Skip to main content
SpringerLink
Log in

Therapeutic Strategies that Target the HIF System

  • Chapter
Angiogenesis

  • 2792 Accesses

Human cells respond to conditions of limiting oxygen by a switching on a response involving a gene array regulated by the transcription factor hypoxia inducible factor (HIF). This hypoxic response works both to limit the damage of hypoxia and improve oxygen supply to tissues including by upregulating angiogenesis and erythropoiesis. Studies on the molecular mechanism of the HIF system have identified a mechanism by which the HIF system senses changes in oxygen levels. Degradation of the HIF-α subunit by the ubiquitin proteasome pathway is signalled for by oxygenase catalyzed post-translational prolyl-hydroxylation. HIF-α asparaginyl hydroxylation reduces by the transcriptional activity of HIF. The dependence of the HIF hydroxylase on oxygen for catalysis enables an oxygen dependent response. Modulation of the activity of HIF is a potential therapeutic avenue for the treatment of both ischemic disease and cancer. This chapter summarises the molecular components of the HIF system and ongoing therapeutic strategies.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 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; 12:5447–5454.

    PubMed  CAS  Google Scholar 

  2. Wang GL, Semenza GL. General involvement of hypoxia-inducible factor 1 in transcriptional response to hypoxia. Proc Natl Acad Sci USA 1993; 90:4304–4308.

    PubMed  CAS  Google Scholar 

  3. Maxwell PH, Pugh CW, Ratcliffe PJ. Inducible operation of the erythropoietin 3’ enhancer in multiple cell lines: Evidence for a widespread oxygen-sensing mechanism. Proc Natl Acad Sci USA 1993; 90:2423–2427.

    PubMed  CAS  Google Scholar 

  4. Wang GL, Semenza GL. Purification and characterization of hypoxia-inducible factor 1. J Biol Chem 1995; 270:1230–1237.

    PubMed  CAS  Google Scholar 

  5. Wang GL, Semenza GL. Characterization of hypoxia-inducible factor 1 and regulation of DNA binding activity by hypoxia. J Biol Chem 1993; 268:21513–21518.

    PubMed  CAS  Google Scholar 

  6. Semenza GL. Hypoxia-inducible factor 1: oxygen homeostasis and disease pathophysiology. Trends Mol Med 2001; 7: 345–350.

    PubMed  CAS  Google Scholar 

  7. Wenger RH. Cellular adaptation to hypoxia: O2-sensing protein hydroxylases, hypoxia-inducible transcription factors, and O2-regulated gene expression. FASEB J 2002; 16:1151–1162.

    PubMed  CAS  Google Scholar 

  8. Pugh CW, Ratcliffe PJ. Regulation of angiogenesis by hypoxia: role of the HIF system. Nat Med 2003; 9:677–684.

    PubMed  CAS  Google Scholar 

  9. Semenza GL. Targeting HIF-1 for cancer therapy. Nat Rev Cancer 2003; 3:721–732.

    PubMed  CAS  Google Scholar 

  10. Huang LE, Bunn HF. Hypoxia-inducible Factor and Its Biomedical Relevance. J Biol Chem 2003; 278:19575–19578.

    PubMed  CAS  Google Scholar 

  11. Ema M, Taya S, Yokotani N, et al. A novel bHLH-PAS factor with close sequence similarity to hypoxia-inducible factor 1 alpha regulates the VEGF expression and is potentially involved in lung and vascular development. Proc Natl Acad Sci USA 1997; 94:4273–4278.

    PubMed  CAS  Google Scholar 

  12. Hogenesch JB, Chan WK, Jackiw VH, et al. Characterization of a subset of the basic-helix-loop-helix-PAS superfamily that interacts with components of the dioxin signaling pathway. J Biol Chem 1997; 272:8581–8593.

    PubMed  CAS  Google Scholar 

  13. Tian H, McKnight SL, Russell DW. Endothelial PAS domain protein 1 (EPAS1), a transcription factor selectively expressed in endothelial cells. Genes Dev 1997; 11:72–82.

    PubMed  CAS  Google Scholar 

  14. Flamme I, Frohlich T, von Reutern M, et al. 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 Develop 1997; 63: 51–60.

    CAS  Google Scholar 

  15. Gu YZ, Moran SM, Hogenesch JB, et al. Molecular characterization and chromosomal localization of a third alpha-class hypoxia inducible factor subunit, HIF-3alpha. Gene Expression 1998; 7:205–213.

    PubMed  CAS  Google Scholar 

  16. Makino Y, Cao R, Svensson K, et al. Inhibitory PAS domain protein is a negative regulator of hypoxia-inducible gene expression. Nature 2001; 414:550–554.

    PubMed  CAS  Google Scholar 

  17. Pugh CW, O’Rourke JF, Nagao M, et al. Activation of hypoxia-inducible factor-1; Definition of regulatory domains within the alpha subunit. J Biol Chem 1997; 272:11205–11214.

    PubMed  CAS  Google Scholar 

  18. Jiang BH, Zheng JZ, Leung SW, et al. Transactivation and inhibitory domains of hypoxia-inducible factor 1 alpha. Modulation of transcriptional activity by oxygen tension. J Biol Chem 1997; 272:19253–19260.

    PubMed  CAS  Google Scholar 

  19. Huang LE, Gu J, Schau M, et al. Regulation of hypoxia-inducible factor 1alpha is mediated by an O2-dependent degradation domain via the ubiquitin-proteasome pathway. Proc Natl Acad Sci USA 1998; 95:7987–7992.

    PubMed  CAS  Google Scholar 

  20. Maxwell PH, Wiesener MS, Chang GW, et al. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 1999; 399:271–275.

    PubMed  CAS  Google Scholar 

  21. Ohh M, Park CW, Ivan M, et al. Ubiquitination of hypoxia-inducible factor requires direct binding to the [bgr]-domain of the von Hippel-Lindau protein. Nat Cell Biol 2000; 2: 423–427.

    PubMed  CAS  Google Scholar 

  22. Lando D, Peet DJ, Whelan DA, Gorman JJ, Whitelaw ML. Asparagine hydroxylation of the HIF transactivation domain: A hypoxic switch. Science 2002; 295:858–861.

    PubMed  CAS  Google Scholar 

  23. Chun YS, Choi E, Yeo EJ, et al. A new HIF-1 alpha variant induced by zinc ion suppresses HIF-1-mediated hypoxic responses. J Cell Sci 2001; 114:4051–4061.

    PubMed  CAS  Google Scholar 

  24. Thrash-Bingham CA, Tartof KD. aHIF: a natural antisense transcript overexpressed in human renal cancer and during hypoxia. J Natl Cancer Inst 1999; 91:143–151.

    PubMed  CAS  Google Scholar 

  25. Chun YS, Choi E, Kim TY, et al. A dominant-negative isoform lacking exons 11 and 12 of the human hypoxia-inducible factor-1alpha gene. Biochem J 2002; 362:71–79.

    PubMed  CAS  Google Scholar 

  26. Semenza GL. HIF-1 and mechanisms of hypoxia sensing. Curr Opin Cell Biol 2001; 13:167–171.

    PubMed  CAS  Google Scholar 

  27. Erbel PJA, Card PB, Karakuzu O, et al. Structural basis for PAS domain heterodimerization in the basic helix-loop-helix-PAS transcription factor hypoxia-inducible factor. Proc Natl Acad Sci USA 2003; 100:15504–15509.

    PubMed  CAS  Google Scholar 

  28. Card PB, Erbel PJA, Gardner KH. Structural basis of ARNT PAS-B dimerization: Use of a common beta-sheet interface for hetero- and homodimerization. J Mol Bio 2005; 353:664–677.

    CAS  Google Scholar 

  29. Schofield CJ, Ratcliffe PJ. Oxygen sensing by HIF hydroxylases. Nat Rev Mol Cell Biol 2004; 5:343–354.

    PubMed  CAS  Google Scholar 

  30. Schofield CJ, Ratcliffe PJ. Signalling hypoxia by HIF hydroxylases. Biochem Bioph Res Co 2005; 338:617–626.

    CAS  Google Scholar 

  31. Kaelin WG. Proline hydroxylation and gene expression. Annu Rev Biochem 2005; 74:115–128.

    PubMed  CAS  Google Scholar 

  32. Dann III CE, Bruick RK. Dioxygenases as O2-dependent regulators of the hypoxic response pathway. Biochem Bioph Res Commun 2005; 338:639–647.

    CAS  Google Scholar 

  33. Yu F, White SB, Zhao Q, et al. HIF-1alpha binding to VHL is regulated by stimulus-sensitive proline hydroxylation. Proc Natl Acad Sci USA 2001; 98:9630–9635.

    PubMed  CAS  Google Scholar 

  34. Ivan M, Kondo K, Yang H, et al. HIF4 Targeted for VHL-Mediated Destruction by Proline Hydroxylation: Implications for O2 Sensing. Science 2001; 292:464–468.

    PubMed  CAS  Google Scholar 

  35. Jaakkola P, Mole DR, Tian YM, et al. Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 2001; 292:468–472.

    PubMed  CAS  Google Scholar 

  36. Masson N, William C, Maxwell PH, et al. Independent function of two destruction domains in hypoxia-inducible factor-alpha chains activated by prolyl hydroxylation. EMBO 2001; 20: 5197–5206.

    CAS  Google Scholar 

  37. Hon WC, Wilson MI, Harlos K, et al. Structural basis for the recognition of hydroxyproline in HIF-1α by pVHL. Nature 2002; 417:975–978.

    PubMed  CAS  Google Scholar 

  38. Min JH, Yang H, Ivan M, et al. Structure of an HIF-1alpha -pVHL complex: Hydroxyproline recognition in signaling. Science 2002; 296:1886–1889.

    PubMed  CAS  Google Scholar 

  39. Kaelin WG. The von Hippel-Lindau tumor suppressor protein: Roles in cancer and oxygen sensing. Cold Spring Harb Sym 2005; 70:159–166.

    CAS  Google Scholar 

  40. Semenza GL. VHL and p53: Tumor suppressors team up to prevent cancer. Mol Cell 2006; 22:437–439.

    PubMed  CAS  Google Scholar 

  41. Haase VH. The VHL//HIF oxygen-sensing pathway and its relevance to kidney disease. Kidney Int 2006; 69:1302–1307.

    PubMed  CAS  Google Scholar 

  42. Kaelin J. The von Hippel-Lindau protein, HIF hydroxylation, and oxygen sensing. Biochem Bioph Res Commun 2005; 338: 627–638.

    CAS  Google Scholar 

  43. Kaelin WG. Molecular basis of the VHL hereditary cancer syndrome. Nat Rev Cancer 2002; 2:673–682.

    PubMed  CAS  Google Scholar 

  44. Epstein ACR, 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; 107:43–54.

    PubMed  CAS  Google Scholar 

  45. Bruick RK, McKnight SL. A conserved family of prolyl-4-hydroxylases that modify HIF. Science 2001; 294:1337–1340.

    PubMed  CAS  Google Scholar 

  46. Elvidge GP, Glenny L, Appelhoff RJ, et al. Concordant regulation of gene expression by hypoxia and 2-oxoglutarate-dependent dioxygenase inhibition: the role of HIF-1α, HIF-2α, and other pathways. J Biol Chem 2006; 281:15215–15226.

    PubMed  CAS  Google Scholar 

  47. Hirsila M, Koivunen P, Gunzler V, et al. Characterization of the human prolyl 4-hydroxylases that modify the hypoxia-inducible factor. J Biol Chem 2003; 278:30772–30780.

    PubMed  Google Scholar 

  48. Schofield CJ, Zhang Z. Structural and mechanistic studies on 2-oxoglutarate-dependent oxygenases and related enzymes. Curr Opin Struc Biol 1999; 9:722–731.

    CAS  Google Scholar 

  49. Clifton IJ, McDonough MA, Ehrismann D, et al. Structural studies on 2-oxoglutarate oxygenases and related double-stranded β-helix fold proteins. J Inorg Biochem 2006; 100:644–669.

    PubMed  CAS  Google Scholar 

  50. Costas M, Mehn MP, Jensen MP, et al. Dioxygen activation at mononuclear nonheme iron active sites: Enzymes, models, and intermediates. Chem Rev 2004; 104:939–986.

    PubMed  CAS  Google Scholar 

  51. Hausinger RP. Fe(II)/{alpha}-ketoglutarate-dependent hydroxylases and related enzymes. Crit Rev Biochem Mol Biol 2004; 39:21–68.

    PubMed  CAS  Google Scholar 

  52. Hegg EL, Que Jr L. The 2-His-1-carboxylate facial triad - An emerging structural motif in mononuclear non-heme iron(II) enzymes. Eur J Biochem 1997; 250:625–629.

    PubMed  CAS  Google Scholar 

  53. Ryle MJ, Hausinger RP. Non-heme iron oxygenases. Curr Opin Chem Biol 2002; 6:193–201.

    PubMed  CAS  Google Scholar 

  54. Berra E, Benizri E, Ginouves A, et al. HIF prolyl-hydroxylase 2 is the key oxygen sensor setting low steady-state levels of HIF-1α in normoxia. EMBO J 2003; 22:4082–4090.

    PubMed  CAS  Google Scholar 

  55. McDonough MA, Li V, Flashman E, et al. Cellular oxygen sensing: Crystal structure of hypoxia-inducible factor prolyl hydroxylase (PHD2). Proc Natl Acad Sci USA 2006; 103:9814–9819.

    PubMed  CAS  Google Scholar 

  56. Jiang BH, Semenza GL, Bauer C, et al. Hypoxia-inducible factor 1 levels vary exponentially over a physiologically relevant range of O2 tension. Am J Physiol Cell Physiol 1996; 271: C1172–C1180.

    CAS  Google Scholar 

  57. Ehrismann D, Flashman E, Genn DN, Mathioudakis N, et al. Studies on the activity of the hypoxia-inducible-factor hydroxylases using an oxygen consumption assay. Biochem J 2007; 401:227–234.

    PubMed  CAS  Google Scholar 

  58. Koivunen P, Hirsila M, Kivirikko KI, et al. The length of peptide substrates has a marked effect on hydroxylation by the hypoxia-inducible factor prolyl 4-hydroxylases. J Biol Chem 2006; 281:28712–28720.

    PubMed  CAS  Google Scholar 

  59. 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 USA 2006; 103:654–659.

    PubMed  CAS  Google Scholar 

  60. McNeill LA, Hewitson KS, Claridge TD, et al. Hypoxia-inducible factor asparaginyl hydroxylase (FIH-1) catalyses hydroxylation at the beta-carbon of asparagine-803. Biochem J 2002; 367:571–575.

    PubMed  CAS  Google Scholar 

  61. Hewitson KS, McNeill LA, Riordan MV, et al. Hypoxia-inducible factor (HIF) asparagine hydroxylase is identical to factor inhibiting HIF (FIH) and is related to the cupin structural family. J Biol Chem 2002; 277:26351–26355.

    PubMed  CAS  Google Scholar 

  62. Freedman SJ, Sun ZY, Poy F, et al. Structural basis for recruitment of CBP/p300 by hypoxia-inducible factor-1alpha. Proc Natl Acad Sci USA 2002; 99:5367–5372.

    PubMed  CAS  Google Scholar 

  63. Dames SA, Martinez-Yamout M, De Guzman RN, et al. Structural basis for Hif-1alpha /CBP recognition in the cellular hypoxic response. Proc Natl Acad Sci USA 2002; 99: 5271–5276.

    PubMed  CAS  Google Scholar 

  64. Mahon PC, Hirota K, Semenza GL. FIH-1: a novel protein that interacts with HIF-1alpha and VHL to mediate repression of HIF-1 transcriptional activity. Genes Dev 2001; 15:2675–2686.

    PubMed  CAS  Google Scholar 

  65. Linke S, Stojkoski C, Kewley RJ, et al. Substrate requirements of the oxygen-sensing asparaginyl hydroxylase factor-inhibiting hypoxia-inducible factor. J Biol Chem 2004; 279:14391–14397.

    PubMed  CAS  Google Scholar 

  66. Huang J, Zhao Q, Mooney SM, et al. Sequence determinants in hypoxia-inducible factor-1 alpha for hydroxylation by the prolyl hydroxylases PHD1, PHD2, and PHD3. J Biol Chem 2002; 277:39792–39800.

    PubMed  CAS  Google Scholar 

  67. Li D, Hirsila M, Koivunen P, et al. Many amino acid substitutions in a hypoxia-inducible transcription factor (HIF)-1{alpha}-like peptide cause only minor changes in its hydroxylation by the HIF prolyl 4-hydroxylases: Substitution of 3, 4-dehydroproline or azetidine-2-carboxylic acid for the proline leads to a high rate of uncoupled 2-oxoglutarate decarboxylation. J Biol Chem 2004; 279:55051–55059.

    PubMed  CAS  Google Scholar 

  68. Dann CE, III, Bruick RK, Deisenhofer J. Structure of factor-inhibiting hypoxia-inducible factor 1: An asparaginyl hydroxylase involved in the hypoxic response pathway. Proc Natl Acad Sci USA 2002; 99:15351–15356.

    PubMed  CAS  Google Scholar 

  69. Hewitson KS, Lienard BMR, McDonough MA, et al. Structural and mechanistic studies on the inhibition of the HIF hydroxylases by tricarboxylic acid cycle intermediates. J Biol Chem 2006; in press.

    Google Scholar 

  70. Chen Z, Zang J, Whetstine J, et al. Structural insights into histone demethylation by JMJD2 family members. Cell 2006; 125: 691–702.

    PubMed  CAS  Google Scholar 

  71. Trewick SC, McLaughlin PJ, Allshire RC. Methylation: lost in hydroxylation? EMBO Rep 2005; 6:315–320.

    PubMed  CAS  Google Scholar 

  72. Elkins JM, Hewitson KS, McNeill LA, et al. Structure of factor-inhibiting hypoxia-inducible factor (HIF) reveals mechanism of oxidative modification of HIF-1 alpha. J Biol Chem 2003; 278:1802–1806.

    PubMed  CAS  Google Scholar 

  73. Lee C, Kim SJ, Jeong DG, et al. Structure of human FIH-1 reveals a unique active site pocket and interaction sites for HIF-1 and von Hippel-Lindau. J Biol Chem 2003; 278:7558–7563.

    PubMed  CAS  Google Scholar 

  74. Cockman ME, Lancaster DE, Stolze IP, et al. 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 2006; 103: 14767–14772.

    PubMed  CAS  Google Scholar 

  75. 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 USA 2003; 100:2706–2711.

    PubMed  CAS  Google Scholar 

  76. Cummins EP, Berra E, Comerford KM, et al. Prolyl hydroxylase-1 negatively regulates IκB kinase-beta, giving insight into hypoxia-induced NFκB activity. Proc Natl Acad Sci USA 2006; 103:18154–18159.

    PubMed  CAS  Google Scholar 

  77. Falnes PO, Johansen RF, Seeberg E. AlkB-mediated oxidative demethylation reverses DNA damage in Escherichia coli. Nature 2002; 419:178–182.

    PubMed  CAS  Google Scholar 

  78. Trewick SC, Henshaw TF, Hausinger RP, et al. Oxidative demethylation by Escherichia coli AlkB directly reverts DNA base damage. Nature 2002; 419:174–178.

    PubMed  CAS  Google Scholar 

  79. McNeill LA, Flashman E, Buck MRG, et al. Hypoxia-inducible factor prolyl hydroxylase 2 has a high affinity for ferrous iron and 2-oxoglutarate. Mol Biosyst 2005; 1:321–324.

    PubMed  CAS  Google Scholar 

  80. Prockop JD. Collagens: Molecular biology, diseases, and potentials for therapy. Annu Rev Biochem 1995; 64:403–434.

    PubMed  CAS  Google Scholar 

  81. King A, Selak MA, Gottlieb E. Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer. Oncogene; 25:4675–4682.

    Google Scholar 

  82. Koivunen P, Hirsila M, Remes AM, et bal. Inhibition of HIF hydroxylases by citric acid cycle intermediates: Possible links between cell metabolism and stabilization of HIF. J Biol Chem 2006; in press.

    Google Scholar 

  83. Metzen E, Zhou J, Jelkmann W, et al. Nitric oxide impairs normoxic degradation of HIF-1α by inhibition of prolyl hydroxylases. Mol Biol Cell 2003; 14:3470–3481.

    PubMed  CAS  Google Scholar 

  84. Kimura H, Weisz A, Kurashima Y, et al. Hypoxia response element of the human vascular endothelial growth factor gene mediates transcriptional regulation by nitric oxide: control of hypoxia-inducible factor-1 activity by nitric oxide. Blood 2000; 95:189–197.

    PubMed  CAS  Google Scholar 

  85. Wang F, Sekine H, Kikuchi Y, et al. HIF-1α-prolyl hydroxylase: molecular target of nitric oxide in the hypoxic signal transduction pathway. Biochem Bioph Res Commun 2002; 295: 657–662.

    CAS  Google Scholar 

  86. Agani FH, Puchowicz M, Chavez JC, et al. Role of nitric oxide in the regulation of HIF-1alpha expression during hypoxia. Am J Physiol Cell Physiol 2002; 283:C178–C186.

    PubMed  CAS  Google Scholar 

  87. Sogawa K, Numayama-Tsuruta K, Ema M, et al. Inhibition of hypoxia-inducible factor 1 activity by nitric oxide donors in hypoxia. Proc Natl Acad Sci USA 1998; 95:7368–7373.

    PubMed  CAS  Google Scholar 

  88. Huang LE, Willmore WG, Gu J, et al. Inhibition of Hypoxia-inducible Factor 1 Activation by Carbon Monoxide and Nitric Oxide. Implications for oxygen sensing and signaling. J Biol Chem 1999; 274:9038–9044.

    PubMed  CAS  Google Scholar 

  89. Brune B, von Knethen A, Sandau KB. Transcription factors p53 and HIF-1α as targets of nitric oxide. Cell Signal 2001; 13:525–533.

    PubMed  CAS  Google Scholar 

  90. Brune B, Zhou J. The role of nitric oxide (NO) in stability regulation of hypoxia inducible factor α (HIF-1α). Curr Med Chem 2003; 10:845–855.

    PubMed  CAS  Google Scholar 

  91. Zhou J, Schmid T, Brune B. HIF-1α and p53 as targets of NO in affecting cell proliferation, death and adaptation. Curr Mol Med 2004; 4:741–751.

    PubMed  CAS  Google Scholar 

  92. Sansal I, Sellers WR. The biology and clinical relevance of the PTEN tumor suppressor pathway. J Clin Oncol 2004; 22: 2954–2963.

    PubMed  CAS  Google Scholar 

  93. Vivanco I, Sawyers CL. The phosphatidylinositol 3-kinase-AKT pathway in human cancer. Nat Rev Cancer 2002; 2:489–501.

    PubMed  CAS  Google Scholar 

  94. Vara JAF, Casado E, de Castro J, et al. PI3K/Akt signaling pathway and cancer. Cancer Treat Rev 2004; 30:193–204.

    CAS  Google Scholar 

  95. Jeong JW, Bae MK, Ahn MY, et al. Regulation and destabilization of HIF-1α by ARD1-Mediated Acetylation. Cell 2002; 111:709–720.

    PubMed  CAS  Google Scholar 

  96. Murray-Rust TA, Oldham NJ, Hewitson KS, et al. Purified recombinant hARD1 does not catalyse acetylation of Lys532 of HIF-1[alpha] fragments in vitro. FEBS Lett 2006; 580: 1911–1918.

    PubMed  CAS  Google Scholar 

  97. Bilton R, Mazure N, Trottier E, et al. Arrest-defective-1 protein, an acetyltransferase, does not alter stability of hypoxia-inducible factor (HIF)-1α and is not induced by hypoxia or HIF. J Biol Chem 2005; 280:31132–31140.

    PubMed  CAS  Google Scholar 

  98. Fisher TS, Des Etages S, Hayes L, et al. Analysis of ARD1 function in hypoxia response using retroviral RNA interference. J Biol Chem 2005; 280:17749–17757.

    PubMed  CAS  Google Scholar 

  99. Ravi R, Mookerjee B, Bhujwalla ZM, Sutter CH, Artemov D, Zeng Q et al. Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1alpha. Genes Dev 2000; 14:34–44.

    PubMed  CAS  Google Scholar 

  100. Hansson LO, Friedler A, Freund S, et al. Two sequence motifs from HIF-1alpha bind to the DNA-binding site of p53. Proc Natl Acad Sci USA 2002; 99:10305–10309.

    PubMed  CAS  Google Scholar 

  101. Hewitson KS, Schofield CJ. The HIF pathway as a therapeutic target. Drug Disc Today 2004; 9:704–711.

    CAS  Google Scholar 

  102. Giaccia A, Siim BG, Johnson RS. HIF-1 as a target for drug development. Nat Rev Drug Discov 2003; 2:803–811.

    PubMed  CAS  Google Scholar 

  103. Paul SAM, Simons JW, Mabjeesh NJ. HIF at the crossroads between ischemia and carcinogenesis. J Cell Physiol 2004; 200:20–30.

    PubMed  CAS  Google Scholar 

  104. Safran M, Kaelin WG, Jr. HIF hydroxylation and the mammalian oxygen-sensing pathway. J Clin Invest 2003; 111: 779–783.

    PubMed  CAS  Google Scholar 

  105. Hockel M, Vaupel P. Tumor hypoxia: Definitions and current clinical, biologic, and molecular aspects. J Natl Cancer Inst 2001; 93:266–276.

    PubMed  CAS  Google Scholar 

  106. Brizel DM, Dodge RK, Clough RW, et al. Oxygenation of head and neck cancer: changes during radiotherapy and impact on treatment outcome. Radiother Oncol 1999; 53:113–117.

    PubMed  CAS  Google Scholar 

  107. Brown JM, Le QT. Tumor hypoxia is important in radiotherapy, but how should we measure it? Int J Radiat Oncol 2002; 54:1299–1301.

    Google Scholar 

  108. Harrison LB, Chadha M, Hill RJ, et al. Impact of tumor hypoxia and anemia on radiation therapy outcomes. Oncologist 2002; 7:492–508.

    PubMed  Google Scholar 

  109. Janssen HLK, Haustermans KMG, Sprong D, et al. HIF-1α, pimonidazole, and iododeoxyuridine to estimate hypoxia and perfusion in human head-and-neck tumors. Int J Radiat Oncol 2002; 54:1537–1549.

    CAS  Google Scholar 

  110. Brown JM, Giaccia AJ. The unique physiology of solid tumors: Opportunities (and problems) for cancer therapy. Cancer Res 1998; 58:1408–1416.

    PubMed  CAS  Google Scholar 

  111. Blouw B, Song H, Tihan T, et al. The hypoxic response of tumors is dependent on their microenvironment. Cancer Cell 2003; 4:133–146.

    PubMed  CAS  Google Scholar 

  112. Carmeliet P, Dor Y, Herbert JM, et al. Role of HIF-1α in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis. Nature 1998; 394:485–490.

    PubMed  CAS  Google Scholar 

  113. Mack FA, Rathmell WK, Arsham AM, et al. Loss of pVHL is sufficient to cause HIF dysregulation in primary cells but does not promote tumor growth. Cancer Cell 2003; 3:75–88.

    PubMed  CAS  Google Scholar 

  114. Acker T, Diez-Juan A, Aragones J, et al. Genetic evidence for a tumor suppressor role of HIF-2α. Cancer Cell 2005; 8: 131–141.

    PubMed  CAS  Google Scholar 

  115. Willam C, Masson N, Tian YM, et al. Peptide blockade of HIF alpha degradation modulates cellular metabolism and angiogenesis. Proc Natl Acad Sci USA 2002; 99:10423–10428.

    PubMed  CAS  Google Scholar 

  116. Li J, Post M, Volk R, et al. PR39, a peptide regulator of angiogenesis. Nat Med 2000; 6:49–55.

    PubMed  CAS  Google Scholar 

  117. Sowter HM, Raval R, Moore J, et al. Predominant role of hypoxia-inducible transcription factor (HIF)-1α versus HIF-2α in regulation of the transcriptional response to hypoxia. Cancer Res 2003; 63:6130–6134.

    PubMed  CAS  Google Scholar 

  118. Wiesener MS, Jurgensen JS, Rosenberger C, et al. Widespread, hypoxia-inducible expression of HIF-2 alpha in distinct cell populations of different organs. FASEB J 2002; 17:271–273.

    PubMed  Google Scholar 

  119. Cejudo-Martin P, Johnson RS. A new notch in the HIF belt: How hypoxia impacts differentiation. Dev Cell 2005; 9: 575–576.

    PubMed  CAS  Google Scholar 

  120. Kotch LE, Iyer NV, Laughner E, et al. Defective vascularization of HIF-1a-null embryos is not associated with VEGF deficiency but with mesenchymal cell death. Dev Biol 1999; 209: 254–267.

    PubMed  CAS  Google Scholar 

  121. Tian H, Hammer RE, Matsumoto AM, et al. The hypoxia-responsive transcription factor EPAS1 is essential for catecholamine homeostasis and protection against heart failure during embryonic development. Genes Dev 1998; 12:3320–3324.

    PubMed  CAS  Google Scholar 

  122. Adelman DM, Gertsenstein M, Nagy A, et al. Placental cell fates are regulated in vivo by HIF-mediated hypoxia responses. Genes Dev 2000; 14:3191–3203.

    PubMed  CAS  Google Scholar 

  123. Roccaro AM, Hideshima T, Richardson PG, et al. Bortezomib as an antitumor agent. Curr Pharm Biotechno 2006; 7:441–448.

    CAS  Google Scholar 

  124. Knowles HJ, Raval RR, Harris AL, et al. Effect of ascorbate on the activity of hypoxia-inducible factor in cancer cells. Cancer Res 2003; 63:1764–1768.

    PubMed  CAS  Google Scholar 

  125. Goldberg MA, Dunning SP, Bunn HF. Regulation of the erythropoietin gene: evidence that the oxygen sensor is a heme protein. Science 1988; 242:1412–1415.

    PubMed  CAS  Google Scholar 

  126. Wang GL, Semenza GL. Desferrioxamine induces erythropoietin gene expression and hypoxia- inducible factor 1 DNA-binding activity: implications for models of hypoxia signal transduction. Blood 1993; 82:3610–3615.

    PubMed  CAS  Google Scholar 

  127. Ran R, Xu H, Lu A, et al. Hypoxia preconditioning in the brain. Dev Neurosci Basel 2005; 27:87–92.

    CAS  Google Scholar 

  128. Richardson DR. Molecular mechanisms of iron uptake by cells and the use of iron chelators for the treatment of cancer. Curr Med Chem 2005; 12:2711–2729.

    PubMed  CAS  Google Scholar 

  129. McDonough MA, McNeill LA, Tilliet M, et al. Selective inhibition of factor inhibiting hypoxia-inducible factor. J Am Chem Soc 2005; 127:7680–7681.

    PubMed  CAS  Google Scholar 

  130. Mole DR, Schlemminger I, McNeill LA, et al. 2-Oxoglutarate analogue inhibitors of HIF prolyl hydroxylase. Bioorgan Med Chem Lett 2003; 13:2677–2680.

    CAS  Google Scholar 

  131. Schlemminger I, Mole DR, McNeill LA, et al. Analogues of dealanylalahopcin are inhibitors of human HIF prolyl hydroxylases. Bioorgan Med Chem Lett 2003; 13:1451–1454.

    CAS  Google Scholar 

  132. Welford RWD, Schlemminger I, McNeill LA, et al. The selectivity and inhibition of AlkB. J Biol Chem 2003; 278: 10157–10161.

    PubMed  CAS  Google Scholar 

  133. Ivan M, Haberberger T, Gervasi DC, et al. Biochemical purification and pharmacological inhibition of a mammalian prolyl hydroxylase acting on hypoxia-inducible factor. Proc Natl Acad Sci USA 2002; 99:13459–13464.

    PubMed  CAS  Google Scholar 

  134. Nwogu JI, Geenen D, Bean M, et al. 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 2001; 104:2216–2221.

    PubMed  CAS  Google Scholar 

  135. Banerji B, Conejo-Garcia A, McNeill LA, et al. The inhibition of factor inhibiting hypoxia-inducible factor (FIH) by β-oxocarboxylic acids. Chem Commun 2005; 5438–5440.

    Google Scholar 

  136. Warshakoon NC, Wu S, Boyer A, et al. A novel series of imidazo[1, 2-a]pyridine derivatives as HIF-1α prolyl hydroxylase inhibitors. Bioorgan Med Chem Lett 2006; 16:5598–5601.

    CAS  Google Scholar 

  137. Warshakoon NC, Wu S, Boyer A, et al. Structure-based design, synthesis, and SAR evaluation of a new series of 8-hydroxyquinolines as HIF-1α prolyl hydroxylase inhibitors. Bioorgan Med Chem Lett 2006; 16:5517–5522.

    CAS  Google Scholar 

  138. Warshakoon NC, Wu S, Boyer A, et al. Design and synthesis of substituted pyridine derivatives as HIF-1α prolyl hydroxylase inhibitors. Bioorgan Med Chem Lett 2006; 16:5616–5620.

    CAS  Google Scholar 

  139. Warshakoon NC, Wu S, Boyer A, et al. Design and synthesis of a series of novel pyrazolopyridines as HIF 1-α prolyl hydroxylase inhibitors. Bioorgan Med Chem Lett 2006; 16:5687–5690.

    CAS  Google Scholar 

  140. Klaus S, Arend M, Fourney P, et al. Induction of erythropoiesis and iron utilization by the HIF prolyl hydroxylase inhibitor FG-4592. American Society of Nephrology (ASN) Renal Week 2005 Session: Complications of ESRD: Bone Disease, Malnutrition, and Anemia, Abstract F-FC050. 11–11–2005.

    Google Scholar 

  141. Gunzler V, Muthukrishnan E, Neumayer HH, et al. FG-2216 increases hemoglobin concentration in anemic patients with chronic kidney disease. American Society of Nephrology (ASN) Renal Week 2005 Session: Anemia and Bone Disease, Abstract SA-PO924. 11–12–2005.

    Google Scholar 

  142. Kung AL, Zabludoff SD, France DS, et al. Small molecule blockade of transcriptional coactivation of the hypoxia-inducible factor pathway. Cancer Cell 2004; 6:33–43.

    PubMed  CAS  Google Scholar 

  143. Olenyuk BZ, Zhang GJ, Klco JM, et al. Inhibition of vascular endothelial growth factor with a sequence-specific hypoxia response element antagonist. Proc Natl Acad Sci USA 2004; 101:16768–16773.

    PubMed  CAS  Google Scholar 

  144. Kong D, Park EJ, Stephen AG, Calvani M, Cardellina JH, Monks A et al. Echinomycin, a small-molecule inhibitor of hypoxia-inducible factor-1 DNA-binding activity. Cancer Res 2005; 65:9047–9055.

    PubMed  CAS  Google Scholar 

  145. Semenza GL. Development of novel therapeutic strategies that target HIF-1. Expert Opin Ther Tar 2006; 10:267–280.

    CAS  Google Scholar 

  146. William JG, Nicholas JV, Lary JK, et al. A phase II clinical trial of echinomycin in metastatic soft tissue sarcoma. Invest New Drug 1995; 13:171–174.

    Google Scholar 

  147. Jones DT, Harris AL. Identification of novel small-molecule inhibitors of hypoxia-inducible factor-1 transactivation and DNA binding. Mol Cancer Ther 2006; 5:2193–2202.

    PubMed  CAS  Google Scholar 

  148. Yang J, Zhang L, Erbel PJA, et al. Functions of the Per/ARNT/Sim domains of the hypoxia-inducible factor. J Biol Chem 2005; 280:36047–36054.

    PubMed  CAS  Google Scholar 

  149. Amezcua CA, Harper SM, Rutter J, et al. Structure and interactions of PAS kinase N-terminal PAS domain: Model for intramolecular kinase regulation. Structure 2002; 10:1349–1361.

    PubMed  CAS  Google Scholar 

  150. Isaacs JS, Jung YJ, Mimnaugh EG, et al. Hsp90 regulates a von Hippel Lindau-independent hypoxia-inducible factor-1alpha -degradative pathway. J Biol Chem 2002; 277:29936–29944.

    PubMed  CAS  Google Scholar 

  151. Neckers L, Neckers K. Heat shock protein 90 inhibitors as novel cancer chemotherapeutic agents. Exp Opin Emerg Drugs 2002; 7:277–288.

    CAS  Google Scholar 

  152. Masson N, Appelhoff RJ, Tuckerman JR, et al. The HIF prolyl hydroxylase PHD3 is a potential substrate of the TRiC chaperonin. FEBS Lett 2004; 570:166–170.

    PubMed  CAS  Google Scholar 

  153. Rapisarda A, Uranchimeg B, Sordet O, et al. Topoisomerase I-mediated inhibition of hypoxia-inducible factor 1: Mechanism and therapeutic implications. Cancer Res 2004; 64: 1475–1482.

    PubMed  CAS  Google Scholar 

  154. Li TK, Liu LF. Tumor cell death induced by topoisomerase-targeting drugs. Annu Rev Pharmacol 2001; 41(1):53–77.

    Google Scholar 

  155. Chang H, Shyu KG, Lee CC, et al. GL331 inhibits HIF-1α expression in a lung cancer model. Biochem Bioph Res Co 2003; 302:95–100.

    CAS  Google Scholar 

  156. Powis G, Kirkpatrick L. Hypoxia inducible factor-1{alpha} as a cancer drug target. Mol Cancer Ther 2004; 3(5):647–654.

    PubMed  CAS  Google Scholar 

  157. Mabjeesh NJ, Escuin D, LaVallee TM, et al. 2ME2 inhibits tumor growth and angiogenesis by disrupting microtubules and dysregulating HIF. Cancer Cell 2003; 3:363–375.

    PubMed  CAS  Google Scholar 

  158. William DF, Erwin AK, Douglas KP, et al. Inhibition of angiogenesis: Treatment options for patients with metastatic prostate cancer. Invest New Drug 2002; 20:183–194.

    Google Scholar 

  159. Maxwell PH. The HIF pathway in cancer. Semin Cell Dev Biol 2005; 16:523–530.

    PubMed  CAS  Google Scholar 

  160. Diaz-Gonzalez JA, Russell J, Rouzaut A, et al. Targeting hypoxia and angiogenesis through HIF-1alpha inhibition. Cancer Biol Ther 2005; 4:1055–1062.

    PubMed  CAS  Google Scholar 

  161. Zhong H, Chiles K, Feldser D, et al. Modulation of hypoxia-inducible factor 1α expression by the epidermal growth factor/phosphatidylinositol 3-kinase/PTEN/AKT/FRAP pathway in human prostate cancer cells: Implications for tumor angiogenesis and therapeutics. Cancer Res 2000; 60:1541–1545.

    PubMed  CAS  Google Scholar 

  162. Chen C, Pore N, Behrooz A, et al. Regulation of glut1 mRNA by hypoxia-inducible Factor-1. Interaction between H-ras and hypoxia. J Biol Chem 2001; 276:9519–9525.

    PubMed  CAS  Google Scholar 

  163. Powis G, Montfort WR. Properties and biological activities of thioredoxins. Annu Rev Pharmacol 2001; 41(1):261–295.

    CAS  Google Scholar 

  164. Berggren M, Gallegos A, Gasdaska JR, et al. Thioredoxin and thioredoxin reductase gene expression in human tumors and cell lines, and the effects of serum stimulation and hypoxia. Anticancer Research 1996; 16:3459–3466.

    PubMed  CAS  Google Scholar 

  165. Huang LE, Arany Z, Livingston DM, et al. Activation of hypoxia-inducible transcription factor depends primarily upon redox-sensitive stabilization of its alpha subunit. J Biol Chem 1996; 271:32253–32259.

    PubMed  CAS  Google Scholar 

  166. Welsh SJ, Bellamy WT, Briehl MM, et al. The redox protein thioredoxin-1 (Trx-1) increases hypoxia-inducible factor 1α protein expression: Trx-1 overexpression results in increased vascular endothelial growth factor production and enhanced tumor angiogenesis. Cancer Res 2002; 62:5089–5095.

    PubMed  CAS  Google Scholar 

  167. Kirkpatrick DL, Kuperus M, Dowdeswell M, et al. Mechanisms of inhibition of the thioredoxin growth factor system by antitumor 2-imidazolyl disulfides. Biochem Pharmacol 1998; 55(7):987–994.

    PubMed  CAS  Google Scholar 

  168. Kirkpatrick L, Dragovich T, Ramanathan R, et al. Results from Phase I study of PX-12, a thioredoxin inhibitor in patients with advanced solid malignancies. J Clin Oncol (Meeting Abstracts) 2004; 22:3089.

    Google Scholar 

  169. Jones DT, Pugh CW, Wigfield S, et al. Novel thioredoxin inhibitors paradoxically increase hypoxia-inducible factor-α expression but decrease functional transcriptional activity, DNA binding, and degradation. Clin Cancer Res 2006; 12:5384–5394.

    PubMed  CAS  Google Scholar 

  170. Ko FN, Wu CC, Kuo SC, et al. YC-1, a novel activator of platelet guanylate cyclase. Blood 1994; 84:4226–4233.

    PubMed  CAS  Google Scholar 

  171. Chun YS, Yeo EJ, Choi E, et al. Inhibitory effect of YC-1 on the hypoxic induction of erythropoietin and vascular endothelial growth factor in Hep3B cells. Biochem Pharmacol 2001; 61(8):947–954.

    PubMed  CAS  Google Scholar 

  172. Yeo EJ, Chun YS, Cho YS, et al. YC-1: A potential anticancer drug targeting hypoxia-inducible factor 1. J Natl Cancer Inst 2003; 95:516–525.

    PubMed  CAS  Google Scholar 

  173. Belozerov VE, Van Meir EG. Hypoxia inducible factor-1: a novel target for cancer therapy. Anti-Cancer Drugs 2005; 16:901–909.

    PubMed  CAS  Google Scholar 

  174. Vincent KA, Shyu KG, Luo Y, et al. Angiogenesis is induced in a rabbit model of hindlimb ischemia by naked DNA encoding an HIF-1α/VP16 hybrid transcription factor. Circulation 2000; 102:2255–2261.

    PubMed  CAS  Google Scholar 

  175. Shyu KG, Wang MT, Wang BW, et al. Intramyocardial injection of naked DNA encoding HIF-1α/VP16 hybrid to enhance angiogenesis in an acute myocardial infarction model in the rat. Cardiovasc Res 2002; 54:576–583.

    PubMed  CAS  Google Scholar 

  176. Sun X, Liu M, Wei Y, et al. Overexpression of von Hippel-Lindau tumor suppressor protein and antisense HIF-1α eradicates gliomas. Cancer Gene Ther 2005; 13:428–435.

    Google Scholar 

  177. Sun X, Kanwar JR, Leung E, et al. Gene transfer of antisense hypoxia inducible factor-1α enhances the therapeutic efficacy of cancer immunotherapy. Nature Gene Therapy 2001; 8: 638–645.

    CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. The Chemistry Research Laboratory, University of Oxford, OX1 3TA, Oxford, UK

    Kristina M. Cook & Christopher J. Schofield

Authors
  1. Kristina M. Cook
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Christopher J. Schofield
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA

    William D. Figg

  2. Department of Surgery Harvard Medical School and Vascular Biology Program, Children's Hospital Boston, Boston, MA, USA

    Judah Folkman

Rights and permissions

Reprints and permissions

Copyright information

© 2008 Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Cook, K.M., Schofield, C.J. (2008). Therapeutic Strategies that Target the HIF System. In: Figg, W.D., Folkman, J. (eds) Angiogenesis. Springer, Boston, MA. https://doi.org/10.1007/978-0-387-71518-6_32

Download citation

  • DOI: https://doi.org/10.1007/978-0-387-71518-6_32

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-0-387-71517-9

  • Online ISBN: 978-0-387-71518-6

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation