Hypoxia, hypoxia-inducible factors (HIF), HIF hydroxylases and oxygen sensing

  • James D. Webb
  • Mathew L. Coleman
  • Christopher W. PughEmail author
Multi-author Review


This article outlines the need for a homeostatic response to alterations in cellular oxygenation. It describes work on erythropoietin control that led to the discovery of the hypoxia-inducible transcription factor (HIF-1) and the parallel recognition that this system was responsive to a widespread oxygen-sensing mechanism. Subsequently, multiple HIF isoforms have been shown to have overlapping but non-redundant functions, controlling expression of genes involved in diverse processes such as angiogenesis, vascular tone, metal transport, glycolysis, mitochondrial function, cell growth and survival. The major role of prolyl and asparaginyl hydroxylation in regulating HIFs is described, as well as the identification of PHD1-3 and FIH as the oxygen-sensing enzymes responsible for these hydroxylations. Current understanding of other processes that modulate overall HIF activity, including influences from other signalling mechanisms such as kinases and nitric oxide levels, and the existence of a variety of feedback loops are outlined. The effects of some mutations in this pathway are documented as is knowledge of other substrates for these enzymes. The importance of PHD1-3 and FIH, and the large family of 2-oxoglutarate and iron(II)-dependent dioxygenases of which they are a part, in biology and medicine are discussed (part of a multi-author review).


Hypoxia HIF Prolyl hydroxylase Asparaginyl hydroxylase Oxygen sensing PHD FIH 



The authors acknowledge many uncited contributions from co-workers in the field and helpful discussions with those involved now, and in the past, with oxygen-sensing research in Oxford. Work in the authors’ laboratory has been funded by the Wellcome Trust, MRC, CRUK, BHF, European Commission and a Fellowship to MC from Jesus College, Oxford. CWP is a scientific co-founder of ReOx Ltd.


  1. 1.
    Gilles-Gonzalez MA, Gonzalez G, Perutz MF (1994) Heme-based sensors, exemplified by the kinas FixL, are a new class of heme protein with distinctive ligand binding and autoxidation. Biochemistry 33:8067–8073PubMedGoogle Scholar
  2. 2.
    Bunn HF, Poyton RO (1996) Oxygen sensing and molecular adaptation to hypoxia. Physiol Rev 76:839–885PubMedGoogle Scholar
  3. 3.
    Zitomer RS, Lowry CV (1992) Regulation of gene expression by oxygen in Saccharomyces cerevisiae. Microbiol Rev 56:1–11PubMedGoogle Scholar
  4. 4.
    Hidalgo E, Ding H, Demple B (1997) Redox signal transduction: mutations shifting [2Fe-2S] centers of the SoxR sensor-regulator to the oxidized form. Cell 88:121–129PubMedGoogle Scholar
  5. 5.
    Spiro S, Roberts RE, Guest JR (1989) FNR-dependent repression of the ndh gene of Escherichia coli and metal ion requirement for FNR-regulated gene expression. Mol Microbiol 3:601–608PubMedGoogle Scholar
  6. 6.
    Spiro S, Guest JR (1990) FNR and its role in oxygen-regulated gene expression in Escherichia coli. FEMS Microbiol Rev 6:399–428PubMedGoogle Scholar
  7. 7.
    Jelkmann W (1992) Erythropoietin: structure, control of production, and function. Physiol Rev 72:449–489PubMedGoogle Scholar
  8. 8.
    Necas E, Neuwirt J (1972) The effect of inhibitors of energy metabolism on erythropoietin production. J Lab Clin Med 79:388–396PubMedGoogle Scholar
  9. 9.
    Necas E, Thorling EB (1972) Unresponsiveness of erythropoietin-producing cells to cyanide. Am J Physiol 222:1187–1190PubMedGoogle Scholar
  10. 10.
    Wang GL, Semenza GL (1993) Desferrioxamine induces erythropoietin gene expression and hypoxia-inducible factor 1 DNA-binding activity: implications for models of hypoxia signal transduction. Blood 82:3610–3615PubMedGoogle Scholar
  11. 11.
    Goldwasser E, Jacobson LO, Fried W, Plazk LF (1958) Studies on erythropoiesis V: the effect of cobalt on the production of erythropoietin. Blood 13:55–60PubMedGoogle Scholar
  12. 12.
    Ho VT, Bunn HF (1996) Effects of transition metals on the expression of the erythropoietin gene: further evidence that the oxygen sensor is a heme protein. Biochem Biophys Res Commun 223:175–180PubMedGoogle Scholar
  13. 13.
    Tan CC, Eckardt K-U, Ratcliffe PJ (1991) Organ distribution of erythropoietin messenger RNA in normal and uremic rats. Kidney Int 40:69–76PubMedGoogle Scholar
  14. 14.
    Maxwell PH, Osmond MK, Pugh CW, Heryet A, Nicholls LG, Tan CC, Doe BG, Ferguson DJP, Johnson MH, Ratcliffe PJ (1993) Identification of the renal erythropoietin-producing cells using transgenic mice. Kidney Int 44:1149–1162PubMedGoogle Scholar
  15. 15.
    Maxwell PH, Ferguson DJP, Osmond MK, Pugh CW, Heryet A, Doe BG, Johnson MH, Ratcliffe PJ (1994) Expression of a homologously recombined erythropoietin-SV40 T antigen fusion gene in mouse liver: evidence for erythropoietin production by Ito cells. Blood 84:1823–1830PubMedGoogle Scholar
  16. 16.
    Koury ST, Bondurant MC, Koury MJ (1988) Localization of erythropoietin synthesizing cells in murine kidneys by in situ hybridization. Blood 71:524–527PubMedGoogle Scholar
  17. 17.
    Koury ST, Bondurant MC, Koury MJ, Semenza GL (1991) Localization of cells producing erythropoietin in murine liver by in situ hybridization. Blood 77:2497–2503PubMedGoogle Scholar
  18. 18.
    Eckardt K-U, Koury ST, Tan CC, Schuster SJ, Kaissling B, Ratcliffe PJ, Kurtz A (1993) Distribution of erythropoietin producing cells in rat kidneys during hypoxic hypoxia. Kidney Int 43:815–823PubMedGoogle Scholar
  19. 19.
    Bachmann S, Le Hir M, Eckardt K-U (1993) Co-localization of erythropoietin messenger RNA and ecto-5′-nucleotidase immunoreactivity in peritubular cells of rat renal cortex indicates that fibroblasts produce erythropoietin. J Histochem Cytochem 41:335–341PubMedGoogle Scholar
  20. 20.
    Goldberg MA, Glass GA, Cunningham JM, Bunn HF (1987) The regulated expression of erythropoietin by two human hepatoma cell lines. Proc Natl Acad Sci USA 84:7972–7976PubMedGoogle Scholar
  21. 21.
    Wang GL, Jiang B-H, Rue EA, Semenza GL (1995) Hypoxia-inducible factor 1 is a basic-helix–loop–helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci USA 92:5510–5514PubMedGoogle Scholar
  22. 22.
    Wang GL, Semenza GL (1995) Purification and characterisation of hypoxia-inducible factor 1. J Biol Chem 270:1230–1237PubMedGoogle Scholar
  23. 23.
    Semenza GL, Nejfelt MK, Chi SM, Antonarakis SE (1991) Hypoxia-inducible nuclear factors bind to an enhancer element located 3′ to the human erythropoietin gene. Proc Natl Acad Sci USA 88:5680–5684PubMedGoogle Scholar
  24. 24.
    Beck I, Ramirez S, Weinmann R, Caro J (1991) Enhancer element at the 3′-flanking region controls transcriptional response to hypoxia in the human erythropoietin gene. J Biol Chem 266:15563–15566PubMedGoogle Scholar
  25. 25.
    Pugh CW, Tan CC, Jones RW, Ratcliffe PJ (1991) Functional analysis of an oxygen-regulated transcriptional enhancer lying 3′ to the mouse erythropoietin gene. Proc Natl Acad Sci USA 88:10553–10557PubMedGoogle Scholar
  26. 26.
    Maxwell PH, Pugh CW, Ratcliffe PJ (1993) Inducible operation of the erythropoietin 3′ enhancer in multiple cell lines: evidence for a widespread oxygen sensing mechanism. Proc Natl Acad Sci USA 90:2423–2427PubMedGoogle Scholar
  27. 27.
    Firth JD, Ebert BL, Ratcliffe PJ (1995) Hypoxic regulation of lactate dehydrogenase A: interaction between hypoxia inducible factor 1 and cAMP response elements. J Biol Chem 270:21021–21027PubMedGoogle Scholar
  28. 28.
    Ebert BL, Firth JD, Ratcliffe PJ (1995) Hypoxia and mitochondrial inhibitors regulate expression of glucose transporter-1 via distinct cis-acting sequences. J Biol Chem 270:29083–29089PubMedGoogle Scholar
  29. 29.
    Gleadle JM, Ebert BL, Firth JD, Ratcliffe PJ (1995) Regulation of angiogenic growth factor expression by hypoxia, transition metals, and chelating agents. Am J Physiol 268:C1362–C1368PubMedGoogle Scholar
  30. 30.
    Firth JD, Ebert BL, Pugh CW, Ratcliffe PJ (1994) Oxygen-regulated control elements in the phosphoglycerate kinase 1 and lactate dehydrogenase A genes: similarities with the erythropoeitin 3′ enhancer. Proc Natl Acad Sci USA 91:6496–6500PubMedGoogle Scholar
  31. 31.
    Semenza GL (2003) Targeting HIF-1 for cancer therapy. Nat Rev Cancer 3:721–732PubMedGoogle Scholar
  32. 32.
    Liu Y, Cox SR, Morita T, Kourembanas S (1995) Hypoxia regulates vascular endothelial growth factor gene expression in endothelial cells. Circ Res 77:638–643PubMedGoogle Scholar
  33. 33.
    Blais JD, Filipenko V, Bi M, Harding HP, Ron D, Koumenis C, Wouters BG, Bell JC (2004) Activating transcription factor 4 is translationally regulated by hypoxic stress. Mol Cell Biol 24:7469–7482PubMedGoogle Scholar
  34. 34.
    Graeber TG, Peterson JF, Tsai M, Monica K, Fornace AJ Jr, Giaccia AJ (1994) Hypoxia induces accumulation of p53 protein, but activation of a G1-phase checkpoint by low-oxygen conditions is independent of p53 status. Mol Cell Biol 14:6264–6277PubMedGoogle Scholar
  35. 35.
    Schmedtje JF Jr, Ji Y-S (1998) Hypoxia and molecular cardiovascular medicine. Trends Cardiovasc Med 8:24–33Google Scholar
  36. 36.
    Zampetaki A, Mitsialis SA, Pfeilschifter J, Kourembanas S (2004) Hypoxia induces macrophage inflammatory protein-2 (MIP-2) gene expression in murine macrophages via NF-κB: the prominent of p42/p44 and PI3 kinase pathways. FASEB J 18:1090–1092PubMedGoogle Scholar
  37. 37.
    Cummins EP, Comerford KM, Scholz C, Bruning U, Taylor CT (2007) Hypoxic regulation of NF-kappaB signaling. Methods Enzymol 435:479–492PubMedGoogle Scholar
  38. 38.
    Koditz J, Nesper J, Wottawa M, Stiehl DP, Camenisch G, Franke C, Myllyharju J, Wenger RH, Katschinski DM (2007) Oxygen-dependent ATF-4 stability is mediated by the PHD3 oxygen sensor. Blood 110:3610–3617PubMedGoogle Scholar
  39. 39.
    Elvidge GP, Glenny L, Appelhoff RJ, Ratcliffe PJ, Ragoussis J, Gleadle JM (2006) Concordant regulation of gene expression by hypoxia and 2-oxoglutarate dependent dioxygenase inhibition; the role of HIF-1alpha, HIF-2alpha and other pathways. J Biol Chem 281:15215–15226PubMedGoogle Scholar
  40. 40.
    Ameri K, Hammond EM, Culmsee C, Raida M, Katschinski DM, Wenger RH, Wagner E, Davis RJ, Hai T, Denko N, Harris AL (2007) Induction of activating transcription factor 3 by anoxia is independent of p53 and the hypoxic HIF signalling pathway. Oncogene 26:284–289PubMedGoogle Scholar
  41. 41.
    Ameri K, Lewis CE, Raida M, Sowter H, Hai T, Harris AL (2004) Anoxic induction of ATF-4 through HIF-1-independent pathways of protein stabilization in human cancer cells. Blood 103:1876–1882PubMedGoogle Scholar
  42. 42.
    Zhulin IB, Taylor BL, Dixon R (1997) PAS domain S-boxes in Archaea, bacteria and sensors for oxygen and redox. Trends Biol Sci 22:331–333Google Scholar
  43. 43.
    Taylor BL, Zhulin IB (1999) PAS domains: internal sensors of oxygen, redox potential, and light. Microbiol Mol Biol Rev 63:479–506PubMedGoogle Scholar
  44. 44.
    Hoffman EC, Reyes H, Chu F-F, Sander F, Conley LH, Brooks BA, Hankinson O (1991) Cloning of a factor required for activity of the Ah (Dioxin) receptor. Science 252:954–958PubMedGoogle Scholar
  45. 45.
    Reyes H, Reisz-Porszasz S, Hankinson O (1992) Identification of the Ah receptor nuclear translocator protein (Arnt) as a component of the DNA binding form of the Ah receptor. Science 256:1193–1195PubMedGoogle Scholar
  46. 46.
    Reisz-Porszasz S, Probst MR, Fukunaga BN, Hankinson O (1994) Identification of functional domains of the aryl hydrocarbon receptor nuclear translocator protein (ARNT). Mol Cell Biol 14:6075–6086PubMedGoogle Scholar
  47. 47.
    Hankinson O (1995) The aryl hydrocarbon complex. Annu Rev Pharmacol Toxicol 35:307–340PubMedGoogle Scholar
  48. 48.
    Arany Z, Huang LE, Eckner R, Bhattacharya S, Jiang C, Goldberg MA, Bunn HF, Livingston DM (1996) An essential role for p300/CBP in the cellular response to hypoxia. Proc Natl Acad Sci USA 93:12969–12973PubMedGoogle Scholar
  49. 49.
    Jiang H, Guo R, Powell-Coffman JA (2001) The Caenorhabditis elegans hif-1 gene encodes a bHLH-PAS protein that is required for adaptation to hypoxia. Proc Natl Acad Sci USA 98:7916–7921PubMedGoogle Scholar
  50. 50.
    Bacon NC, Wappner P, O’Rourke JF, Bartlett SM, Shilo B, Pugh CW, Ratcliffe PJ (1998) Regulation of the Drosophila basic helix–loop–helix PAS protein Sima by hypoxia: functional evidence for homology with mammalian HIF-1 alpha. Biochem Biophys Res Commun 249:811–816PubMedGoogle Scholar
  51. 51.
    Lavista-Llanos S, Centanin L, Irisarri M, Russo DM, Gleadle JM, Bocca SN, Muzzopappa M, Ratcliffe PJ, Wappner P (2002) Control of the hypoxic reponse in Drosophila melanogaster by the basic helix–loop–helix PAS protein similar. Mol Cell Biol 22:6842–6853PubMedGoogle Scholar
  52. 52.
    Sonnenfeld M, Ward M, Nystrom G, Mosher J, Stahl S, Crews S (1997) The Drosophila tango gene ecodes a bHLH-PAS protein that is orthologous to mammalian Arnt and controls CNS midline and tracheal development. Development 124:4571–4582PubMedGoogle Scholar
  53. 53.
    Tian H, McKnight SL, Russell DW (1997) Endothelial PAS domain protein 1 (EPAS1), a transcription factor selectively expressed in endothelial cells. Genes Dev 11:72–82PubMedGoogle Scholar
  54. 54.
    Ema M, Taya S, Yokotani N, Sogawa K, Matsuda Y, Fujii-Kuriyama Y (1997) A novel bHLH-PAS factor with close sequence similarity to hypoxia-inducible factor 1α regulates the VEGF expression and is potentially involved in lung and vascular development. Proc Natl Acad Sci USA 94:4273–4278PubMedGoogle Scholar
  55. 55.
    Flamme I, Fröhlich T, von Reutern M, Kappel A, Damert A, Risau W (1997) HRF, a putative basic helix–loop–helix-PAS-domain transcription factor is closely related to hypoxia-inducible factor-1α and developmentally expressed in blood vessels. Mech Dev 63:51–60PubMedGoogle Scholar
  56. 56.
    Hara S, Hamada J, Kobayashi C, Kondo Y, Imura N (2001) Expression and characterization of hypoxia-inducible factor (HIF)-3α in human kidney: suppression of HIF-mediated gene expression by HIF-3α. Biochem Biophys Res Commun 287:808–813PubMedGoogle Scholar
  57. 57.
    Maynard MA, Qi H, Chung J, Lee EHL, Kondo Y, Hara S, Conaway RC, Conaway JW, Ohh M (2003) Multiple splice variants of the human HIF-3α locus are targets of the von Hippel-Lindau E3 ubiquitin ligase complex. J Biol Chem 278:11032–11040PubMedGoogle Scholar
  58. 58.
    Heidbreder M, Frohlich F, Johren O, Dendorfer A, Qadri F, Dominiak P (2003) Hypoxia rapidly activates HIF-3α mRNA expression. FASEB J 17:1541–1543PubMedGoogle Scholar
  59. 59.
    Makino Y, Cao R, Svensson K, Bertilsson G, Asman M, Tanaka H, Cao Y, Berkenstam A, Poellinger L (2001) Inhibitory PAS domain protein is a negative regulator of hypoxia-inducible gene expression. Nature 414:550–554PubMedGoogle Scholar
  60. 60.
    Makino Y, Kanopka A, Wilson WJ, Tanaka H, Poellinger L (2002) Inhibitory PAS domain protein (IPAS) is a hypoxia-inducible splicing variant of the hypoxia-inducible factor-3α locus. J Biol Chem 277:32405–32408PubMedGoogle Scholar
  61. 61.
    Hirose K, Morita M, Ema M, Mimura J, Hamada H, Fujii H, Saijo Y, Gotoh O, Sogawa K, Fujii-Kuriyama Y (1996) cDNA cloning and tissue-specific expression of a novel basic helix–loop–helix/PAS factor (Arnt2) with close sequence similarity to the aryl hydrocarbon receptor nuclear translocator (Arnt). Mol Cell Biol 16:1706–1713PubMedGoogle Scholar
  62. 62.
    Ikeda M, Nomura M (1997) cDNA cloning and tissue-specific expression of a novel basic helix–loop–helix/PAS protein (BMAL1) and identification of alternatively spliced variants with alternative translation initiation site usage. Biochem Biophys Res Commun 233:258–264PubMedGoogle Scholar
  63. 63.
    Hogenesch JB, Guy Y–Z, Jain S, Bradfield CA (1998) The basic-helix–loop–helix-PAS orphan MOP3 forms transcriptionally active complexes with circadian and hypoxia factors. Proc Natl Acad Sci USA 95:5474–5479PubMedGoogle Scholar
  64. 64.
    Hogenesch JB, Gu Y–Z, Moran SM, Shimomura K, Radcliffe LA, Takahashi JS, Bradfield CA (2000) The basic helix–loop–helix-PAS protein MOP9 is a brain-specific heterodimeric partner of circadian and hypoxia factors. J Neurosci 20:1–5Google Scholar
  65. 65.
    Wiesener MS, Jurgensen JS, Rosenberger C, Scholze C, Horstrup JH, Wamecke C, Mandriota S, Bechmann I, Frei UA, Pugh CW, Ratcliffe PJ, Bachmann S, Maxwell PH, Eckardt K-U (2002) Widespread, hypoxia-inducible expression of HIF-2α in distinct cell populations of different organs. FASEB J 17:271–273PubMedGoogle Scholar
  66. 66.
    Carver LA, Hogenesch JB, Bradfield CA (1994) Tissue specific expression of the rat Ah-receptor and ARNT mRNAs. Nucleic Acids Res 22:3038–3044PubMedGoogle Scholar
  67. 67.
    Drutel G, Kathmann M, Heron A, Schwartz J-C, Arrang J-M (1996) Cloning and selective expression in brain and kidney of ARNT2 homologous to the Ah receptor nuclear translocator (ARNT). Biochem Biophys Res Commun 225:333–339PubMedGoogle Scholar
  68. 68.
    Shimba S, Ishii N, Ohta Y, Ohno T, Watabe Y, Hayashi M, Wada T, Aoyagi T, Tezuka M (2005) Brain and muscle Arnt-like protein-1 (BMAL1), a component of the molecular clock, regulates adipogenesis. Proc Natl Acad Sci USA 102:12071–12076PubMedGoogle Scholar
  69. 69.
    Ryan HE, Lo J, Johnson RS (1998) HIF-1α is required for solid tumor formation and embryonic vascularization. EMBO J 17:3005–3015PubMedGoogle Scholar
  70. 70.
    Iyer NV, Kotch LE, Agani F, Leung SW, Laughner E, Wenger RH, Gassmann M, Gearhart JD, Lawler AM, Yu AY, Semenza GL (1998) Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1α. Genes Dev 12:149–162PubMedGoogle Scholar
  71. 71.
    Tian H, Hammer RE, Matsumoto AM, Russell DW, McKnight SL (1998) The hypoxia responsive transcription factor EPAS1 is essential for catecholamine homeostasis and protection against heart failure during embryonic development. Genes Dev 12:3320–3324PubMedGoogle Scholar
  72. 72.
    Peng J, Zhang L, Drysdale L, Fong GH (2000) The transcription factor EPAS-1/hypoxia-inducible factor 2α plays an important role in vascular remodeling. Proc Natl Acad Sci USA 97:8386–8391PubMedGoogle Scholar
  73. 73.
    Compernolle V, Brusselmans K, Acker T, Hoet P, Tjwa M, Beck H, Plaisance S, Dor Y, Keshet E, Lupu F, Nemery B, Dewerchin M, Van Veldhoven P, Plate K, Moons L, Collen D, Carmeliet P (2002) Loss of HIF-2α and inhibition of VEGF impair fetal lung maturation, whereas treatment with VEGF prevents fatal respiratory distress in premature mice. Nat Med 8:702–710PubMedGoogle Scholar
  74. 74.
    Scortegagna M, Ding K, Oktay Y, Gaur A, Thurmond F, Yan L-J, Marck BT, Matsumoto AM, Shelton JM, Richardson JA, Bennett MJ, Garcia JA (2003) Multiple organ pathology, metabolic abnormalities and impaired homeostasis of reactive oxygen species in Epas1 −/− mice. Nat Genet 35:331–340PubMedGoogle Scholar
  75. 75.
    Kozak KR, Abbott B, Hankinson O (1997) ARNT-deficient mice and placental differentiation. Dev Biol 191:247–305Google Scholar
  76. 76.
    Keith B, Adelman DM, Simon MC (2001) Targeted mutation of the murine arhylhydrocarbon receptor nuclear translocator 2 (Arnt2) gene reveals partial redundancy with Arnt. Proc Natl Acad Sci USA 98:6692–6697PubMedGoogle Scholar
  77. 77.
    Hu CJ, Sataur A, Wang L, Chen H, Simon MC (2007) The N-terminal transactivation domain confers target gene specificity of hypoxia-inducible factors HIF-1alpha and HIF-2alpha. Mol Biol Cell 18:4528–4542PubMedGoogle Scholar
  78. 78.
    Sowter HM, Raval RR, Moore J, Ratcliffe PJ, Harris AL (2003) Predominant role of hypoxia-inducible transcription factor (Hif)-1α versus Hif-2α in regulation of the transcription. Cancer Res 63:6130–6134PubMedGoogle Scholar
  79. 79.
    Raval RR, Lau KW, Tran MG, Sowter HM, Mandriota SJ, Li JL, Pugh CW, Maxwell PH, Harris AL, Ratcliffe PJ (2005) Contrasting properties of hypoxia-inducible factor 1 (hif-1) and hif-2 in von Hippel-Lindau-associated renal cell carcinoma. Mol Cell Biol 25:5675–5686PubMedGoogle Scholar
  80. 80.
    Kondo K, Kim WY, Lechpammer M, Kaelin WG Jr (2003) Inhibition of HIF2α is sufficient to suppress pVHL-defective tumor growth. PLoS Biol 1:439–444Google Scholar
  81. 81.
    Kondo K, Kico J, Nakamura E, Lechpammer M, Kaelin WGJ (2002) Inhibition of HIF is necessary for tumor suppression by the von Hippel-Lindau protein. Cancer Cell 1:237–246PubMedGoogle Scholar
  82. 82.
    Maranchie JK, Vasselli JR, Riss J, Bonifacino JS, Linehan WM, Klausner RD (2002) The contribution of VHL substrate binding and HIF1-α to the phenotype of VHL loss in renal cell carcinoma. Cancer Cell 1:247–255PubMedGoogle Scholar
  83. 83.
    Mandriota SJ, Turner KJ, Davies DR, Murray PG, Morgan NV, Sowter HM, Wykoff CC, Maher ER, Harris AL, Ratcliffe PJ, Maxwell PH (2002) HIF activation identifies early lesions in VHL kidneys: evidence for site-specific tumor suppressor function in the nephron. Cancer Cell 1:459–468PubMedGoogle Scholar
  84. 84.
    Covello KL, Simon MC, Keith B (2005) Targeted replacement of hypoxia-inducible factor-1alpha by a hypoxia-inducible factor-2alpha knock-in allele promotes tumor growth. Cancer Res 65:2277–2286PubMedGoogle Scholar
  85. 85.
    Brusselmans K, Bono F, Maxwell P, Dor Y, Dewerchin M, Collen D, Herbert JM, Carmeliet P (2001) Hypoxia-inducible factor-2α (HIF-2α) is involved in the apoptotic response to hypoglycemia but not to hypoxia. J Biol Chem 276:39192–391966PubMedGoogle Scholar
  86. 86.
    Lau KW, Tian YM, Raval RR, Ratcliffe PJ, Pugh CW (2007) Target gene selectivity of hypoxia-inducible factor-alpha in renal cancer cells is conveyed by post-DNA-binding mechanisms. Br J Cancer 96:1284–1292PubMedGoogle Scholar
  87. 87.
    Dayan F, Roux D, Brahimi-Horn MC, Pouyssegur J, Mazure NM (2006) The oxygen sensor factor-inhibiting hypoxia-inducible factor-1 controls expression of distinct genes through the bifunctional transcriptional character of hypoxia-inducible factor-1alpha. Cancer Res 66:3688–3698PubMedGoogle Scholar
  88. 88.
    Gordan JD, Bertout JA, Hu CJ, Diehl JA, Simon MC (2007) HIF-2alpha promotes hypoxic cell proliferation by enhancing c-myc transcriptional activity. Cancer Cell 11:335–347PubMedGoogle Scholar
  89. 89.
    Gu YZ, Moran SM, Hogenesch JB, Wartman L, Bradfield CA (1998) Molecular characterization and chromosomal localization of a third alpha-class hypoxia inducible factor subunit, HIF3alpha. Gene Expr 7:205–213PubMedGoogle Scholar
  90. 90.
    Hara S, Hamada J, Kobayashi C, Kondo Y, Imura N (2001) Expression and characterization of hypoxia-inducible factor (HIF)-3alpha in human kidney: suppression of HIF-mediated gene expression by HIF-3alpha. Biochem Biophys Res Commun 287:808–813PubMedGoogle Scholar
  91. 91.
    Young RM, Wang SJ, Gordan JD, Ji X, Liebhaber SA, Simon MC (2008) Hypoxia-mediated selective mRNA translation by an internal ribosome entry site-independent mechanism. J Biol Chem 283:16309–16319PubMedGoogle Scholar
  92. 92.
    Kallio PJ, Okamoto K, O’Brien S, Carrero P, Makino Y, Tanaka H, Poellinger L (1998) Signal transduction in hypoxic cells: inducible nuclear translocation and recruitment of the CBP/p300 coactivator by the hypoxia-inducible factor-1α. EMBO J 17:6573–6586PubMedGoogle Scholar
  93. 93.
    Salceda S, Caro J (1997) Hypoxia-inducible factor 1α (HIF-1α) protein is rapidly degraded by the ubiquitin–proteasome system under normoxic conditions. J Biol Chem 272:22642–22647PubMedGoogle Scholar
  94. 94.
    Tanimoto K, Makino Y, Pereira T, Poellinger L (2000) Mechanism of regulation of the hypoxia-inducible factor-1α by the von Hippel-Lindau tumor suppressor protein. EMBO J 19:4298–4309PubMedGoogle Scholar
  95. 95.
    Paltoglou S, Roberts BJ (2007) HIF-1alpha and EPAS ubiquitination mediated by the VHL tumour suppressor involves flexibility in the ubiquitination mechanism, similar to other RING E3 ligases. Oncogene 26:604–609PubMedGoogle Scholar
  96. 96.
    Maxwell PH, Wiesener MS, Chang G-W, Clifford SC, Vaux EC, Cockman ME, Wykoff CC, Pugh CW, Maher ER, Ratcliffe PJ (1999) The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 399:271–275PubMedGoogle Scholar
  97. 97.
    Clifford SC, Cockman ME, Smallwood AC, Mole DR, Woodward ER, Maxwell PH, Ratcliffe PJ, Maher ER (2001) Contrasting effects on HIF-1α regulation by disease-causing pVHL mutations correlate with patterns of tumourigenesis in von Hippel-Lindau disease. Hum Mol Genet 10:1029–1038PubMedGoogle Scholar
  98. 98.
    Ohh M, Park CW, Ivan M, Hoffman MA, Kim TY, Huang LE, Pavletich N, Chau V, Kaelin WG (2000) Ubiquitination of hypoxia-inducible factor requires direct binding to the beta-domain of the von Hippel-Lindau protein. Nat Cell Biol 2:423–427PubMedGoogle Scholar
  99. 99.
    Cockman ME, Masson N, Mole DR, Jaakkola P, Chang GW, Clifford SC, Maher ER, Pugh CW, Ratcliffe PJ, Maxwell PH (2000) Hypoxia inducible factor-α binding and ubiquitylation by the von Hippel-Lindau tumor suppressor protein. J Biol Chem 275:25733–25741PubMedGoogle Scholar
  100. 100.
    Hoffman MA, Ohh M, Yang H, Klco JM, Ivan M, Kaelin WGJ (2001) von Hippel-Lindau protein mutants linked to type 2C VHL disease preserve the ability to downregulate HIF. Hum Mol Genet 10:1019–1027PubMedGoogle Scholar
  101. 101.
    Ang SO, Chen H, Hirota K, Gordeuk VR, Jelinek J, Guan Y, Liu E, Sergueeva AI, Miasnikova GY, Mole D, Maxwell PH, Stockton DW, Semenza GL, Prchal JT (2002) Disruption of oxygen homeostasis underlies congenital Chuvash polycythemia. Nat Genet 32:614–621PubMedGoogle Scholar
  102. 102.
    Jaakkola P, Mole DR, Tian Y-M, Wilson MI, Gielbert J, Gaskell SJ, Kriegsheim A, von Hebestreit HF, Mukherji M, Schofield CJ, Maxwell PH, Pugh CW, Ratcliffe PJ (2001) Targeting of HIF-α to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 292:468–472PubMedGoogle Scholar
  103. 103.
    Epstein ACR, Gleadle JM, McNeill LA, Hewitson KS, O’Rourke J, Mole DR, Mukherji M, Metzen E, Wilson MI, Dhanda A, Tian Y-M, Masson N, Hamilton DL, Jaakkola P, Barstead R, Hodgkin J, Maxwell PH, Pugh CW, Schofield CJ, Ratcliffe PJ (2001) C. elegans EGL-9 and mammalian homologues define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell 107:43–54PubMedGoogle Scholar
  104. 104.
    Masson N, Willam C, Maxwell PH, Pugh CW, Ratcliffe PJ (2001) Independent function of two destruction domains in hypoxia-inducible factor-α chains activated by prolyl hydroxylation. EMBO J 20:5197–5206PubMedGoogle Scholar
  105. 105.
    Ivan M, Kondo K, Yang H, Kim W, Valiando J, Ohh M, Salic A, Asara JM, Lane WS, Kaelin WGJr (2001) HIFα targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science 292:464–468PubMedGoogle Scholar
  106. 106.
    Bruick RK, McKnight SL (2001) A conserved family of prolyl-4-hydroxylases that modify HIF. Science 294:1337–1340PubMedGoogle Scholar
  107. 107.
    Hon WC, Wilson MI, Harlos K, Claridge TD, Schofield CJ, Pugh CW, Maxwell PH, Ratcliffe PJ, Stuart DI, Jones EY (2002) Structural basis for the recognition of hydroxyproline in HIF-1α by pVHL. Nature 417:975–978PubMedGoogle Scholar
  108. 108.
    Lando D, Peet DJ, Whelan DA, Gorman JJ, Whitelaw ML (2002) Asparagine hydroxylation of the HIF transactivation domain: a hypoxic switch. Science 295:858–861PubMedGoogle Scholar
  109. 109.
    Lando D, Peet DJ, Gorman JJ, Whelan DA, Whitelaw ML, Bruick RK (2002) FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor. Genes Dev 16:1466–1471PubMedGoogle Scholar
  110. 110.
    Hewitson KS, McNeill LA, Riordan MV, Tian Y-M, Bullock AN, Welford RW, Elkins JM, Oldham NJ, Bhattacharya S, Gleadle JM, Ratcliffe PJ, Pugh CW, Schofield CJ (2002) Hypoxia inducible factor (HIF) asparagine hydroxylase is identical to factor inhibiting HIF (FIH) and is related to the cupin structural family. J Biol Chem 277:26351–26355PubMedGoogle Scholar
  111. 111.
    Elkins JM, Hewitson KS, McNeill LA, Seibel JF, Schlemminger I, Pugh CW, Ratcliffe PJ, Schofield CJ (2003) Structure of factor-inhibiting hypoxia-inducible factor (HIF) reveals mechanism of oxidative modification of HIF-1α. J Biol Chem 278:1802–1806PubMedGoogle Scholar
  112. 112.
    McDonough MA, Li V, Flashman E, Chowdhury R, Mohr C, Lienard BM, Zondlo J, Oldham NJ, Clifton IJ, Lewis J, McNeill LA, Kurzeja RJ, Hewitson KS, Yang E, Jordan S, Syed RS, Schofield CJ (2006) Cellular oxygen sensing: crystal structure of hypoxia-inducible factor prolyl hydroxylase (PHD2). Proc Natl Acad Sci USA 103:9814–9819PubMedGoogle Scholar
  113. 113.
    Wenger RH, Stiehl DP, Camenisch G (2005) Integration of oxygen signaling at the consensus HRE. Science signal 306:re12Google Scholar
  114. 114.
    Ivan M, Harris AL, Martelli F, Kulshreshtha R (2008) Hypoxia response and microRNAs: no longer two separate worlds. J Cell Mol Med 12:1426–1431PubMedGoogle Scholar
  115. 115.
    Centanin L, Ratcliffe PJ, Wappner P (2005) Reversion of lethality and growth defects in fatiga oxygen-sensor mutant flies by loss of hypoxia-inducible factor-alpha/sima. EMBO Rep 6:1070–1075PubMedGoogle Scholar
  116. 116.
    Koivunen P, Tiainen P, Hyvarinen J, Williams KE, Sormunen R, Klaus SJ, Kivirikko KI, Myllyharju J (2007) An endoplasmic reticulum transmembrane prolyl 4-hydroxylase is induced by hypoxia and acts on hypoxia-inducible factor alpha. J Biol Chem 282:30544–30552PubMedGoogle Scholar
  117. 117.
    Lancaster DE, McNeill LA, McDonough MA, Aplin RT, Hewitson KS, Pugh CW, Ratcliffe PJ, Schofield CJ (2004) Disruption of dimerization and substrate phosphorylation inhibit factor inhibiting hypoxia-inducible factor (FIH) activity. Biochem J 383:429–437PubMedGoogle Scholar
  118. 118.
    Hirsila M, Koivunen P, Gunzler V, Kivirikko KI, Myllyharju J (2003) Characterization of the human prolyl 4-hydroxylases that modify the hypoxia-inducible factor HIF. J Biol Chem 278:30772–30780PubMedGoogle Scholar
  119. 119.
    Koivunen P, Hirsila M, Kivirikko KI, Myllyharju J (2006) The length of peptide substrates has a marked effect on hydroxylation by the hypoxia-inducible factor prolyl 4 hydroxylases. J Biol Chem 281:28712–28720PubMedGoogle Scholar
  120. 120.
    Ehrismann D, Flashman E, Genn DN, Mathioudakis N, Hewitson KS, Ratcliffe PJ, Schofield CJ (2007) Studies on the activity of the hypoxia-inducible factor hydroxylases using an oxygen consumption assay. Biochem J 401:227–234PubMedGoogle Scholar
  121. 121.
    Stolze IP, Tian YM, Appelhoff RJ, Turley H, Wykoff CC, Gleadle JM, Ratcliffe PJ (2004) Genetic analysis of the role of the asparaginyl hydroxylase FIH in regulating HIF transcriptional target genes. J Biol Chem 279:42719–42725PubMedGoogle Scholar
  122. 122.
    Berra E, Benizri E, Ginouves A, Volmat V, Roux D, Pouyssegur J (2003) HIF prolyl-hydroxylase 2 is the key oxygen sensor setting low steady-state levels of HIF-1α in normoxia. EMBO J 22:4082–4090PubMedGoogle Scholar
  123. 123.
    Appelhoff RJ, Tian YM, Raval RR, Turley H, Harris AL, Pugh CW, Ratcliffe PJ, Gleadle JM (2004) Differential function of the prolyl hydroxylases PHD1, PHD2 and PHD3 in the regulation of hypoxia-inducible factor. J Biol Chem 279:38458–38465PubMedGoogle Scholar
  124. 124.
    Tian YM, Mole DR, Ratcliffe PJ, Gleadle JM (2006) Characterization of different isoforms of the HIF prolyl hydroxylase PHD1 generated by alternative initiation. Biochem J 397:179–186PubMedGoogle Scholar
  125. 125.
    Habelhah H, Laine A, Erdjument-Bromage H, Tempst P, Gershwin ME, Bowtell DD, Ronai Z (2004) Regulation of 2-oxoglutarate (alpha-ketoglutarate) dehydrogenase stability by the RING finger ubiquitin ligase Siah. J Biol Chem 279:53782–53788PubMedGoogle Scholar
  126. 126.
    Nakayama K, Frew IJ, Hagensen M, Skals M, Habelhah H, Bhoumik A, Kadoya T, Erdjument-Bromage H, Tempst P, Frappell PB, Bowtell DD, Ronai Z (2004) Siah2 regulates stability of prolyl-hydroxylases, controls HIF1α abundance, and modulates physiological responses to hypoxia. Cell 117:941–952PubMedGoogle Scholar
  127. 127.
    Fukuba H, Yamashita H, Nagano Y, Jin HG, Hiji M, Ohtsuki T, Takahashi T, Kohriyama T, Matsumoto M (2007) Siah-1 facilitates ubiquitination and degradation of factor inhibiting HIF-1alpha (FIH). Biochem Biophys Res Commun 353:324–329PubMedGoogle Scholar
  128. 128.
    Barth S, Nesper J, Hasgall PA, Wirthner R, Nytko KJ, Edlich F, Katschinski DM, Stiehl DP, Wenger RH, Camenisch G (2007) The peptidyl prolyl cis/trans isomerase FKBP38 determines hypoxia-inducible transcription factor prolyl-4-hydroxylase PHD2 protein stability. Mol Cell Biol 27:3758–3768PubMedGoogle Scholar
  129. 129.
    Knowles HJ, Raval RR, Harris AL, Ratcliffe PJ (2003) Effect of ascorbate on the activity of hypoxia inducible factor (HIF) in cancer cells. Cancer Res 63:1764–1768PubMedGoogle Scholar
  130. 130.
    Isaacs JS, Jung YJ, Mole DR, Lee S, Torres-Cabala C, Merino M, Trepel J, Zbar B, Toro J, Ratcliffe PJ, Lineham M, Neckers L (2005) HIF overexpression correlates with biallelic loss of fumarate hydratase in renal cancer: novel role of fumarate in regulation of HIF stability. Cancer Cell 8:143–153PubMedGoogle Scholar
  131. 131.
    Ginouves A, Ilc K, Macias N, Pouyssegur J, Berra E (2008) PHDs overactivation during chronic hypoxia “desensitizes” HIFalpha and protects cells from necrosis. Proc Natl Acad Sci USA 105:4745–4750PubMedGoogle Scholar
  132. 132.
    Wax SD, Tsao L, Lieb ME, Fallon JT, Taubman MB (1996) SM-20 is a novel 40-kd protein whose expression in the arterial wall is restricted to smooth muscle. Lab Invest 74:797–808PubMedGoogle Scholar
  133. 133.
    Willam C, Maxwell PH, Nichols L, Lygate C, Tian YM, Bernhardt W, Wiesener M, Ratcliffe PJ, Eckardt KU, Pugh CW (2006) HIF prolyl hydroxylases in the rat; organ distribution and changes in expression following hypoxia and coronary artery ligation. J Mol Cell Cardiol 41:68–77PubMedGoogle Scholar
  134. 134.
    Metzen E, Berchner-Pfannschmidt U, Stengel P, Marxsen JH, Stolze I, Klinger M, Huang WQ, Wotzlaw C, Hellwig-Burgel T, Jelkmann W, Acker H, Fandrey J (2002) Intracellular localisation of human HIF-1α hydroylases: implications for oxygen sensing. J Cell Sci 116:1319–1326Google Scholar
  135. 135.
    Percy MJ, Zhao Q, Flores A, Harrison C, Lappin TR, Maxwell PH, McMullin MF, Lee FS (2006) A family with erythrocytosis establishes a role for prolyl hydroxylase domain protein 2 in oxygen homeostasis. Proc Natl Acad Sci USA 103:654–659PubMedGoogle Scholar
  136. 136.
    Percy MJ, Furlow PW, Beer PA, Lappin TR, McMullin MF, Lee FS (2007) A novel erythrocytosis-associated PHD2 mutation suggests the location of a HIF binding groove. Blood 110:2193–2196PubMedGoogle Scholar
  137. 137.
    Takeda K, Ho V, Takeda H, Duan LJ, Nagy A, Fong GH (2006) Placental but not heart defect is associated with elevated hif{alpha} levels in mice lacking prolyl hydroxylase domain protein 2. Mol Cell Biol 26:8336–8346PubMedGoogle Scholar
  138. 138.
    Minamishima YA, Moslehi J, Bardeesy N, Cullen D, Bronson RT, Kaelin WG Jr (2008) Somatic inactivation of the PHD2 prolyl hydroxylase causes polycythemia and congestive heart failure. Blood 111:3236–3244PubMedGoogle Scholar
  139. 139.
    Aragones J, Schneider M, Van Geyte K, Fraisl P, Dresselaers T, Mazzone M, Dirkx R, Zacchigna S, Lemieux H, Jeoung NH, Lambrechts D, Bishop T, Lafuste P, Diez-Juan A, Harten SK, Van Noten P, De Bock K, Willam C, Tjwa M, Grosfeld A, Navet R, Moons L, Vandendriessche T, Deroose C, Wijeyekoon B, Nuyts J, Jordan B, Silasi-Mansat R, Lupu F, Dewerchin M, Pugh C, Salmon P, Mortelmans L, Gallez B, Gorus F, Buyse J, Sluse F, Harris RA, Gnaiger E, Hespel P, Van Hecke P, Schuit F, Van Veldhoven P, Ratcliffe P, Baes M, Maxwell P, Carmeliet P (2008) Deficiency or inhibition of oxygen sensor Phd1 induces hypoxia tolerance by reprogramming basal metabolism. Nat Genet 40:170–180PubMedGoogle Scholar
  140. 140.
    Bishop T, Gallagher D, Pascual A, Lygate CA, de Bono JP, Nicholls LG, Ortega-Saenz P, Oster H, Wijeyekoon B, Sutherland AI, Grosfeld A, Aragones J, Schneider M, van Geyte K, Teixeira D, Diez-Juan A, Lopez-Barneo J, Channon KM, Maxwell PH, Pugh CW, Davies AM, Carmeliet P, Ratcliffe PJ (2008) Abnormal sympathoadrenal development and systemic hypotension in PHD3−/− mice. Mol Cell Biol 28:3386–3400PubMedGoogle Scholar
  141. 141.
    Kuznetsova AV, Meller J, Schnell PO, Nash JA, Ignacak ML, Sanchez Y, Conaway JW, Conaway RC, Czyzyk-Krzeska MF (2003) 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 USA 100:2706–2711PubMedGoogle Scholar
  142. 142.
    Mikhaylova O, Ignacak ML, Barankiewicz TJ, Harbaugh SV, Yi Y, Maxwell PH, Schneider M, Van Geyte K, Carmeliet P, Revelo MP, Wyder M, Greis KD, Meller J, Czyzyk-Krzeska MF (2008) 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 28:2701–2717PubMedGoogle Scholar
  143. 143.
    Cummins EP, Berra E, Comerford KM, Ginouves A, Fitzgerald KT, Seeballuck F, Godson C, Nielsen JE, Moynagh P, Pouyssegur J, Taylor CT (2006) Prolyl hydroxylase-1 negatively regulates I{kappa}B kinase-beta, giving insight into hypoxia-induced NF{kappa}B activity. Proc Natl Acad Sci USA 103:18154–18159PubMedGoogle Scholar
  144. 144.
    Xie L, Xiao K, Whalen EJ, Forrester MT, Freeman RS, Fong G, Gygi SP, Lefkowitz RJ, Stamler JS (2009) Oxygen-regulated beta(2)-adrenergic receptor hydroxylation by EGLN3 and ubiquitylation by VHL. Sci Signal 2:ra33Google Scholar
  145. 145.
    Cockman ME, Lancaster DE, Stolze IP, Hewitson KS, McDonough MA, Coleman ML, Coles CH, Yu X, Hay RT, Ley SC, Pugh CW, Oldham NJ, Masson N, Schofield CJ, Ratcliffe PJ (2006) Posttranslational hydroxylation of ankyrin repeats in I{kappa}B proteins by the hypoxia-inducible factor (HIF) asparaginyl hydroxylase, factor inhibiting HIF (FIH). Proc Natl Acad Sci USA 103:14767–14772PubMedGoogle Scholar
  146. 146.
    Coleman ML, McDonough MA, Hewitson KS, Coles C, Mecinovic J, Edelmann M, Cook KM, Cockman ME, Lancaster DE, Kessler BM, Oldham NJ, Ratcliffe PJ, Schofield CJ (2007) Asparaginyl hydroxylation of the Notch ankyrin repeat domain by factor inhibiting hypoxia-inducible factor. J Biol Chem 282:24027–24038PubMedGoogle Scholar
  147. 147.
    Ferguson JE 3rd, Wu Y, Smith K, Charles P, Powers K, Wang H, Patterson C (2007) ASB4 is a hydroxylation substrate of FIH and promotes vascular differentiation via an oxygen-dependent mechanism. Mol Cell Biol 27:6407–6419PubMedGoogle Scholar
  148. 148.
    Zheng X, Linke S, Dias JM, Zheng X, Gradin K, Wallis TP, Hamilton BR, Gustafsson M, Ruas JL, Wilkins S, Bilton RL, Brismar K, Whitelaw ML, Pereira T, Gorman JJ, Ericson J, Peet DJ, Lendahl U, Poellinger L (2008) Interaction with factor inhibiting HIF-1 defines an additional mode of cross-coupling between the Notch and hypoxia signaling pathways. Proc Natl Acad Sci USA 105:3368–3373PubMedGoogle Scholar
  149. 149.
    Gradin K, Takasaki C, Fujii-Kuriyama Y, Sogawa K (2002) The transcriptional activation function of the HIF-like factor requires phosphorylation at a conserved threonine. J Biol Chem 277:23508–23514PubMedGoogle Scholar
  150. 150.
    Sang N, Stiehl DP, Bohensky J, Leshchinsky I, Srinivas V, Caro J (2003) Mitogen-activated protein kinase (MAPK) signaling up-regulates the activity of hypoxia-inducible factors by its effects on p300. J Biol Chem 278:14013–14019PubMedGoogle Scholar
  151. 151.
    Mylonis I, Chachami G, Samiotaki M, Panayotou G, Paraskeva E, Kalousi A, Georgatsou E, Bonanou S, Simos G (2006) Identification of MAPK phosphorylation sites and their role in the localization and activity of hypoxia-inducible factor-1alpha. J Biol Chem 281:33095–33106PubMedGoogle Scholar
  152. 152.
    Mylonis I, Chachami G, Paraskeva E, Simos G (2008) An atypical CRM1-dependent nuclear export signal mediates regulation of hypoxia-inducible factor HIF-1alpha by MAPK. J Biol Chem 283:27620–27627PubMedGoogle Scholar
  153. 153.
    Brugarolas JB, Vazquez F, Reddy A, Sellers WR, Kalin WGJ (2003) TSC2 regulates VEGF through mTOR-dependent and -independent pathways. Cancer Cell 4:147–157PubMedGoogle Scholar
  154. 154.
    Brugarolas J, Kaelin WG Jr (2004) Dysregulation of HIF and VEGF is a unifying feature of the familial hamartoma syndromes. Cancer Cell 6:7–10PubMedGoogle Scholar
  155. 155.
    Brugarolas J, Lei K, Hurley RL, Manning BD, Reiling JH, Hafen E, Witters LA, Ellisen LW, Kaelin WG Jr (2004) Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex. Genes Dev 18:2893–2904PubMedGoogle Scholar
  156. 156.
    Jeong J-W, Bae M–K, Ahn M-Y, Kim S–H, Sohn T-K, Bae M-H, Yoo M-A, Song EJ, Lee K-J, Kim K-W (2002) Regulation and destabilization of HIF-1α by ARD1-mediated acetylation. Cell 111:709–720PubMedGoogle Scholar
  157. 157.
    Bae SH, Jeong JW, Park JA, Kim SH, Bae MK, Choi SJ, Kim KW (2004) Sumoylation increases HIF-1alpha stability and its transcriptional activity. Biochem Biophys Res Commun 324:394–400PubMedGoogle Scholar
  158. 158.
    Fisher TS, Etages SD, Hayes L, Crimin K, Li B (2005) Analysis of ARD1 function in hypoxia response using retroviral RNA interference. J Biol Chem 280:17749–17757PubMedGoogle Scholar
  159. 159.
    Bilton R, Mazure N, Trottier E, Hattab M, Dery MA, Richard DE, Pouyssegur J, Brahimi-Horn MC (2005) ARD1, an acetyltransferase, does not alter stability of hypoxia-inducible factor-1alpha and is not induced by hypoxia or HIF. J Biol Chem 280:31132–31140PubMedGoogle Scholar
  160. 160.
    Arnesen T, Kong X, Evjenth R, Gromyko D, Varhaug JE, Lin Z, Sang N, Caro J, Lillehaug JR (2005) Interaction between HIF-1 alpha (ODD) and hARD1 does not induce acetylation and destabilization of HIF-1 alpha. FEBS Lett 579:6428–6432PubMedGoogle Scholar
  161. 161.
    Berta MA MN, Hattab M, Pouysségur J, Brahimi-Horn MC (2007) SUMOylation of hypoxia-inducible factor-1alpha reduces its transcriptional activity. Biochem Biophys Res Commun 360:646–652PubMedGoogle Scholar
  162. 162.
    Cash TP, Pan Y, Simon MC (2007) Reactive oxygen species and cellular oxygen sensing. Free Radic Biol Med 43:1219–1225PubMedGoogle Scholar
  163. 163.
    Sogawa K, Numayama-Tsuruta K, Ema M, Abe M, Abe H, Fujii-Kuriyama Y (1998) Inhibition of hypoxia-inducible factor 1 activity by nitric oxide donors in hypoxia. Proc Natl Acad Sci USA 95:7368–7373PubMedGoogle Scholar
  164. 164.
    Sandau KB, Zhou J, Kietzmann T, Brune B (2001) Regulation of the hypoxia-inducible factor 1α by the inflammatory mediators nitric oxide and tumor necrosis factor-α in contrast to desferroxamine and phenylarsine oxide. J Biol Chem 276:39805–39811PubMedGoogle Scholar
  165. 165.
    Wang F, Sekine H, Kikuchi Y, Takasaki C, Miura C, Heiwa O, Shuin T, Fujii-Kuriyama Y, Sogawa K (2002) HIF-1a-prolyl hydroxylase: molecular target of nitric oxide in the hypoxic signal transduction pathway. Biochem Biophys Res Commun 295:657–662PubMedGoogle Scholar
  166. 166.
    Metzen E, Zhou J, Jelkmann W, Fandrey J, Brune B (2003) Nitric oxide impairs normoxic degradation of HIF-1alpha by inhibition of prolyl hydroxylases. Mol Biol Cell 14:3470–3481PubMedGoogle Scholar
  167. 167.
    Berchner-Pfannschmidt U, Yamac H, Trinidad B, Fandrey J (2007) Nitric oxide modulates oxygen sensing by hypoxia-inducible factor 1-dependent induction of prolyl hydroxylase 2. J Biol Chem 282:1788–1796PubMedGoogle Scholar
  168. 168.
    Hagen T, Taylor CT, Lam F, Moncada S (2003) Redistribution of intracellular oxygen in hypoxia by nitric oxide: effect on HIF-1α. Science 302:1975–1978PubMedGoogle Scholar
  169. 169.
    Baek JH, Mahon PC, Oh J, Kelly B, Krishnamachary B, Pearson M, Chan DA, Giaccia AJ, Semenza GL (2005) OS-9 interacts with hypoxia-inducible factor 1alpha and prolyl hydroxylases to promote oxygen-dependent degradation of HIF-1alpha. Molecular Cell 17:503–512PubMedGoogle Scholar
  170. 170.
    Ozer A, Wu LC, Bruick RK (2005) The candidate tumor suppressor ING4 represses activation of the hypoxia inducible factor (HIF). Proc Natl Acad Sci USA 102:7481–7486PubMedGoogle Scholar
  171. 171.
    Hopfer U, Hopfer H, Jablonski K, Stahl RA, Wolf G (2006) The novel WD-repeat protein Morg1 acts as a molecular scaffold for hypoxia-inducible factor prolyl hydroxylase 3 (PHD3). J Biol Chem 281:8645–8655PubMedGoogle Scholar
  172. 172.
    Masson N, Appelhoff RJ, Tuckerman JR, Tian YM, Demol H, Puype M, Vandekerckhove J, Ratcliffe PJ, Pugh CW (2004) The HIF prolyl hydroxylase PHD3 is a potential substrate of the TRiC chaperonin. FEBS Lett 570:166–170PubMedGoogle Scholar
  173. 173.
    Bracken CP, Whitelaw ML, Peet DJ (2005) Activity of hypoxia-inducible factor 2 alpha (HIF-2 alpha) is regulated by association with the NF-kappa B essential modulator (NEMO/IKK gamma). J Biol Chem 280:14240–14251PubMedGoogle Scholar
  174. 174.
    Bhattacharya S, Michels CL, Leung M–K, Arany ZP, Kung AL, Livingston DM (1999) Functional role of p35srj, a novel p300/CBP binding protein, during transactivation by HIF-1. Genes Dev 13:64–75PubMedGoogle Scholar
  175. 175.
    Alam NA, Rowan AJ, Wortham NC, Pollard PJ, Mitchell M, Tyrer JP, Barclay E, Calonje E, Manek S, Adams SJ, Bowers PW, Burrows NP, Charles-Holmes R, Cook LJ, Daly BM, Ford GP, Fuller LC, Hadfield-Jones SE, Hardwick N, Highet AS, Keefe M, MacDonald-Hull SP, Potts EDA, Crone M, Wilkinson S, Camacho-Martinez F, Jablonska S, Ratnavel R, MacDonald A, Mann RJ, Grice K, Guillet G, Lewis-Jones MS, McGrath H, Seukeran DC, Morrison PJ, Fleming S, Rahman S, Kelsell D, Leigh I, Olpin S, Tomlinson IPM (2003) Genetic and functional analyses of FH mutations in multiple cutaneous and uterine leiomyomatosis, heritary leiomyomatosis and renal cancer, and fumarate hydratase deficiency. Hum Mol Genet 12:1241–1252PubMedGoogle Scholar
  176. 176.
    Pollard PJ, Briere JJ, Alam NA, Barwell J, Barclay E, Wortham NC, Hunt T, Mitchell M, Olpin S, Moat SJ, Hargreaves IP, Heales SJ, Chung YL, Griffiths JR, Dalgleish A, McGrath JA, Gleeson MJ, Hodgson SV, Poulsom R, Rustin P, Tomlinson IP (2005) Accumulation of Krebs cycle intermediates and over-expression of HIF1alpha in tumours which result from germline FH and SDH mutations. Hum Mol Genet 14:2231–2239PubMedGoogle Scholar
  177. 177.
    Pollard PJ, Spencer-Dene B, Shukla D, Howarth K, Nye E, El-Bahrawy M, Deheragoda M, Joannou M, MacDonald S, Martin A, Igarashi P, Varsani-Brown S, Rosewell I, Poulsom R, Maxwell PH, Stamp GW, Tomlinson IP (2007) Targeted inactivation of Fh1 causes proliferative renal cyst development and activation of the hypoxia pathway. Cancer Cell 11:311–319PubMedGoogle Scholar
  178. 178.
    Thrash-Bingham CA, Tartof KD (1999) aHIF: a natural antisense transcript overexpressed in human renal cancer and during hypoxia. J Natl Cancer Inst 91:143–151PubMedGoogle Scholar
  179. 179.
    Semenza GL (2001) Hypoxia-inducible factor 1: control of oxygen homeostasis in health and disease. Pediatr Res 49:614–617PubMedGoogle Scholar
  180. 180.
    Semenza GL (2001) Hypoxia-inducible factor 1: oxygen homeostasis and disease pathophysiology. Trends Mol Med 7:345–350PubMedGoogle Scholar
  181. 181.
    Vincent KA, Shyu KG, Luo Y, Magner M, Tio RA, Jiang C, Goldberg MA, Akita GY, Gregory RJ, Isner JM (2000) Angiogenesis is induced in a rabbit model of hindlimb ischemia by naked DNA encoding an HIF-1a/VP16 hybrid transcription factor. Circulation 102:2255–22561PubMedGoogle Scholar
  182. 182.
    Shyu KG, Wang MT, Wang BW, Chang CC, Leu JG, Kuan P, Chang H (2002) Intramyocardial injection of naked DNA encoding HIF-1α/VP16 hybrid to enhance angiogenesis in an acute myocardial infarction model in the rat. Cardiovasc Res 54:576–583PubMedGoogle Scholar
  183. 183.
    Philipp S, Cui L, Ludolph B, Kelm M, Schulz R, Cohen MV, Downey JM (2006) Desferoxamine and ethyl-3, 4-dihydroxybenzoate protect myocardium by activating NOS and generating mitochondrial ROS. Am J Physiol Heart Circ Physiol 290:H450–H457PubMedGoogle Scholar
  184. 184.
    Xi L, Taher M, Yin C, Salloum F, Kukreja RC (2004) Cobalt chloride induces delayed cardiac preconditioning in mice through selective activation of HIF-1alpha and AP-1 and iNOS signaling. Am J Physiol Heart Circ Physiol 287:H2369–H2375PubMedGoogle Scholar
  185. 185.
    Nwogu NI, Greenen D, Bean M, Brenner MC, Huang X, Buttrick PM (2001) Inhibition of collagen synthesis with prolyl 4-hydroxylase inhibitor improves left ventricular function and alters the pattern of left ventricular dilatation after myocardial infarction. Circulation 104:2216–2221PubMedGoogle Scholar
  186. 186.
    Ivan M, Haberberger T, Gervasi DC, Michelson KS, Gunzler V, Kondo K, Yang H, Sorokina I, Conaway RC, Conaway JW, Kaelin WG Jr (2002) Biochemical purification and pharmacological inhibition of a mammalian prolyl hydroxylase acting on hypoxia-inducible factor. Proc Natl Acad Sci USA 99:13459–13464PubMedGoogle Scholar
  187. 187.
    Warnecke C, Griethe W, Weidemann A, Jurgensen JS, Willam C, Bachmann S, Ivashchenko Y, Wagner I, Frei U, Wiesener M, Eckardt KU (2003) Activation of the hypoxia-inducible factor-pathway and stimulation of angiogenesis by application of prolyl hydroxylase inhibitors. FASEB J 17:1186–1188PubMedGoogle Scholar
  188. 188.
    Milkiewicz M, Pugh CW, Egginton S (2004) Inhibition of endogenous HIF inactivation induces angiogenesis in ischaemic skeletal muscles of mice. J Physiol 560:21–26PubMedGoogle Scholar
  189. 189.
    Philipp S, Jurgensen JS, Fielitz J, Bernhardt WM, Weidemann A, Schiche A, Pilz B, Dietz R, Regitz-Zagrosek V, Eckardt KU, Willenbrock R (2006) Stabilization of hypoxia inducible factor rather than modulation of collagen metabolism improves cardiac function after acute myocardial infarction in rats. Eur J Heart Fail 8:347–354PubMedGoogle Scholar
  190. 190.
    Bernhardt WM, Campean V, Kany S, Jurgensen JS, Weidemann A, Warnecke C, Arend M, Klaus S, Gunzler V, Amann K, Willam C, Wiesener MS, Eckardt KU (2006) Preconditional activation of hypoxia-inducible factors ameliorates ischemic acute renal failure. J Am Soc Nephrol 17:1970–1978PubMedGoogle Scholar
  191. 191.
    Kung AL, Wang S, Klco JM, Kaelin WG, Livingston DM (2000) Suppression of tumor growth through disruption of hypoxia-inducible transcription. Nat Med 6:1335–1340PubMedGoogle Scholar
  192. 192.
    Kung AL, Zabludoff SD, France DS, Freedman SJ, Tanner EA, Vieira A, Cornell-Kennon S, Lee J, Wang B, Wang J, Memmert K, Naegeli HU, Petersen F, Eck MJ, Bair KW, Wood AW, Livingston DM (2004) Small molecule blockade of transcriptional coactivation of the hypoxia-inducible factor pathway. Cancer Cell 6:33–43PubMedGoogle Scholar
  193. 193.
    Carroll VA, Ashcroft M (2006) Role of hypoxia-inducible factor (HIF)-1alpha versus HIF-2alpha in the regulation of HIF target genes in response to hypoxia, insulin-like growth factor-I, or loss of von Hippel-Lindau function: implications for targeting the HIF pathway. Cancer Res 66:6264–6270PubMedGoogle Scholar
  194. 194.
    Zhang H, Gao P, Fukuda R, Kumar G, Krishnamachary B, Zeller KI, Dang CV, Semenza GL (2007) HIF-1 inhibits mitochondrial biogenesis and cellular respiration in VHL-deficient renal cell carcinoma by repression of C-MYC activity. Cancer Cell 11:407–420PubMedGoogle Scholar
  195. 195.
    Aravind L, Koonin EV (2001) The DNA-repair protein AlkB, EGL-9, and leprecan define new families of 2-oxoglutarate- and iron-dependent dioxygenases. Genome Biol 2:RESEARCH0007PubMedGoogle Scholar
  196. 196.
    Hewitson KS, Granatino N, Welford RW, McDonough MA, Schofield CJ (2005) Oxidation by 2-oxoglutarate oxygenases: non-haem iron systems in catalysis and signalling. Philos Transact A Math Phys Eng Sci 363:807–828PubMedGoogle Scholar
  197. 197.
    Duncan T, Trewick SC, Koivisto P, Bates PA, Lindahl T, Sedgwick B (2002) Reversal of DNA alkylation damage by two human dioxygenases. Proc Natl Acad Sci USA 99:16660–16665PubMedGoogle Scholar
  198. 198.
    Trewick SC, McLaughlin PJ, Allshire RC (2005) Methylation: lost in hydroxylation? EMBO Rep 6:315–320PubMedGoogle Scholar
  199. 199.
    Valegard K, van Scheltinga AC, Lloyd MD, Hara T, Ramaswamy S, Perrakis A, Thompson A, Lee HJ, Baldwin JE, Schofield CJ, Hajdu J, Andersson I (1998) Structure of a cephalosporin synthase. Nature 394:805–809PubMedGoogle Scholar
  200. 200.
    Kivirikko KI, Myllyla R (1980) The hydroxylation of prolyl and lysyl residues. In: Freeman RB, Hawkins HC (eds) The enzymology of post-translational modification of proteins. Academic Press, London, pp 53–104Google Scholar
  201. 201.
    Gerken T, Girard CA, Tung YC, Webby CJ, Saudek V, Hewitson KS, Yeo GS, McDonough MA, Cunliffe S, McNeill LA, Galvanovskis J, Rorsman P, Robins P, Prieur X, Coll AP, Ma M, Jovanovic Z, Farooqi IS, Sedgwick B, Barroso I, Lindahl T, Ponting CP, Ashcroft FM, O’Rahilly S, Schofield CJ (2007) The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase. Sciencexpress 318:1469–1472Google Scholar
  202. 202.
    Mukherji M, Chien W, Kershaw NJ, Clifton IJ, Schofield CJ, Wierzbicki AS, Lloyd MD (2001) Structure–function analysis of phytanoyl-CoA 2-hydroxylase mutations causing Refsum’s disease. Hum Mol Genet 10:1971–1982PubMedGoogle Scholar
  203. 203.
    Wierzbicki AS, Mitchell J, Lambert-Hammill M, Hancock M, Greenwood J, Sidey MC, de Belleroche J, Gibberd FB (2000) Identification of genetic heterogeneity in Refsum’s disease. Eur J Hum Genet 8:649–651PubMedGoogle Scholar
  204. 204.
    Whetstine JR, Nottke A, Lan F, Huarte M, Smolikov S, Chen Z, Spooner E, Li E, Zhang G, Colaiacovo M, Shi Y (2006) Reversal of histone lysine trimethylation by the JMJD2 family of histone demethylases. Cell 125:467–481PubMedGoogle Scholar
  205. 205.
    Tsukada Y, Fang J, Erdjument-Bromage H, Warren ME, Borchers CH, Tempst P, Zhang Y (2006) Histone demethylation by a family of JmjC domain-containing proteins. Nature 439:811–816PubMedGoogle Scholar
  206. 206.
    Frescas D, Guardavaccaro D, Bassermann F, Koyama-Nasu R, Pagano M (2007) JHDM1B/FBXL10 is a nucleolar protein that represses transcription of ribosomal RNA genes. Nature 450:309–313PubMedGoogle Scholar
  207. 207.
    Hulse JD, Ellis SR, Henderson LM (1978) Carnitine biosynthesis beta-hydroxylation of trimethyllysine by an alpha-ketoglutarate-dependent mitochondrial dioxygenase. J Biol Chem 253:1654–1659PubMedGoogle Scholar
  208. 208.
    Lindblad B, Lindstedt G, Tofft M, Lindstedt S (1969) The mechanism of alpha-ketoglutarate oxidation in coupled enzymatic reactions. J Am Chem Soc 91:4604–4606Google Scholar
  209. 209.
    Lindstedt G, Lindstedt S (1970) Co-factor requirements of gamma-butyrobetaine hydroxylase from rat liver. J Biol Chem 245:4178–4186PubMedGoogle Scholar
  210. 210.
    Vaz FM, Wanders RJ (2002) Carnitine biosynthesis in mammals. Biochem J 361:417–429PubMedGoogle Scholar
  211. 211.
    Hanson ES, Rawlins ML, Leibold EA (2003) Oxygen and iron regulation of iron regulatory protein 2. J Biol Chem 278:40337–40342PubMedGoogle Scholar

Copyright information

© Birkhäuser Verlag, Basel/Switzerland 2009

Authors and Affiliations

  • James D. Webb
    • 1
  • Mathew L. Coleman
    • 1
  • Christopher W. Pugh
    • 1
    Email author
  1. 1.Henry Wellcome Building for Molecular PhysiologyUniversity of OxfordOxfordUK

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