321-9 pubmed publisher
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    ..These results suggest that HIF activation is a viable approach to increase vascularity and bone formation following skeletal trauma. ..
  67. Myllymäki M, Määttä J, Dimova E, Izzi V, Väisänen T, Myllyharju J, et al. Notch Downregulation and Extramedullary Erythrocytosis in Hypoxia-Inducible Factor Prolyl 4-Hydroxylase 2-Deficient Mice. Mol Cell Biol. 2017;37: pubmed publisher
    ..Mutations in HIF prolyl 4-hydroxylase 2 (HIF-P4H-2) (PHD2/EGLN1), the major downregulator of HIF? subunits, are found in familiar erythrocytosis, and large-spectrum conditional ..
  68. Lieb M, Menzies K, Moschella M, Ni R, Taubman M. Mammalian EGLN genes have distinct patterns of mRNA expression and regulation. Biochem Cell Biol. 2002;80:421-6 pubmed
    The mammalian EGLN family contains three paralagous genes (EGLN1, EGLN2, and EGLN3) encoding prolyl hydroxylase isoforms that mediate the oxygen-dependent targeting of the transcription factor hypoxia inducible factor alpha to the ..
  69. Kuchnio A, Moens S, Bruning U, Kuchnio K, Cruys B, Thienpont B, et al. The Cancer Cell Oxygen Sensor PHD2 Promotes Metastasis via Activation of Cancer-Associated Fibroblasts. Cell Rep. 2015;12:992-1005 pubmed publisher
    Several questions about the role of the oxygen sensor prolyl-hydroxylase 2 (PHD2) in cancer have not been addressed. First, the role of PHD2 in metastasis has not been studied in a spontaneous tumor model...
  70. 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 ..
  71. Manresa M, Tambuwala M, Radhakrishnan P, Harnoss J, Brown E, Cavadas M, et al. Hydroxylase inhibition regulates inflammation-induced intestinal fibrosis through the suppression of ERK-mediated TGF-?1 signaling. [corrected]. Am J Physiol Gastrointest Liver Physiol. 2016;311:G1076-G1090 pubmed publisher
    ..We hypothesize that in addition to previously reported immunosupressive effects, hydroxylase inhibitors independently suppress profibrotic pathways. ..
  72. Zhu K, Song P, Lai Y, Liu C, Xiao G. Prolyl hydroxylase domain proteins regulate bone mass through their expression in osteoblasts. Gene. 2016;594:125-130 pubmed publisher
    ..Here we deleted the expression of genes encoding PHD1, PHD2, and PHD3 in osteoblasts in mice by breeding the floxed Phd1-3 mice with Col1a1-Cre transgenic mice...
  73. Cheng S, Xing W, Pourteymoor S, Schulte J, Mohan S. Conditional Deletion of Prolyl Hydroxylase Domain-Containing Protein 2 (Phd2) Gene Reveals Its Essential Role in Chondrocyte Function and Endochondral Bone Formation. Endocrinology. 2016;157:127-40 pubmed publisher
    ..HIF proteins are tightly regulated by prolyl hydroxylase domain-containing protein 2 (Phd2)-mediated proteosomal degradation...
  74. Klotzsche von Ameln A, Muschter A, Heimesaat M, Breier G, Wielockx B. HIF prolyl hydroxylase-2 inhibition diminishes tumor growth through matrix metalloproteinase-induced TGF? activation. Cancer Biol Ther. 2012;13:216-23 pubmed publisher
    ..Recently we have shown that inhibition of the oxygen sensor PHD2 in tumor cells blocks tumor growth due to the anti-proliferative activity of TGF?...
  75. Minamishima Y, Moslehi J, Padera R, Bronson R, Liao R, Kaelin W. A feedback loop involving the Phd3 prolyl hydroxylase tunes the mammalian hypoxic response in vivo. Mol Cell Biol. 2009;29:5729-41 pubmed publisher
    ..Among the three Phd family members, Phd2 appears to be the primary HIF prolyl hydroxylase...
  76. Zimmermann A, Morrison S, Hu M, Li S, Nauta A, Sorkin M, et al. Epidermal or dermal specific knockout of PHD-2 enhances wound healing and minimizes ischemic injury. PLoS ONE. 2014;9:e93373 pubmed publisher
    ..Further exploration shows PHD-2 KO increases cellular levels of HIF-1? and this increase leads to the transcription of downstream angiogenic factors such as VEGF. ..
  77. Stegen S, van Gastel N, Eelen G, Ghesquière B, D Anna F, Thienpont B, et al. HIF-1α Promotes Glutamine-Mediated Redox Homeostasis and Glycogen-Dependent Bioenergetics to Support Postimplantation Bone Cell Survival. Cell Metab. 2016;23:265-79 pubmed publisher
    ..and ischemic environment of the bone defect site by deleting prolyl hydroxylase domain-containing protein 2 (PHD2), resulting in hypoxia-inducible factor 1 alpha (HIF-1α) stabilization...