PHD2: from hypoxia regulation to disease progression

References

• Wenger RH, Kurtcuoglu V, Scholz CC, Marti HH, Hoogewijs D. Frequently asked questions in hypoxia research. J Hypoxia. 2015;3:35–43.
   PubMed Web of Science ®Google Scholar
• Semenza GL, Wang GL. A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Mol Cell Biol. 1992;12(12):5447–5454.
   PubMed Web of Science ®Google Scholar
• Wang GL, Jiang BH, Rue EA, Semenza GL. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci U S A. 1995;92(12):5510–5514.
   PubMed Web of Science ®Google Scholar
• Semenza GL, Jiang BH, Leung SW, et al. Hypoxia response elements in the aldolase A, enolase 1, and lactate dehydrogenase A gene promoters contain essential binding sites for hypoxia-inducible factor 1. J Biol Chem. 1996;271(51):32529–32537.
   PubMed Web of Science ®Google Scholar
• Mole DR, Blancher C, Copley RR, et al. Genome-wide association of hypoxia-inducible factor (HIF)-1α and HIF-2α DNA binding with expression profiling of hypoxia-inducible transcripts. J Biol Chem. 2009;284(25):16767–16775.
   PubMed Web of Science ®Google Scholar
• Kim JW, Tchernyshyov I, Semenza GL, Dang CV. HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab. 2006;3(3):177–185.
   PubMed Web of Science ®Google Scholar
• Wiesener MS, Jürgensen JS, Rosenberger C, et al. Widespread hypoxia-inducible expression of HIF-2α in distinct cell populations of different organs. FASEB J Off Publ Fed Am Soc Exp Biol. 2003;17(2):271–273.
   PubMedGoogle Scholar
• Hu CJ, Wang LY, Chodosh LA, Keith B, Simon MC. Differential roles of hypoxia-inducible factor 1α (HIF-1α) and HIF-2α in hypoxic gene regulation. Mol Cell Biol. 2003;23(24):9361–9374.
   PubMed Web of Science ®Google Scholar
• Ratcliffe PJ. HIF-1 and HIF-2: working alone or together in hypoxia? J Clin Invest. 2007;117(4):862–865.
   PubMed Web of Science ®Google Scholar
• Semenza GL. Oxygen sensing, homeostasis, and disease. N Engl J Med. 2011;365(6):537–547.
   PubMed Web of Science ®Google Scholar
• Mahon PC, Hirota K, Semenza GL. FIH-1: a novel protein that interacts with HIF-1α and VHL to mediate repression of HIF-1 transcriptional activity. Genes Dev. 2001;15(20):2675–2686.
   PubMed Web of Science ®Google Scholar
• Bruick RK, McKnight SL. A conserved family of prolyl-4-hydroxylases that modify HIF. Science. 2001;294(5545):1337–1340.
   PubMed Web of Science ®Google Scholar
• Pereira T, Zheng X, Ruas JL, Tanimoto K, Poellinger L. Identification of residues critical for regulation of protein stability and the transactivation function of the hypoxia-inducible factor-1α by the von Hippel-Lindau tumor suppressor gene product. J Biol Chem. 2003;278(9):6816–6823.
   PubMed Web of Science ®Google Scholar
• Hirsilä M, Koivunen P, Günzler V, Kivirikko KI, Myllyharju J. Characterization of the human prolyl 4-hydroxylases that modify the hypoxia-inducible factor. J Biol Chem. 2003;278(33): 30772–30780.
   PubMed Web of Science ®Google Scholar
• Min JH, Yang H, Ivan M, Gertler F, Kaelin WG Jr, Pavletich NP. Structure of an HIF-1α-pVHL complex: hydroxyproline recognition in signaling. Science. 2002;296(5574):1886–1889.
   PubMed Web of Science ®Google Scholar
• Ivan M, Kondo K, Yang H, et al. HIFα targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science. 2001;292(5516):464–468.
   PubMed Web of Science ®Google Scholar
• Jaakkola P, Mole DR, Tian YM, et al. Targeting of HIF-α to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science. 2001;292(5516):468–472.
   PubMed Web of Science ®Google Scholar
• Maxwell PH, Wiesener MS, Chang GW, et al. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature. 1999;399(6733):271–275.
   PubMed Web of Science ®Google Scholar
• Epstein AC, Gleadle JM, McNeill LA, et al. C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell. 2001;107(1):43–54.
   PubMed Web of Science ®Google Scholar
• Schödel J, Oikonomopoulos S, Ragoussis J, Pugh CW, Ratcliffe PJ, Mole DR. High-resolution genome-wide mapping of HIF-binding sites by ChIP-seq. Blood. 2011;117(23):e207–e217.
   PubMed Web of Science ®Google Scholar
• Semenza GL. Oxygen sensing, hypoxia-inducible factors, and disease pathophysiology. Annu Rev Pathol Mech Dis. 2014;9(1):47–71.
   PubMedGoogle Scholar
• Lee KE, Simon MC. SnapShot: hypoxia-inducible factors. Cell. 2015;163(5):1288.e1–1288.e1.
   Web of Science ®Google Scholar
• Schofield CJ, Ratcliffe PJ. Oxygen sensing by HIF hydroxylases. Nat Rev Mol Cell Biol. 2004;5(5):343–354.
   PubMed Web of Science ®Google Scholar
• Schofield CJ, Zhang Z. Structural and mechanistic studies on 2-oxoglutarate-dependent oxygenases and related enzymes. Curr Opin Struct Biol. 1999;9(6):722–731.
   PubMed Web of Science ®Google Scholar
• Rabinowitz MH. Inhibition of hypoxia-inducible factor prolyl hydroxylase domain oxygen sensors: tricking the body into mounting orchestrated survival and repair responses. J Med Chem. 2013;56(23):9369–9402.
   PubMed Web of Science ®Google Scholar
• Jokilehto T, Jaakkola PM. The role of HIF prolyl hydroxylases in tumour growth. J Cell Mol Med. 2010;14(4):758–770.
   PubMed Web of Science ®Google Scholar
• Metzen E, Berchner-Pfannschmidt U, Stengel P, et al. Intracellular localisation of human HIF-1α hydroxylases: implications for oxygen sensing. J Cell Sci. 2003;116(Pt 7):1319–1326.
   PubMed Web of Science ®Google Scholar
• Huang J, Zhao Q, Mooney SM, Lee FS. Sequence determinants in hypoxia-inducible factor-1α for hydroxylation by the prolyl hydroxylases PHD1, PHD2, and PHD3. J Biol Chem. 2002;277(42): 39792–39800.
   PubMed Web of Science ®Google Scholar
• Steinhoff A, Pientka FK, Mockel S, 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(4):705–711.
   PubMed Web of Science ®Google Scholar
• Yasumoto K, Kowata Y, Yoshida A, Torii S, Sogawa K. Role of the intracellular localization of HIF-prolyl hydroxylases. Biochim Biophys Acta. 2009;1793(5):792–797.
   PubMed Web of Science ®Google Scholar
• Appelhoff RJ, Tian YM, Raval RR, et al. Differential function of the prolyl hydroxylases PHD1, PHD2, and PHD3 in the regulation of hypoxia-inducible factor. J Biol Chem. 2004;279(37):38458–38465.
   PubMed Web of Science ®Google Scholar
• Zhang Q, Gu J, Li L, et al. Control of cyclin D1 and breast tumorigenesis by the EglN2 prolyl hydroxylase. Cancer Cell. 2009;16(5):413–424.
   PubMed Web of Science ®Google Scholar
• Katschinski DM. In vivo functions of the prolyl-4-hydroxylase domain oxygen sensors: direct route to the treatment of anaemia and the protection of ischaemic tissues. Acta Physiol (Oxf). 2009;195(4): 407–414.
   PubMed Web of Science ®Google Scholar
• Mollenhauer M, Kiss J, Dudda J, et al. Deficiency of the oxygen sensor PHD1 augments liver regeneration after partial hepatectomy. Langenbecks Arch Surg. 2012;397(8):1313–1322.
   PubMed Web of Science ®Google Scholar
• Tambuwala MM, Cummins EP, Lenihan CR, et al. Loss of prolyl hydroxylase-1 protects against colitis through reduced epithelial cell apoptosis and increased barrier function. Gastroenterology. 2010;139(6):2093–2101.
   PubMed Web of Science ®Google Scholar
• Minamishima YA, Moslehi J, Bardeesy N, Cullen D, Bronson RT, Kaelin WG Jr. Somatic inactivation of the PHD2 prolyl hydroxylase causes polycythemia and congestive heart failure. Blood. 2008;111(6):3236–3244.
   PubMed Web of Science ®Google Scholar
• Singh RP, Franke K, Kalucka J, et al. HIF prolyl hydroxylase 2 (PHD2) is a critical regulator of hematopoietic stem cell maintenance during steady-state and stress. Blood. 2013;121(26):5158–5166.
   PubMed Web of Science ®Google Scholar
• Takeda K, Cowan A, Fong GH. Essential role for prolyl hydroxylase domain protein 2 in oxygen homeostasis of the adult vascular system. Circulation. 2007;116(7):774–781.
   PubMed Web of Science ®Google Scholar
• Takeda K, Aguila HL, Parikh NS, et al. Regulation of adult erythropoiesis by prolyl hydroxylase domain proteins. Blood. 2008;111(6):3229–3235.
   PubMed Web of Science ®Google Scholar
• Chan MC, Holt-Martyn JP, Schofield CJ, Ratcliffe PJ. Pharmacological targeting of the HIF hydroxylases – a new field in medicine development. Mol Aspects Med. 2016;47–48:54–75.
   PubMed Web of Science ®Google Scholar
• Selak MA, Armour SM, MacKenzie ED, et al. Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-α prolyl hydroxylase. Cancer Cell. 2005;7(1):77–85.
   PubMed Web of Science ®Google Scholar
• Wong BW, Kuchnio A, Bruning U, Carmeliet P. Emerging novel functions of the oxygen-sensing prolyl hydroxylase domain enzymes. Trends Biochem Sci. 2013;38(1):3–11.
   PubMed Web of Science ®Google Scholar
• Li Y, Zhang D, Wang X, et al. Hypoxia-inducible miR-182 enhances HIF1α signaling via targeting PHD2 and FIH1 in prostate cancer. Sci Rep. 2015;5:12495.
   PubMed Web of Science ®Google Scholar
• Barth S, Edlich F, Berchner-Pfannschmidt U, et al. Hypoxia-inducible factor prolyl-4-hydroxylase PHD2 protein abundance depends on integral membrane anchoring of FKBP38. J Biol Chem. 2009;284(34):23046–23058.
   PubMed Web of Science ®Google Scholar
• Aprelikova O, Pandolfi S, Tackett S, et al. Melanoma antigen-11 inhibits the hypoxia-inducible factor prolyl hydroxylase 2 and activates hypoxic response. Cancer Res. 2009;69(2):616–624.
   PubMed Web of Science ®Google Scholar
• D’Angelo G, Duplan E, Boyer N, Vigne P, Frelin C. Hypoxia up-regulates prolyl hydroxylase activity: a feedback mechanism that limits HIF-1 responses during reoxygenation. J Biol Chem. 2003;278(40):38183–38187.
   PubMed Web of Science ®Google Scholar
• EGLN1 (PNAS-118) Result Summary | BioGRID. Available from: http://thebiogrid.org/120060/summary/homo-sapiens/egln1.html. Accessed March 3, 2016.
   Google Scholar
• Baek JH, Mahon PC, Oh J, et al. OS-9 interacts with hypoxia-inducible factor 1α and prolyl hydroxylases to promote oxygen-dependent degradation of HIF-1α. Mol Cell. 2005;17(4):503–512.
   PubMed Web of Science ®Google Scholar
• Foxler DE, Bridge KS, James V, et al. The LIMD1 protein bridges an association between the prolyl hydroxylases and VHL to repress HIF-1 activity. Nat Cell Biol. 2012;14(2):201–208.
   PubMed Web of Science ®Google Scholar
• Zhang CS, Liu Q, Li M, et al. RHOBTB3 promotes proteasomal degradation of HIFα through facilitating hydroxylation and suppresses the Warburg effect. Cell Res. 2015;25(9):1025–1042.
   PubMed Web of Science ®Google Scholar
• Park MH, Choi KY, Jung Y, Min DS. Phospholipase D1 protein coordinates dynamic assembly of HIF-1α-PHD-VHL to regulate HIF-1α stability. Oncotarget. 2014;5(23):11857–11872.
   PubMedGoogle Scholar
• Wong W, Goehring AS, Kapiloff MS, Langeberg LK, Scott JD. mAKAP compartmentalizes oxygen-dependent control of HIF-1α. Sci Signal. 2008;1(51):ra18.
   Web of Science ®Google Scholar
• Choi YK, Kim JH, Kim WJ, et al. AKAP12 regulates human blood-retinal barrier formation by downregulation of hypoxia-inducible factor-1α. J Neurosci. 2007;27(16):4472–4481.
   PubMed Web of Science ®Google Scholar
• Lee SH, Bae SC, Kim KW, Lee YM. RUNX3 inhibits hypoxia-inducible factor-1α protein stability by interacting with prolyl hydroxylases in gastric cancer cells. Oncogene. 2014;33(11): 1458–1467.
   PubMed Web of Science ®Google Scholar
• Colla S, Tagliaferri S, Morandi F, et al. The new tumor-suppressor gene inhibitor of growth family member 4 (ING4) regulates the production of proangiogenic molecules by myeloma cells and suppresses hypoxia-inducible factor-1α (HIF-1α) activity: involvement in myeloma-induced angiogenesi. Blood. 2007;110(13):4464–4475.
   PubMed Web of Science ®Google Scholar
• Song D, Li LS, Heaton-Johnson KJ, Arsenault PR, Master SR, Lee FS. 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(14):9662–9674.
   PubMed Web of Science ®Google Scholar
• Cummins EP, Berra E, Comerford KM, et al. Prolyl hydroxylase-1 negatively regulates IκB kinase-β, giving insight into hypoxia-induced NFκB activity. Proc Natl Acad Sci U S A. 2006;103(48):18154–18159.
   PubMed Web of Science ®Google Scholar
• Chan DA, Kawahara TLA, Sutphin PD, Chang HY, Chi JT, Giaccia AJ. Tumor vasculature is regulated by PHD2-mediated angiogenesis and bone marrow-derived cell recruitment. Cancer Cell. 2009;15(6): 527–538.
   PubMed Web of Science ®Google Scholar
• Romero-Ruiz A, Bautista L, Navarro V, et al. Prolyl hydroxylase-dependent modulation of eukaryotic elongation factor 2 activity and protein translation under acute hypoxia. J Biol Chem. 2012;287(12): 9651–9658.
   PubMed Web of Science ®Google Scholar
• Moore CEJ, Mikolajek H, Regufe da Mota S, et al. Elongation factor 2 kinase is regulated by proline hydroxylation and protects cells during hypoxia. Mol Cell Biol. 2015;35(10):1788–1804.
   PubMed Web of Science ®Google Scholar
• Huo Z, Ye JC, Chen J, 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(1):73–79.
   PubMed Web of Science ®Google Scholar
• Xie L, Pi X, Townley-Tilson WHD, et al. PHD2/3-dependent hydroxylation tunes cardiac response to β-adrenergic stress via phospholamban. J Clin Invest. 2015;125(7):2759–2771.
   PubMed Web of Science ®Google Scholar
• Lee DC, Sohn HA, Park ZY, et al. A lactate-induced response to hypoxia. Cell. 2015;161(3):595–609.
   PubMed Web of Science ®Google Scholar
• Kuznetsova AV, Meller J, Schnell PO, et al. von Hippel-Lindau protein binds hyperphosphorylated large subunit of RNA polymerase II through a proline hydroxylation motif and targets it for ubiquitination. Proc Natl Acad Sci U S A. 2003;100(5):2706–2711.
   PubMed Web of Science ®Google Scholar
• Mikhaylova O, Ignacak ML, Barankiewicz TJ, 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(8):2701–2717.
   PubMed Web of Science ®Google Scholar
• Yi Y, Mikhaylova O, Mamedova A, et al. von Hippel-Lindau-dependent patterns of RNA polymerase II hydroxylation in human renal clear cell carcinomas. Clin Cancer Res. 2010;16(21):5142–5152.
   PubMed Web of Science ®Google Scholar
• Franke K, Gassmann M, Wielockx B. Erythrocytosis: the HIF pathway in control. Blood. 2013;122(7):1122–1128.
   PubMed Web of Science ®Google Scholar
• Ikeda E. Cellular response to tissue hypoxia and its involvement in disease progression. Pathol Int. 2005;55(10):603–610.
   PubMed Web of Science ®Google Scholar
• Ebert BL, Bunn HF. Regulation of the erythropoietin gene. Blood. 1999;94(6):1864–1877.
   PubMed Web of Science ®Google Scholar
• Goldberg MA, Dunning SP, Bunn HF. Regulation of the erythropoietin gene: evidence that the oxygen sensor is a heme protein. Science. 1988;242(4884):1412–1415.
   PubMed Web of Science ®Google Scholar
• Kapitsinou PP, Liu Q, Unger TL, et al. Hepatic HIF-2 regulates erythropoietic responses to hypoxia in renal anemia. Blood. 2010;116(16):3039–3048.
   PubMed Web of Science ®Google Scholar
• Al-Sheikh M, Moradkhani K, Lopez M, Wajcman H, Prehu C. Disturbance in the HIF-1α pathway associated with erythrocytosis: further evidences brought by frameshift and nonsense mutations in the prolyl hydroxylase domain protein 2 (PHD2) gene. Blood Cells Mol Dis. 2008;40(2):160–165.
   PubMed Web of Science ®Google Scholar
• Ladroue C, Carcenac R, Leporrier M, et al. PHD2 mutation and congenital erythrocytosis with paraganglioma. N Engl J Med. 2008;359(25):2685–2692.
   PubMed Web of Science ®Google Scholar
• Percy MJ, Zhao Q, Flores A, 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(3):654–659.
   PubMed Web of Science ®Google Scholar
• Mazzone M, Dettori D, Leite de Oliveira R, et al. Heterozygous deficiency of PHD2 restores tumor oxygenation and inhibits metastasis via endothelial normalization. Cell. 2009;136(5):839–851.
   PubMed Web of Science ®Google Scholar
• Minamishima YA, Kaelin WGJ. Reactivation of hepatic EPO synthesis in mice after PHD loss. Science. 2010;329(5990):407.
   PubMed Web of Science ®Google Scholar
• Minamishima YA, Moslehi J, Padera RF, Bronson RT, Liao R, Kaelin WGJ. A feedback loop involving the Phd3 prolyl hydroxylase tunes the mammalian hypoxic response in vivo. Mol Cell Biol. 2009;29(21):5729–5741.
   PubMed Web of Science ®Google Scholar
• Arsenault PR, Pei F, Lee R, et al. A knock-in mouse model of human PHD2 gene-associated erythrocytosis establishes a haploinsufficiency mechanism. J Biol Chem. 2013;288(47):33571–33584.
   PubMed Web of Science ®Google Scholar
• Franke K, Kalucka J, Mamlouk S, et al. HIF-1α is a protective factor in conditional PHD2-deficient mice suffering from severe HIF-2α-induced excessive erythropoiesis. Blood. 2013;121(8): 1436–1445.
   PubMed Web of Science ®Google Scholar
• Tojo Y, Sekine H, Hirano I, et al. Hypoxia signaling cascade for erythropoietin production in hepatocytes. Mol Cell Biol. 2015;35(15):2658–2672.
   PubMed Web of Science ®Google Scholar
• Duan LJ, Takeda K, Fong GH. Hematological, hepatic, and retinal phenotypes in mice deficient for prolyl hydroxylase domain proteins in the liver. Am J Pathol. 2014;184(4):1240–1250.
   PubMed Web of Science ®Google Scholar
• Soni H. Prolyl hydroxylase domain-2 (PHD2) inhibition may be a better therapeutic strategy in renal anemia. Med Hypotheses. 2014;82(5):547–550.
   PubMed Web of Science ®Google Scholar
• Maxwell PH, Eckardt KU. HIF prolyl hydroxylase inhibitors for the treatment of renal anaemia and beyond. Nat Rev Nephrol. 2015; 12(3):157–168.
   PubMed Web of Science ®Google Scholar
• Brigandi RA, Johnson B, Oei C, et al. A novel hypoxia-inducible factor – prolyl hydroxylase inhibitor (GSK1278863) for anemia in CKD: a 28-day, phase 2A randomized trial. Am J Kidney Dis. Epub January 27, 2016.
   Google Scholar
• Fu Q, Colgan SP, Shelley CS. Hypoxia: the force that drives chronic kidney disease. Clin Med Res. Epub February 4, 2016.
   Google Scholar
• Shoji K, Tanaka T, Nangaku M. Role of hypoxia in progressive chronic kidney disease and implications for therapy. Curr Opin Nephrol Hypertens. 2014;23(2):161–168.
   PubMed Web of Science ®Google Scholar
• Tanaka T, Nangaku M. Angiogenesis and hypoxia in the kidney. Nat Rev Nephrol. 2013;9(4):211–222.
   PubMed Web of Science ®Google Scholar
• Wang Z, Zhu Q, Li PL, et al. Silencing of hypoxia-inducible factor-1α gene attenuates chronic ischemic renal injury in two-kidney, one-clip rats. Am J Physiol Renal Physiol. 2014;306(10):F1236–F1242.
   PubMed Web of Science ®Google Scholar
• Casazza A, Di Conza G, Wenes M, Finisguerra V, Deschoemaeker S, Mazzone M. Tumor stroma: a complexity dictated by the hypoxic tumor microenvironment. Oncogene. 2014;33(14):1743–1754.
   PubMed Web of Science ®Google Scholar
• Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000; 100(1):57–70.
   PubMed Web of Science ®Google Scholar
• Gray LH, Conger AD, Ebert M, Hornsey S, Scott OC. The concentration of oxygen dissolved in tissues at the time of irradiation as a factor in radiotherapy. Br J Radiol. 1953;26(312):638–648.
   PubMed Web of Science ®Google Scholar
• Thomlinson RH, Gray LH. The histological structure of some human lung cancers and the possible implications for radiotherapy. Br J Cancer. 1955;9(4):539–549.
   PubMed Web of Science ®Google Scholar
• Brown JM, Wilson WR. Exploiting tumour hypoxia in cancer treatment. Nat Rev Cancer. 2004;4(6):437–447.
   PubMed Web of Science ®Google Scholar
• Vaupel P, Mayer A. Hypoxia in cancer: significance and impact on clinical outcome. Cancer Metastasis Rev. 2007;26(2):225–239.
   PubMed Web of Science ®Google Scholar
• Bertout JA, Patel SA, Simon MC. The impact of O2 availability on human cancer. Nat Rev Cancer. 2008;8(12):967–975.
   PubMed Web of Science ®Google Scholar
• Keith B, Johnson RS, Simon MC. HIF1α and HIF2α: sibling rivalry in hypoxic tumour growth and progression. Nat Rev Cancer. 2012;12(1):9–22.
   Web of Science ®Google Scholar
• Rhodes DR, Kalyana-Sundaram S, Mahavisno V, et al. Oncomine 3.0: genes, pathways, and networks in a collection of 18,000 cancer gene expression profiles. Neoplasia. 2007;9(2):166–180.
   PubMed Web of Science ®Google Scholar
• Rawluszko A, Bujnicka K, Horbacka K, Krokowicz P, Jagodzinski P. Expression and DNA methylation levels of prolyl hydroxylases PHD1, PHD2, PHD3 and asparaginyl hydroxylase FIH in colorectal cancer. BMC Cancer. 2013;13(1):526.
   PubMedGoogle Scholar
• Xie G, Zheng L, Ou 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. 2012;237(7):860–866.
   Web of Science ®Google Scholar
• Ladroue C, Hoogewijs D, Gad S, et al. Distinct deregulation of the hypoxia inducible factor by PHD2 mutants identified in germline DNA of patients with polycythemia. Haematologica. 2012;97(1):9–14.
   PubMed Web of Science ®Google Scholar
• Bordoli MR, Stiehl DP, Borsig L, et al. Prolyl-4-hydroxylase PHD2- and hypoxia-inducible factor 2-dependent regulation of amphiregulin contributes to breast tumorigenesis. Oncogene. 2011;30(5): 548–560.
   PubMed Web of Science ®Google Scholar
• Wottawa M, Leisering P, Ahlen M von, et al. Knockdown of prolyl-4-hydroxylase domain 2 inhibits tumor growth of human breast cancer MDA-MB-231 cells by affecting TGF-β1 processing. Int J Cancer. 2013;132(12):2787–2798.
   PubMed Web of Science ®Google Scholar
• Naba A, Clauser KR, Lamar JM, Carr SA, Hynes RO. Extracellular matrix signatures of human mammary carcinoma identify novel metastasis promoters. Elife. 2014;3:e01308.
   PubMed Web of Science ®Google Scholar
• Kuchnio A, Moens S, Bruning U, et al. The cancer cell oxygen sensor PHD2 promotes metastasis via activation of cancer-associated fibroblasts. Cell Rep. 2015;12(6):992–1005.
   PubMed Web of Science ®Google Scholar
• Klotzsche-von Ameln A, Muschter A, Heimesaat MM, Breier G, Wielockx B. HIF prolyl hydroxylase-2 inhibition diminishes tumor growth through matrix metalloproteinase-induced TGFβ activation. Cancer Biol Ther. 2012;13(4):216–223.
   PubMed Web of Science ®Google Scholar
• Klotzsche-von Ameln A, Muschter A, Mamlouk S, et al. Inhibition of HIF prolyl hydroxylase-2 blocks tumor growth in mice through the antiproliferative activity of TGFβ. Cancer Res. 2011;71(9):3306–3316.
   PubMed Web of Science ®Google Scholar
• Mamlouk S, Wielockx B. Hypoxia-inducible factors as key regulators of tumor inflammation. Int J Cancer. 2013;132(12):2721–2729.
   PubMed Web of Science ®Google Scholar
• Leite de Oliveira R, Deschoemaeker S, Henze AT, et al. Gene-targeting of Phd2 improves tumor response to chemotherapy and prevents side-toxicity. Cancer Cell. 2012;22(2):263–277.
   PubMed Web of Science ®Google Scholar
• Madsen CD, Pedersen JT, Venning FA, et al. Hypoxia and loss of PHD2 inactivate stromal fibroblasts to decrease tumour stiffness and metastasis. EMBO Rep. 2015;16(10):1394–1408.
   PubMed Web of Science ®Google Scholar
• Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–674.
   PubMed Web of Science ®Google Scholar
• Kumar V, Gabrilovich DI. Hypoxia-inducible factors in regulation of immune responses in tumour microenvironment. Immunology. 2014;143(4):512–519.
   PubMed Web of Science ®Google Scholar
• Dang EV, Barbi J, Yang HY, et al. Control of T(H)17/T(reg) balance by hypoxia-inducible factor 1. Cell. 2011;146(5):772–784.
   PubMed Web of Science ®Google Scholar
• Mamlouk S, Kalucka J, Singh RP, et al. Loss of prolyl hydroxylase-2 in myeloid cells and T-lymphocytes impairs tumor development. Int J Cancer. 2013;134(4):849–858.
   PubMed Web of Science ®Google Scholar
• Natarajan R, Salloum FN, Fisher BJ, Kukreja RC, Fowler AA. Hypoxia inducible factor-1 activation by prolyl 4-hydroxylase-2 gene silencing attenuates myocardial ischemia reperfusion injury. Circ Res. 2006;98 (1):133–140.
   PubMed Web of Science ®Google Scholar
• Kunze R, Zhou W, Veltkamp R, Wielockx B, Breier G, Marti HH. Neuron-specific prolyl-4-hydroxylase domain 2 knockout reduces brain injury after transient cerebral ischemia. Stroke. 2012;43(10): 2748–2756.
   PubMed Web of Science ®Google Scholar
• Hölscher M, Silter M, Krull S, et al. Cardiomyocyte-specific prolyl-4-hydroxylase domain 2 knock out protects from acute myocardial ischemic injury. J Biol Chem. 2011;286(13):11185–11194.
   PubMed Web of Science ®Google Scholar
• Howangyin KY, Loinard C, Bakker W, et al. HIF-prolyl hydroxylase 2 inhibition enhances the efficiency of mesenchymal stem cell-based therapies for the treatment of critical limb ischemia. Stem Cells. 2014;32:231–243.
   PubMed Web of Science ®Google Scholar
• Schirmer SH, van Nooijen FC, Piek JJ, van Royen N. Stimulation of collateral artery growth: travelling further down the road to clinical application. Heart. 2009;95(3):191–197.
   PubMed Web of Science ®Google Scholar
• Takeda Y, Costa S, Delamarre E, et al. Macrophage skewing by Phd2 haplodeficiency prevents ischaemia by inducing arteriogenesis. Nature. 2011;479(7371):122–126.
   PubMed Web of Science ®Google Scholar
• Hamm A, Veschini L, Takeda Y, et al. PHD2 regulates arteriogenic macrophages through TIE2 signalling. EMBO Mol Med. 2013; 5(6):843–857.
   PubMed Web of Science ®Google Scholar
• Ikeda J, Ichiki T, Matsuura H, et al. Deletion of phd2 in myeloid lineage attenuates hypertensive cardiovascular remodeling. J Am Heart Assoc. 2013;2(3):e000178.
   PubMed Web of Science ®Google Scholar
• Wei H, Bedja D, Koitabashi N, et al. Endothelial expression of hypoxia-inducible factor 1 protects the murine heart and aorta from pressure overload by suppression of TGF-β signaling. Proc Natl Acad Sci U S A. 2012;109(14):E841–E850.
   PubMed Web of Science ®Google Scholar
• Rezvani HR, Ali N, Nissen LJ, et al. HIF-1α in epidermis: oxygen sensing, cutaneous angiogenesis, cancer, and non-cancer disorders. J Invest Dermatol. 2011;131(9):1793–1805.
   PubMed Web of Science ®Google Scholar
• Kalucka J, Ettinger A, Franke K, et al. Loss of epithelial hypoxia-inducible factor prolyl hydroxylase 2 accelerates skin wound healing in mice. Mol Cell Biol. 2013;33(17):3426–3438.
   PubMed Web of Science ®Google Scholar
• Zhang X, Yan X, Cheng L, et al. Wound healing improvement with PHD-2 silenced fibroblasts in diabetic mice. PLoS One. 2013;8(12):e84548.
   PubMed Web of Science ®Google Scholar
• Wetterau M, George F, Weinstein A, et al. Topical prolyl hydroxylase domain-2 silencing improves diabetic murine wound closure. Wound Repair Regen. 2011;19(4):481–486.
   PubMed Web of Science ®Google Scholar
• Vandegrift MT, Szpalski C, Knobel D, et al. Acellular dermal matrix-based gene therapy augments graft incorporation. J Surg Res. 2015;195(1):360–367.
   PubMed Web of Science ®Google Scholar
• Huerta-Yepez S, Baay-Guzman GJ, Bebenek IG, et al. Hypoxia inducible factor promotes murine allergic airway inflammation and is increased in asthma and rhinitis. Allergy. 2011;66(7):909–918.
   PubMed Web of Science ®Google Scholar
• Ahmad T, Kumar M, Mabalirajan U, et al. Hypoxia response in asthma: differential modulation on inflammation and epithelial injury. Am J Respir Cell Mol Biol. 2012;47(1):1–10.
   PubMed Web of Science ®Google Scholar
• Huerta-Yepez S, Baay-Guzman GJ, Garcia-Zepeda R, et al. 2-Methoxyestradiol (2-ME) reduces the airway inflammation and remodeling in an experimental mouse model. Clin Immunol. 2008;129(2):313–324.
   PubMed Web of Science ®Google Scholar
• Matsuura H, Ichiki T, Inoue E, et al. Prolyl hydroxylase domain protein 2 plays a critical role in diet-induced obesity and glucose intolerance. Circulation. 2013;127(21):2078–2087.
   PubMed Web of Science ®Google Scholar
• Michailidou Z, Morton NM, Moreno Navarrete JM, et al. Adipocyte pseudohypoxia suppresses lipolysis and facilitates benign adipose tissue expansion. Diabetes. 2015;64(3):733–745.
   PubMed Web of Science ®Google Scholar