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  • Review Article
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HIF1 and oxygen sensing in the brain

Nature Reviews Neuroscience volume 5, pages 437–448 (2004)Cite this article

Key Points

  • The brain depends on a continuous supply of oxygen, so it is crucial for the body to be able to detect and respond rapidly to hypoxia. This review highlights the central role of the transcription factor hypoxia-inducible factor 1 (HIF1) in hypoxia sensing at the cellular level.

  • HIF1 consists of two subunits — HIF1α and HIF1β. HIF1β is expressed constitutively in all cells and does not respond to changes in oxygen tension, but it is essential for hypoxia-induced transcriptional changes mediated by the HIF1 heterodimer. HIF1α is made continuously and accumulates in hypoxic cells, but is rapidly degraded and is virtually absent in normoxic cells.

  • HIF1 regulates the expression of a range of genes that facilitate acclimatization to low oxygen conditions. Its targets include genes that code for molecules that participate in vasomotor control, angiogenesis, erythropoiesis, iron metabolism, cell proliferation and cell cycle control, cell death, and energy metabolism.

  • Under hypoxic conditions, prolyl- and asparaginyl-hydroxylases are inhibited, thereby preventing hydroxylation of HIF1α. Inhibiting prolyl-hydroxylases decreases degradation of HIF1α, leading to rapid HIF1α protein accumulation. The HIF1α protein is phosphorylated and dimerizes with HIF1β. The HIF1α/HIF1β dimer binds p300/CBP, thereby activating hypoxia response elements in HIF target genes.

  • HIF1 has been implicated in a range of brain pathologies, and it can be harmful or beneficial, depending on the circumstances. HIF1 has been implicated not only in conditions that can be directly attributed to hypoxia, such as cerebral and retinal ischaemia, but also in diseases with less well-defined aetiologies.

  • Hypoxic preconditioning, or hypoxia-induced tolerance, refers to a brief period of hypoxia that protects against an otherwise lethal subsequent insult, such as stroke. It has been proposed that preconditioning is due, at least in part, to hypoxic induction of HIF1 and HIF1 target genes.

  • The ability to modify the HIF1 pathway using specific tools, such as prolyl-hydroxylase inhibitors, might facilitate the development of pharmaceutical strategies to treat pathologies in which HIF1 activation might be beneficial. By contrast, strategies for blocking the HIF1 pathway might be useful for treating brain tumours in which a poor prognosis has been attributed to the hypoxic status.

Abstract

Of all the chemical elements, oxygen is the most vital to the human body. The brain is the most sensitive organ to oxygen deprivation (hypoxia), which, over an extended period, can cause coma, seizures, cognitive impairment and other neurological disabilities, and even brain death. However, during mild hypoxia of short duration, the brain develops adaptative mechanisms that allow it to maintain normal physiological conditions. In this review, we discuss some of the molecular mechanisms of oxygen sensing in the brain. Particular emphasis is placed on the oxygen-dependant regulation of the transcription factor HIF1 (hypoxia-inducible factor 1) — one of the main cellular responses to hypoxia that operates in numerous cell types.

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Figure 1: Oxygen sensing.
Figure 2: Continuous degradation of hypoxia-inducible factor 1α (HIF1α) during normoxia.
Figure 3: Decreased activation of hypoxia-inducible factor 1α (HIF1α) target gene expression during normoxia.
Figure 4: Induction of hypoxia-inducible factor 1 (HIF1) target genes by hypoxia.
Figure 5: Hypoxia-induced protection against ischaemic injury.
Figure 6: Hypoxia and desferrioxamine (DFX) or cobalt chloride (CoCl2) induce hypoxia-inducible factor 1 (HIF1) in the brain and protect against focal ischaemia.

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References

  1. Silver, I. & Erecinska, M. Oxygen and ion concentrations in normoxic and hypoxic brain cells. Adv. Exp. Med. Biol. 454, 7–16 (1998).

    Article  CAS  PubMed  Google Scholar 

  2. Ray, C. J., Abbas, M. R., Coney, A. M. & Marshall, J. M. Interactions of adenosine, prostaglandins and nitric oxide in hypoxia-induced vasodilatation: in vivo and in vitro studies. J. Physiol. (Lond.) 544, 195–209 (2002).

    Article  CAS  Google Scholar 

  3. Van Mil, A. H. et al. Nitric oxide mediates hypoxia-induced cerebral vasodilation in humans. J. Appl. Physiol. 92, 962–966 (2002).

    Article  CAS  PubMed  Google Scholar 

  4. Peers, C. Oxygen-sensitive ion channels. Trends Pharmacol. Sci. 18, 405–408 (1997).

    Article  CAS  PubMed  Google Scholar 

  5. Wang, G. L., Jiang, B. H., Rue, E. A. & Semenza, G. L. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc. Natl Acad. Sci. USA 92, 5510–5514 (1995).

    Article  CAS  PubMed  Google Scholar 

  6. Wood, S. M., Gleadle, J. M., Pugh, C. W., Hankinson, O. & Ratcliffe, P. J. The role of the aryl hydrocarbon receptor nuclear translocator (ARNT) in hypoxic induction of gene expression. Studies in ARNT-deficient cells. J. Biol. Chem. 271, 15117–15123 (1996).

    Article  CAS  PubMed  Google Scholar 

  7. Jiang, B. H., Semenza, G. L., Bauer, C. & Marti, H. H. Hypoxia-inducible factor 1 levels vary exponentially over a physiologically relevant range of O2 tension. Am. J. Physiol. 271, C1172–1180 (1996).

    Article  CAS  PubMed  Google Scholar 

  8. Huang, L. E., Gu, J., Schau, M. & Bunn, H. F. Regulation of hypoxia-inducible factor 1α is mediated by an O2-dependent degradation domain via the ubiquitin-proteasome pathway. Proc. Natl Acad. Sci. USA 95, 7987–7992 (1998).

    Article  CAS  PubMed  Google Scholar 

  9. Ema, M. et al. 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, 4273–4278 (1997). References 9 and 10 provided the first evidence of the HIF1α-related protein HIF2α.

    Article  CAS  PubMed  Google Scholar 

  10. Tian, H., McKnight, S. L. & Russell, D. W. Endothelial PAS domain protein 1 (EPAS1), a transcription factor selectively expressed in endothelial cells. Genes Dev. 11, 72–82 (1997).

    Article  CAS  PubMed  Google Scholar 

  11. Gu, Y. Z., Moran, S. M., Hogenesch, J. B., Wartman, L. & Bradfield, C. A. Molecular characterization and chromosomal localization of a third alpha-class hypoxia inducible factor subunit, HIF3α. Gene Expr. 7, 205–213 (1998). These authors cloned the cDNA that encodes HIF3α and showed that it binds to HIF1β, is activated by hypoxia and binds as a heterodimer to the HRE sequence.

    CAS  PubMed  Google Scholar 

  12. Iyer, N. V. et al. Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1α. Genes Dev. 12, 149–162 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Ryan, H. E., Lo, J. & Johnson, R. S. HIF-1α is required for solid tumor formation and embryonic vascularization. EMBO J. 17, 3005–3015 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Tian, H., Hammer, R. E., Matsumoto, A. M., Russell, D. W. & McKnight, S. L. The hypoxia-responsive transcription factor EPAS1 is essential for catecholamine homeostasis and protection against heart failure during embryonic development. Genes Dev. 12, 3320–3324 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Peng, J., Zhang, L., Drysdale, L. & Fong, G. H. The transcription factor EPAS-1/hypoxia-inducible factor 2α plays an important role in vascular remodeling. Proc. Natl Acad. Sci. USA 97, 8386–8391 (2000).

    Article  CAS  PubMed  Google Scholar 

  16. Compernolle, V. et al. Loss of HIF-2α and inhibition of VEGF impair fetal lung maturation, whereas treatment with VEGF prevents fatal respiratory distress in premature mice. Nature Med. 8, 702–710 (2002).

    Article  CAS  PubMed  Google Scholar 

  17. Wiesener, M. S. et al. Widespread hypoxia-inducible expression of HIF-2α in distinct cell populations of different organs. FASEB J. 17, 271–273 (2003).

    Article  CAS  PubMed  Google Scholar 

  18. Makino, Y., Kanopka, A., Wilson, W. J., Tanaka, H. & Poellinger, L. Inhibitory PAS domain protein (IPAS) is a hypoxia-inducible splicing variant of the hypoxia-inducible factor-3α locus. J. Biol. Chem. 277, 32405–32408 (2002).

    Article  CAS  PubMed  Google Scholar 

  19. Ruscher, K. et al. Induction of hypoxia inducible factor 1 by oxygen glucose deprivation is attenuated by hypoxic preconditioning in rat cultured neurons. Neurosci. Lett. 254, 117–120 (1998).

    Article  CAS  PubMed  Google Scholar 

  20. Chavez, J. C., Agani, F., Pichiule, P. & LaManna, J. C. Expression of hypoxia-inducible factor-1α in the brain of rats during chronic hypoxia. J. Appl. Physiol. 89, 1937–1942 (2000).

    Article  CAS  PubMed  Google Scholar 

  21. Ralph, G. S. et al. Identification of potential stroke targets by lentiviral vector mediated overexpression of HIF-1α and HIF-2α in a primary neuronal model of hypoxia. J. Cereb. Blood Flow Metab. 24, 245–258 (2004).

    Article  CAS  PubMed  Google Scholar 

  22. Makino, Y. et al. Inhibitory PAS domain protein is a negative regulator of hypoxia-inducible gene expression. Nature 414, 550–554 (2001).

    Article  CAS  PubMed  Google Scholar 

  23. Yu, A. Y. et al. Impaired physiological responses to chronic hypoxia in mice partially deficient for hypoxia-inducible factor 1α. J. Clin. Invest. 103, 691–696 (1999). A study that provides, with the use of total or partial HIF1 deficiency in mice, definitive evidence that HIF1 is essential for normal embryonic development. It also provides a definitive connection between HIF1 expression and physiological responses to hypoxia in adult animals.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Tomita, S. et al. Defective brain development in mice lacking the Hif-1α gene in neural cells. Mol. Cell. Biol. 23, 6739–6749 (2003). These results show that expression of HIF1α in neural cells is essential for normal development of the brain.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Kojima, H. et al. Abnormal B lymphocyte development and autoimmunity in hypoxia-inducible factor 1α-deficient chimeric mice. Proc. Natl Acad. Sci. USA 99, 2170–2174 (2002).

    Article  CAS  PubMed  Google Scholar 

  26. Cramer, T. et al. HIF-1α is essential for myeloid cell-mediated inflammation. Cell 112, 645–657 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Bruick, R. K. Expression of the gene encoding the proapoptotic Nip3 protein is induced by hypoxia. Proc. Natl Acad. Sci. USA 97, 9082–9087 (2000).

    Article  CAS  PubMed  Google Scholar 

  28. Sowter, H. M., Ratcliffe, P. J., Watson, P., Greenberg, A. H. & Harris, A. L. HIF-1-dependent regulation of hypoxic induction of the cell death factors BNIP3 and NIX in human tumors. Cancer Res. 61, 6669–6673 (2001).

    CAS  PubMed  Google Scholar 

  29. Forsythe, J. A. et al. Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol. Cell. Biol. 16, 4604–4613 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Gerber, H. P., Condorelli, F., Park, J. & Ferrara, N. Differential transcriptional regulation of the two vascular endothelial growth factor receptor genes. Flt-1, but not Flk-1/KDR, is up-regulated by hypoxia. J. Biol. Chem. 272, 23659–23667 (1997).

    Article  CAS  PubMed  Google Scholar 

  31. Wang, G. L. & Semenza, G. L. Characterization of hypoxia-inducible factor 1 and regulation of DNA binding activity by hypoxia. J. Biol. Chem. 268, 21513–21518 (1993).

    CAS  PubMed  Google Scholar 

  32. Ebert, B. L., Firth, J. D. & Ratcliffe, P. J. Hypoxia and mitochondrial inhibitors regulate expression of glucose transporter-1 via distinct Cis-acting sequences. J. Biol. Chem. 270, 29083–29089 (1995).

    Article  CAS  PubMed  Google Scholar 

  33. Cormier-Regard, S., Nguyen, S. V. & Claycomb, W. C. Adrenomedullin gene expression is developmentally regulated and induced by hypoxia in rat ventricular cardiac myocytes. J. Biol. Chem. 273, 17787–17792 (1998).

    Article  CAS  PubMed  Google Scholar 

  34. Takahashi, Y., Takahashi, S., Shiga, Y., Yoshimi, T. & Miura, T. Hypoxic induction of prolyl 4-hydroxylase α (I) in cultured cells. J. Biol. Chem. 275, 14139–14146 (2000).

    Article  CAS  PubMed  Google Scholar 

  35. Palmer, L. A., Semenza, G. L., Stoler, M. H. & Johns, R. A. Hypoxia induces type II NOS gene expression in pulmonary artery endothelial cells via HIF-1. Am. J. Physiol. 274, L212–219 (1998).

    CAS  PubMed  Google Scholar 

  36. Eckhart, A. D., Yang, N., Xin, X. & Faber, J. E. Characterization of the α1B-adrenergic receptor gene promoter region and hypoxia regulatory elements in vascular smooth muscle. Proc. Natl Acad. Sci. USA 94, 9487–9492 (1997).

    Article  CAS  PubMed  Google Scholar 

  37. Hu, J., Discher, D. J., Bishopric, N. H. & Webster, K. A. Hypoxia regulates expression of the endothelin-1 gene through a proximal hypoxia-inducible factor-1 binding site on the antisense strand. Biochem. Biophys. Res. Commun. 245, 894–899 (1998).

    Article  CAS  PubMed  Google Scholar 

  38. Kietzmann, T., Roth, U. & Jungermann, K. Induction of the plasminogen activator inhibitor-1 gene expression by mild hypoxia via a hypoxia response element binding the hypoxia-inducible factor-1 in rat hepatocytes. Blood 94, 4177–4185 (1999).

    CAS  PubMed  Google Scholar 

  39. Schaffer, L. et al. Oxygen-regulated expression of TGF-β3, a growth factor involved in trophoblast differentiation. Placenta 24, 941–950 (2003).

    Article  CAS  PubMed  Google Scholar 

  40. Rolfs, A., Kvietikova, I., Gassmann, M. & Wenger, R. H. Oxygen-regulated transferrin expression is mediated by hypoxia-inducible factor-1. J. Biol. Chem. 272, 20055–20062 (1997).

    Article  CAS  PubMed  Google Scholar 

  41. Tacchini, L., Bianchi, L., Bernelli-Zazzera, A. & Cairo, G. Transferrin receptor induction by hypoxia. HIF-1-mediated transcriptional activation and cell-specific post-transcriptional regulation. J. Biol. Chem. 274, 24142–24146 (1999).

    Article  CAS  PubMed  Google Scholar 

  42. Mukhopadhyay, C. K., Mazumder, B. & Fox, P. L. Role of hypoxia-inducible factor-1 in transcriptional activation of ceruloplasmin by iron deficiency. J. Biol. Chem. 275, 21048–21054 (2000).

    Article  CAS  PubMed  Google Scholar 

  43. Bhattacharya, S. et al. Functional role of p35srj, a novel p300/CBP binding protein, during transactivation by HIF-1. Genes Dev. 13, 64–75 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Feldser, D. et al. Reciprocal positive regulation of hypoxia-inducible factor 1α and insulin-like growth factor 2. Cancer Res. 59, 3915–3918 (1999).

    CAS  PubMed  Google Scholar 

  45. Tazuke, S. I. et al. Hypoxia stimulates insulin-like growth factor binding protein 1 (IGFBP-1) gene expression in HepG2 cells: a possible model for IGFBP-1 expression in fetal hypoxia. Proc. Natl Acad. Sci. USA 95, 10188–10193 (1998).

    Article  CAS  PubMed  Google Scholar 

  46. Lee, P. J. et al. Hypoxia-inducible factor-1 mediates transcriptional activation of the heme oxygenase-1 gene in response to hypoxia. J. Biol. Chem. 272, 5375–5381 (1997).

    Article  CAS  PubMed  Google Scholar 

  47. O'Rourke, J. F., Pugh, C. W., Bartlett, S. M. & Ratcliffe, P. J. Identification of hypoxically inducible mRNAs in HeLa cells using differential-display PCR. Role of hypoxia-inducible factor-1. Eur. J. Biochem. 241, 403–410 (1996).

    Article  CAS  PubMed  Google Scholar 

  48. Semenza, G. L., Roth, P. H., Fang, H. M. & Wang, G. L. Transcriptional regulation of genes encoding glycolytic enzymes by hypoxia-inducible factor 1. J. Biol. Chem. 269, 23757–23763 (1994).

    CAS  PubMed  Google Scholar 

  49. Kaluz, S. et al. Lowered oxygen tension induces expression of the hypoxia marker MN/carbonic anhydrase IX in the absence of hypoxia-inducible factor 1α stabilization: a role for phosphatidylinositol 3'-kinase. Cancer Res. 62, 4469–4477 (2002).

    CAS  PubMed  Google Scholar 

  50. Graven, K. K., Yu, Q., Pan, D., Roncarati, J. S. & Farber, H. W. Identification of an oxygen responsive enhancer element in the glyceraldehyde-3-phosphate dehydrogenase gene. Biochim. Biophys. Acta 1447, 208–218 (1999).

    Article  CAS  PubMed  Google Scholar 

  51. Shoshani, T. et al. Identification of a novel hypoxia-inducible factor 1-responsive gene, RTP801, involved in apoptosis. Mol. Cell. Biol. 22, 2283–2293 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Miyazaki, K. et al. Identification of functional hypoxia response elements in the promoter region of the DEC1 and DEC2 genes. J. Biol. Chem. 277, 47014–47021 (2002).

    Article  CAS  PubMed  Google Scholar 

  53. Seta, K. A., Kim, R., Kim, H. W., Millhorn, D. E. & Beitner-Johnson, D. Hypoxia-induced regulation of MAPK phosphatase-1 as identified by subtractive suppression hybridization and cDNA microarray analysis. J. Biol. Chem. 276, 44405–44412 (2001).

    Article  CAS  PubMed  Google Scholar 

  54. Burmester, T., Weich, B., Reinhardt, S. & Hankeln, T. A vertebrate globin expressed in the brain. Nature 407, 520–523 (2000). This study reports the identification of a third globin type in human and mouse, predominantly expressed in the brain and therefore called neuroglobin, which might help to transport oxygen across the blood–brain barrier and increase the availability of oxygen to the metabolically active neuronal tissues.

    Article  CAS  PubMed  Google Scholar 

  55. Pichiule, P., Chavez, J. C. & LaManna, J. C. Hypoxic regulation of angiopoietin-2 expression in endothelial cells. J. Biol. Chem. 279, 12171–12180 (2003).

    Article  CAS  PubMed  Google Scholar 

  56. Pichiule, P. & LaManna, J. C. Angiopoietin-2 and rat brain capillary remodeling during adaptation and deadaptation to prolonged mild hypoxia. J. Appl. Physiol. 93, 1131–1139 (2002).

    Article  CAS  PubMed  Google Scholar 

  57. Metzen, E. et al. Intracellular localisation of human HIF-1α hydroxylases: implications for oxygen sensing. J. Cell Sci. 116, 1319–1326 (2003).

    Article  CAS  PubMed  Google Scholar 

  58. Epstein, A. C. et al. C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell 107, 43–54 (2001). The authors show that HIF1 is regulated through prolyl-hydroxylation at a conserved core LXXLAP motif, and define the novel class of HIF1 prolyl-hydroxylases (PHDs), providing the basis for an oxygen-sensing function.

    Article  CAS  PubMed  Google Scholar 

  59. Bruick, R. K. & McKnight, S. L. A conserved family of prolyl-4-hydroxylases that modify HIF. Science 294, 1337–1340 (2001). The same year as reference 58, these authors also revealed a family of HIF1 prolyl-hydroxylases named HPHs, which seemed to be identical to the PHD class of HIF1 prolyl-hydroxylase described by Epstein et al.

    Article  CAS  PubMed  Google Scholar 

  60. Taylor, M. S. Characterization and comparative analysis of the EGLN gene family. Gene 275, 125–132 (2001).

    Article  CAS  PubMed  Google Scholar 

  61. Oehme, F. et al. Overexpression of PH-4, a novel putative proline 4-hydroxylase, modulates activity of hypoxia-inducible transcription factors. Biochem. Biophys. Res. Commun. 296, 343–349 (2002).

    Article  CAS  PubMed  Google Scholar 

  62. Mole, D. R., Maxwell, P. H., Pugh, C. W. & Ratcliffe, P. J. Regulation of HIF by the von Hippel-Lindau tumour suppressor: implications for cellular oxygen sensing. IUBMB Life 52, 43–47 (2001).

    Article  CAS  PubMed  Google Scholar 

  63. Hon, W. C. et al. Structural basis for the recognition of hydroxyproline in HIF-1α by pVHL. Nature 417, 975–978 (2002).

    Article  CAS  PubMed  Google Scholar 

  64. Jaakkola, P. et al. Targeting of HIF-α to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 292, 468–472 (2001).

    Article  CAS  PubMed  Google Scholar 

  65. Masson, N., Willam, C., Maxwell, P. H., Pugh, C. W. & Ratcliffe, P. J. Independent function of two destruction domains in hypoxia-inducible factor-α chains activated by prolyl hydroxylation. EMBO J. 20, 5197–5206 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Min, J. H. et al. Structure of an HIF-1α–pVHL complex: hydroxyproline recognition in signaling. Science 296, 1886–1889 (2002).

    Article  CAS  PubMed  Google Scholar 

  67. Kibel, A., Iliopoulos, O., DeCaprio, J. A. & Kaelin, W. G. Jr. Binding of the von Hippel-Lindau tumor suppressor protein to Elongin B and C. Science 269, 1444–1446 (1995).

    Article  CAS  PubMed  Google Scholar 

  68. Pause, A. et al. The von Hippel-Lindau tumor-suppressor gene product forms a stable complex with human CUL-2, a member of the Cdc53 family of proteins. Proc. Natl Acad. Sci. USA 94, 2156–2161 (1997).

    Article  CAS  PubMed  Google Scholar 

  69. Iwai, K. et al. Identification of the von Hippel-Lindau tumor-suppressor protein as part of an active E3 ubiquitin ligase complex. Proc. Natl Acad. Sci. USA 96, 12436–12441 (1999).

    Article  CAS  PubMed  Google Scholar 

  70. Maxwell, P. H. et al. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 399, 271–275 (1999). The first evidence that VHL binds to HIF1 and HIF2 and targets them for destruction.

    Article  CAS  PubMed  Google Scholar 

  71. Ivan, M. et al. HIFα targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science 292, 464–468 (2001).

    Article  CAS  PubMed  Google Scholar 

  72. Huang, L. E. & Bunn, H. F. Hypoxia-inducible factor and its biomedical relevance. J. Biol. Chem. 278, 19575–19578 (2003).

    Article  CAS  PubMed  Google Scholar 

  73. Ratcliffe, P. J., O'Rourke, J. F., Maxwell, P. H. & Pugh, C. W. Oxygen sensing, hypoxia-inducible factor-1 and the regulation of mammalian gene expression. J. Exp. Biol. 201, 1153–1162 (1998).

    CAS  PubMed  Google Scholar 

  74. Wang, G. L. & Semenza, G. L. Desferrioxamine induces erythropoietin gene expression and hypoxia-inducible factor 1 DNA-binding activity: implications for models of hypoxia signal transduction. Blood 82, 3610–3615 (1993).

    CAS  PubMed  Google Scholar 

  75. Yuan, Y., Hilliard, G., Ferguson, T. & Millhorn, D. E. Cobalt inhibits the interaction between hypoxia-inducible factor-α and von Hippel-Lindau protein by direct binding to hypoxia-inducible factor-α. J. Biol. Chem. 278, 15911–15916 (2003). Until this study, cobalt had been thought to activate HIF1 through HIF1 prolyl-hydroxylase inhibition. Here, the authors show that cobalt can also inhibit VHL binding to HIFα by direct binding to the VHL-binding domain.

    Article  CAS  PubMed  Google Scholar 

  76. Jeong, J. W. et al. Regulation and destabilization of HIF-1α by ARD1-mediated acetylation. Cell 111, 709–720 (2002).

    Article  CAS  PubMed  Google Scholar 

  77. Isaacs, J. S. et al. Hsp90 regulates a von Hippel Lindau-independent hypoxia-inducible factor-1α-degradative pathway. J. Biol. Chem. 277, 29936–29944 (2002).

    Article  CAS  PubMed  Google Scholar 

  78. Mahon, P. C., Hirota, K. & Semenza, G. L. FIH-1: a novel protein that interacts with HIF-1α and VHL to mediate repression of HIF-1 transcriptional activity. Genes Dev. 15, 2675–2686 (2001). The identification and characterization of FIH1 (factor inhibiting HIF1), a negative regulator of HIF1 transactivation-domain function. The authors demonstrate that FIH1 interacts with HIF1, as well as with VHL, and that both FIH1 and VHL inhibit HIF1 transactivation-domain function, establishing a unifying mechanism for the modulation of HIF1 protein stabilization and transcriptional activation in response to changes in cellular O 2 concentration.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Hewitson, K. S. 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. 277, 26351–26355 (2002).

    Article  CAS  PubMed  Google Scholar 

  80. Lando, D. et al. FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor. Genes Dev. 16, 1466–1471 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Elkins, J. M. et al. Structure of factor-inhibiting hypoxia-inducible factor (HIF) reveals mechanism of oxidative modification of HIF-1α. J. Biol. Chem. 278, 1802–1806 (2003).

    Article  CAS  PubMed  Google Scholar 

  82. Freedman, S. J. et al. Structural basis for recruitment of CBP/p300 by hypoxia-inducible factor-1α. Proc. Natl Acad. Sci. USA 99, 5367–5372 (2002).

    Article  CAS  PubMed  Google Scholar 

  83. Lando, D., Peet, D. J., Whelan, D. A., Gorman, J. J. & Whitelaw, M. L. Asparagine hydroxylation of the HIF transactivation domain a hypoxic switch. Science 295, 858–861 (2002).

    Article  CAS  PubMed  Google Scholar 

  84. Huang, J., Zhao, Q., Mooney, S. M. & Lee, F. S. Sequence determinants in hypoxia-inducible factor-1α for hydroxylation by the prolyl hydroxylases PHD1, PHD2, and PHD3. J. Biol. Chem. 277, 39792–39800 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Lipscomb, E. A., Sarmiere, P. D. & Freeman, R. S. SM-20 is a novel mitochondrial protein that causes caspase-dependent cell death in nerve growth factor-dependent neurons. J. Biol. Chem. 276, 5085–5092 (2001).

    Article  CAS  PubMed  Google Scholar 

  86. Lieb, M. E., Menzies, K., Moschella, M. C., Ni, R. & Taubman, M. B. Mammalian EGLN genes have distinct patterns of mRNA expression and regulation. Biochem. Cell Biol. 80, 421–426 (2002).

    Article  CAS  PubMed  Google Scholar 

  87. Lipscomb, E. A., Sarmiere, P. D., Crowder, R. J. & Freeman, R. S. Expression of the SM-20 gene promotes death in nerve growth factor-dependent sympathetic neurons. J. Neurochem. 73, 429–432 (1999).

    Article  CAS  PubMed  Google Scholar 

  88. Semenza, G. L. Hypoxia-inducible factor 1: oxygen homeostasis and disease pathophysiology. Trends Mol. Med. 7, 345–350 (2001).

    Article  CAS  PubMed  Google Scholar 

  89. Agani, F. H., Pichiule, P., Chavez, J. C. & LaManna, J. C. The role of mitochondria in the regulation of hypoxia-inducible factor 1 expression during hypoxia. J. Biol. Chem. 275, 35863–35867 (2000).

    Article  CAS  PubMed  Google Scholar 

  90. Chandel, N. S. et al. Reactive oxygen species generated at mitochondrial complex III stabilize hypoxia-inducible factor-1α during hypoxia: a mechanism of O2 sensing. J. Biol. Chem. 275, 25130–25138 (2000).

    Article  CAS  PubMed  Google Scholar 

  91. Vaux, E. C., Metzen, E., Yeates, K. M. & Ratcliffe, P. J. Regulation of hypoxia-inducible factor is preserved in the absence of a functioning mitochondrial respiratory chain. Blood 98, 296–302 (2001).

    Article  CAS  PubMed  Google Scholar 

  92. Bergeron, M., Yu, A. Y., Solway, K. E., Semenza, G. L. & Sharp, F. R. Induction of hypoxia-inducible factor-1 (HIF-1) and its target genes following focal ischaemia in rat brain. Eur. J. Neurosci. 11, 4159–4170 (1999). The first study reporting HIF1 upregulation in the brain after focal cerebral ischaemia.

    Article  CAS  PubMed  Google Scholar 

  93. Bergeron, M. et al. Role of hypoxia-inducible factor-1 in hypoxia-induced ischemic tolerance in neonatal rat brain. Ann. Neurol. 48, 285–296 (2000).

    Article  CAS  PubMed  Google Scholar 

  94. Semenza, G. Signal transduction to hypoxia-inducible factor 1. Biochem. Pharmacol. 64, 993–998 (2002).

    Article  CAS  PubMed  Google Scholar 

  95. Fukuda, R. et al. Insulin-like growth factor 1 induces hypoxia-inducible factor 1-mediated vascular endothelial growth factor expression, which is dependent on MAP kinase and phosphatidylinositol 3-kinase signaling in colon cancer cells. J. Biol. Chem. 277, 38205–38211 (2002).

    Article  CAS  PubMed  Google Scholar 

  96. Laughner, E., Taghavi, P., Chiles, K., Mahon, P. C. & Semenza, G. L. HER2 (neu) signaling increases the rate of hypoxia-inducible factor 1α (HIF-1α) synthesis: novel mechanism for HIF-1-mediated vascular endothelial growth factor expression. Mol. Cell. Biol. 21, 3995–4004 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Chavez, J. C. & LaManna, J. C. Activation of hypoxia-inducible factor-1 in the rat cerebral cortex after transient global ischemia: potential role of insulin-like growth factor-1. J. Neurosci. 22, 8922–8931 (2002).

    Article  CAS  PubMed  Google Scholar 

  98. Jiang, B. H. et al. Phosphatidylinositol 3-kinase signaling controls levels of hypoxia-inducible factor 1. Cell Growth Differ. 12, 363–369 (2001).

    CAS  PubMed  Google Scholar 

  99. Xi, G., Reiser, G. & Keep, R. F. The role of thrombin and thrombin receptors in ischemic, hemorrhagic and traumatic brain injury: deleterious or protective? J. Neurochem. 84, 3–9 (2003).

    Article  CAS  PubMed  Google Scholar 

  100. Lu, H., Forbes, R. A. & Verma, A. Hypoxia-inducible factor 1 activation by aerobic glycolysis implicates the Warburg effect in carcinogenesis. J. Biol. Chem. 277, 23111–23115 (2002).

    Article  CAS  PubMed  Google Scholar 

  101. Dalgard, C., Lu, H., Mohyeldin, A. & Verma, A. Endogenous 2-oxoacids differentially regulate expression of oxygen sensors. Biochem. J. 25 Feb 2004 (doi:10.1042/BJ20031647)

  102. Metzen, E., Zhou, J., Jelkmann, W., Fandrey, J. & Brune, B. Nitric oxide impairs normoxic degradation of HIF-1α by inhibition of prolyl hydroxylases. Mol. Biol. Cell 14, 3470–3481 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Hagen, T., Taylor, C. T., Lam, F. & Moncada, S. Redistribution of intracellular oxygen in hypoxia by nitric oxide: effect on HIF1α. Science 302, 1975–1978 (2003).

    Article  CAS  PubMed  Google Scholar 

  104. Arsham, A. M., Howell, J. J. & Simon, M. C. A novel hypoxia-inducible factor-independent hypoxic response regulating mammalian target of rapamycin and its targets. J. Biol. Chem. 278, 29655–29660 (2003).

    Article  CAS  PubMed  Google Scholar 

  105. Hudson, C. C. et al. Regulation of hypoxia-inducible factor 1α expression and function by the mammalian target of rapamycin. Mol. Cell. Biol. 22, 7004–7014 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Marti, H. J. et al. Hypoxia-induced vascular endothelial growth factor expression precedes neovascularization after cerebral ischemia. Am. J. Pathol. 156, 965–976 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Pichiule, P., Agani, F., Chavez, J. C., Xu, K. & LaManna, J. C. HIF-1α and VEGF expression after transient global cerebral ischemia. Adv. Exp. Med. Biol. 530, 611–617 (2003).

    Article  CAS  PubMed  Google Scholar 

  108. Iadecola, C., Zhang, F., Xu, S., Casey, R. & Ross, M. E. Inducible nitric oxide synthase gene expression in brain following cerebral ischemia. J. Cereb. Blood Flow Metab. 15, 378–384 (1995).

    Article  CAS  PubMed  Google Scholar 

  109. Wang, X. et al. Discovery of adrenomedullin in rat ischemic cortex and evidence for its role in exacerbating focal brain ischemic damage. Proc. Natl Acad. Sci. USA 92, 11480–11484 (1995).

    Article  CAS  PubMed  Google Scholar 

  110. Serrano, J. et al. Adrenomedullin expression is up-regulated by ischemia-reperfusion in the cerebral cortex of the adult rat. Neuroscience 109, 717–731 (2002).

    Article  CAS  PubMed  Google Scholar 

  111. Encinas, J. M., Serrano, J., Alonso, D., Fernandez, A. P. & Rodrigo, J. Adrenomedullin over-expression in the caudate-putamen of the adult rat brain after ischaemia-reperfusion injury. Neurosci. Lett. 329, 197–200 (2002).

    Article  CAS  PubMed  Google Scholar 

  112. Zhang, F., White, J. G. & Iadecola, C. Nitric oxide donors increase blood flow and reduce brain damage in focal ischemia: evidence that nitric oxide is beneficial in the early stages of cerebral ischemia. J. Cereb. Blood Flow Metab. 14, 217–226 (1994).

    Article  CAS  PubMed  Google Scholar 

  113. Dogan, A. et al. Intravenous infusion of adrenomedullin and increase in regional cerebral blood flow and prevention of ischemic brain injury after middle cerebral artery occlusion in rats. J. Cereb. Blood Flow Metab. 17, 19–25 (1997).

    Article  CAS  PubMed  Google Scholar 

  114. Watanabe, K. et al. Adrenomedullin reduces ischemic brain injury after transient middle cerebral artery occlusion in rats. Acta Neurochir. (Wien) 143, 1157–1161 (2001).

    Article  CAS  Google Scholar 

  115. Dalkara, T., Yoshida, T., Irikura, K. & Moskowitz, M. A. Dual role of nitric oxide in focal cerebral ischemia. Neuropharmacology 33, 1447–1452 (1994).

    Article  CAS  PubMed  Google Scholar 

  116. Kim, W. et al. Angiogenic role of adrenomedullin through activation of Akt, mitogen-activated protein kinase, and focal adhesion kinase in endothelial cells. FASEB J. 17, 1937–1939 (2003).

    Article  CAS  PubMed  Google Scholar 

  117. Hayashi, T., Abe, K., Suzuki, H. & Itoyama, Y. Rapid induction of vascular endothelial growth factor gene expression after transient middle cerebral artery occlusion in rats. Stroke 28, 2039–2044 (1997).

    Article  CAS  PubMed  Google Scholar 

  118. Lennmyr, F., Ata, K. A., Funa, K., Olsson, Y. & Terent, A. Expression of vascular endothelial growth factor (VEGF) and its receptors (Flt-1 and Flk-1) following permanent and transient occlusion of the middle cerebral artery in the rat. J. Neuropathol. Exp. Neurol. 57, 874–882 (1998).

    Article  CAS  PubMed  Google Scholar 

  119. Docagne, F. et al. Transforming growth factor-β1 as a regulator of the serpins/t-PA axis in cerebral ischemia. FASEB J. 13, 1315–1324 (1999).

    Article  CAS  PubMed  Google Scholar 

  120. Krupinski, J., Kaluza, J., Kumar, P., Kumar, S. & Wang, J. M. Role of angiogenesis in patients with cerebral ischemic stroke. Stroke 25, 1794–1798 (1994).

    Article  CAS  PubMed  Google Scholar 

  121. O'Rourke, J. F. et al. Hypoxia response elements. Oncol. Res. 9, 327–332 (1997).

    CAS  PubMed  Google Scholar 

  122. Semenza, G. L., Nejfelt, M. K., Chi, S. M. & Antonarakis, S. E. Hypoxia-inducible nuclear factors bind to an enhancer element located 3' to the human erythropoietin gene. Proc. Natl Acad. Sci. USA 88, 5680–5684 (1991).

    Article  CAS  PubMed  Google Scholar 

  123. Semenza, G. L. et al. Hypoxia response elements in the aldolase A, enolase 1, and lactate dehydrogenase A gene promoters contain essential binding sites for hypoxia-inducible factor 1. J. Biol. Chem. 271, 32529–32537 (1996).

    Article  CAS  PubMed  Google Scholar 

  124. Wenger, R. H. Cellular adaptation to hypoxia: O2-sensing protein hydroxylases, hypoxia-inducible transcription factors, and O2-regulated gene expression. FASEB J. 16, 1151–1162 (2002).

    Article  CAS  PubMed  Google Scholar 

  125. Buemi, M. et al. Erythropoietin and the brain: from neurodevelopment to neuroprotection. Clin. Sci. (Lond.) 103, 275–282 (2002).

    Article  CAS  Google Scholar 

  126. Schmidt-Kastner, R. et al. Differential changes of bax, caspase-3 and p21 mRNA expression after transient focal brain ischemia in the rat. Brain Res. Mol. Brain Res. 79, 88–101 (2000).

    Article  CAS  PubMed  Google Scholar 

  127. van Lookeren Campagne, M. & Gill, R. Increased expression of cyclin G1 and p21WAF1/CIP1 in neurons following transient forebrain ischemia: comparison with early DNA damage. J. Neurosci. Res. 53, 279–296 (1998).

    Article  CAS  PubMed  Google Scholar 

  128. Sun, Y., Jin, K., Mao, X. O., Zhu, Y. & Greenberg, D. A. Neuroglobin is up-regulated by and protects neurons from hypoxic-ischemic injury. Proc. Natl Acad. Sci. USA 98, 15306–15311 (2001).

    Article  CAS  PubMed  Google Scholar 

  129. Sun, Y. et al. Neuroglobin protects the brain from experimental stroke in vivo. Proc. Natl Acad. Sci. USA 100, 3497–3500 (2003).

    Article  CAS  PubMed  Google Scholar 

  130. Ozaki, H. et al. Hypoxia inducible factor-1α is increased in ischemic retina: temporal and spatial correlation with VEGF expression. Invest. Ophthalmol. Vis. Sci. 40, 182–189 (1999).

    CAS  PubMed  Google Scholar 

  131. Junk, A. K. et al. Erythropoietin administration protects retinal neurons from acute ischemia-reperfusion injury. Proc. Natl Acad. Sci. USA 99, 10659–10664 (2002).

    Article  CAS  PubMed  Google Scholar 

  132. Vinores, S. A. et al. Upregulation of vascular endothelial growth factor in ischemic and non-ischemic human and experimental retinal disease. Histol. Histopathol. 12, 99–109 (1997).

    CAS  PubMed  Google Scholar 

  133. Gidday, J. M. et al. Nitric oxide mediates cerebral ischemic tolerance in a neonatal rat model of hypoxic preconditioning. J. Cereb. Blood Flow Metab. 19, 331–340 (1999).

    Article  CAS  PubMed  Google Scholar 

  134. Marber, M. S. & Yellon, D. M. Hypoxic preconditioning of ischaemic myocardium. Cardiovasc. Res. 26, 556–557 (1992).

    Article  CAS  PubMed  Google Scholar 

  135. Perez-Pinzon, M. A., Mumford, P. L., Rosenthal, M. & Sick, T. J. Anoxic preconditioning in hippocampal slices: role of adenosine. Neuroscience 75, 687–694 (1996).

    Article  CAS  PubMed  Google Scholar 

  136. Schurr, A., Payne, R. S., Tseng, M. T., Gozal, E. & Gozal, D. Excitotoxic preconditioning elicited by both glutamate and hypoxia and abolished by lactate transport inhibition in rat hippocampal slices. Neurosci. Lett. 307, 151–154 (2001).

    Article  CAS  PubMed  Google Scholar 

  137. Vannucci, R. C., Towfighi, J. & Vannucci, S. J. Hypoxic preconditioning and hypoxic-ischemic brain damage in the immature rat: pathologic and metabolic correlates. J. Neurochem. 71, 1215–1220 (1998).

    Article  CAS  PubMed  Google Scholar 

  138. Bernaudin, M. et al. Normobaric hypoxia induces tolerance to focal permanent cerebral ischemia in association with an increased expression of hypoxia-inducible factor-1 and its target genes, erythropoietin and VEGF, in the adult mouse brain. J. Cereb. Blood Flow Metab. 22, 393–403 (2002).

    Article  CAS  PubMed  Google Scholar 

  139. Gidday, J. M., Fitzgibbons, J. C., Shah, A. R. & Park, T. S. Neuroprotection from ischemic brain injury by hypoxic preconditioning in the neonatal rat. Neurosci. Lett. 168, 221–224 (1994).

    Article  CAS  PubMed  Google Scholar 

  140. Miller, B. A. et al. Cerebral protection by hypoxic preconditioning in a murine model of focal ischemia-reperfusion. Neuroreport 12, 1663–1669 (2001). In this study, the authors report for the first time that hypoxic preconditioning protects against cerebral ischaemia in the adult brain as well as the neonatal brain.

    Article  CAS  PubMed  Google Scholar 

  141. Wick, A. et al. Neuroprotection by hypoxic preconditioning requires sequential activation of vascular endothelial growth factor receptor and Akt. J. Neurosci. 22, 6401–6407 (2002).

    Article  CAS  PubMed  Google Scholar 

  142. Bernaudin, M., Tang, Y., Reilly, M., Petit, E. & Sharp, F. R. Brain genomic response following hypoxia and re-oxygenation in the neonatal rat. Identification of genes that might contribute to hypoxia-induced ischemic tolerance. J. Biol. Chem. 277, 39728–39738 (2002). A genomic analysis revealing new genes that are regulated by hypoxic preconditioning and that might be implicated in brain oxygen sensing and in the brain's adaptation to subsequent ischaemia in the neonatal rat.

    Article  CAS  PubMed  Google Scholar 

  143. Jones, N. M. & Bergeron, M. Hypoxic preconditioning induces changes in HIF-1 target genes in neonatal rat brain. J. Cereb. Blood Flow Metab. 21, 1105–1114 (2001).

    Article  CAS  PubMed  Google Scholar 

  144. Prass, K. et al. Desferrioxamine induces delayed tolerance against cerebral ischemia in vivo and in vitro. J. Cereb. Blood Flow Metab. 22, 520–525 (2002).

    Article  CAS  PubMed  Google Scholar 

  145. Bernaudin, M. et al. A potential role for erythropoietin in focal permanent cerebral ischemia in mice. J. Cereb. Blood Flow Metab. 19, 643–651 (1999).

    Article  CAS  PubMed  Google Scholar 

  146. Brines, M. L. et al. Erythropoietin crosses the blood–brain barrier to protect against experimental brain injury. Proc. Natl Acad. Sci. USA 97, 10526–10531 (2000).

    Article  CAS  PubMed  Google Scholar 

  147. Ehrenreich, H. et al. Erythropoietin therapy for acute stroke is both safe and beneficial. Mol. Med. 8, 495–505 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Sakanaka, M. et al. In vivo evidence that erythropoietin protects neurons from ischemic damage. Proc. Natl Acad. Sci. USA 95, 4635–4640 (1998).

    Article  CAS  PubMed  Google Scholar 

  149. Lawrence, M. S., Ho, D. Y., Dash, R. & Sapolsky, R. M. Herpes simplex virus vectors overexpressing the glucose transporter gene protect against seizure-induced neuron loss. Proc. Natl Acad. Sci. USA 92, 7247–7251 (1995).

    Article  CAS  PubMed  Google Scholar 

  150. Rumora, L., Shaver, A., Zanic Grubisic, T. & Maysinger, D. MKP-1 as a target for pharmacological manipulations in PC12 cell survival. Neurochem. Int. 39, 25–32 (2001).

    Article  CAS  PubMed  Google Scholar 

  151. Yan, S. F. et al. Egr-1, a master switch coordinating upregulation of divergent gene families underlying ischemic stress. Nature Med. 6, 1355–1361 (2000).

    Article  CAS  PubMed  Google Scholar 

  152. Beitner-Johnson, D. & Millhorn, D. E. Hypoxia induces phosphorylation of the cyclic AMP response element-binding protein by a novel signaling mechanism. J. Biol. Chem. 273, 19834–19839 (1998).

    Article  CAS  PubMed  Google Scholar 

  153. Zaman, K. et al. Protection from oxidative stress-induced apoptosis in cortical neuronal cultures by iron chelators is associated with enhanced DNA binding of hypoxia-inducible factor-1 and ATF-1/CREB and increased expression of glycolytic enzymes, p21(waf1/cip1), and erythropoietin. J. Neurosci. 19, 9821–9830 (1999).

    Article  CAS  PubMed  Google Scholar 

  154. Blondeau, N., Widmann, C., Lazdunski, M. & Heurteaux, C. Activation of the nuclear factor-κB is a key event in brain tolerance. J. Neurosci. 21, 4668–4677 (2001).

    Article  CAS  PubMed  Google Scholar 

  155. Silverman, E. S. et al. Egr-1 and Sp1 interact functionally with the 5-lipoxygenase promoter and its naturally occurring mutants. Am. J. Respir. Cell Mol. Biol. 19, 316–323 (1998).

    Article  CAS  PubMed  Google Scholar 

  156. Murphy, B. J. et al. Activation of metallothionein gene expression by hypoxia involves metal response elements and metal transcription factor-1. Cancer Res. 59, 1315–1322 (1999).

    CAS  PubMed  Google Scholar 

  157. van Lookeren Campagne, M. et al. Evidence for a protective role of metallothionein-1 in focal cerebral ischemia. Proc. Natl Acad. Sci. USA 96, 12870–12875 (1999).

    Article  CAS  PubMed  Google Scholar 

  158. Sanchez-Elsner, T. et al. Synergistic cooperation between hypoxia and transforming growth factor-β pathways on human vascular endothelial growth factor gene expression. J. Biol. Chem. 276, 38527–38535 (2001).

    Article  CAS  PubMed  Google Scholar 

  159. Silins, G., Grimmond, S., Egerton, M. & Hayward, N. Analysis of the promoter region of the human VEGF-related factor gene. Biochem. Biophys. Res. Commun. 230, 413–418 (1997).

    Article  CAS  PubMed  Google Scholar 

  160. Hyder, S. M., Nawaz, Z., Chiappetta, C. & Stancel, G. M. Identification of functional estrogen response elements in the gene coding for the potent angiogenic factor vascular endothelial growth factor. Cancer Res. 60, 3183–3190 (2000).

    CAS  PubMed  Google Scholar 

  161. Schipani, E. et al. Hypoxia in cartilage: HIF-1α is essential for chondrocyte growth arrest and survival. Genes Dev. 15, 2865–2876 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. Simon, R. P. Hypoxia versus ischemia. Neurology 52, 7–8 (1999).

    Article  CAS  PubMed  Google Scholar 

  163. Tang, Y., Lu, A., Aronow, B. J., Wagner, K. R. & Sharp, F. R. Genomic responses of the brain to ischemic stroke, intracerebral haemorrhage, kainate seizures, hypoglycemia, and hypoxia. Eur. J. Neurosci. 15, 1937–1952 (2002).

    Article  PubMed  Google Scholar 

  164. Tang, Y., Nee, A. C., Lu, A., Ran, R. & Sharp, F. R. Blood genomic expression profile for neuronal injury. J. Cereb. Blood Flow Metab. 23, 310–319 (2003).

    Article  CAS  PubMed  Google Scholar 

  165. Englander, E. W., Greeley, G. H. Jr, Wang, G., Perez-Polo, J. R. & Lee, H. M. Hypoxia-induced mitochondrial and nuclear DNA damage in the rat brain. J. Neurosci. Res. 58, 262–269 (1999).

    Article  CAS  PubMed  Google Scholar 

  166. Clanton, T. L. & Klawitter, P. F. Adaptive responses of skeletal muscle to intermittent hypoxia: the known and the unknown. J. Appl. Physiol. 90, 2476–2487 (2001).

    Article  CAS  PubMed  Google Scholar 

  167. Reynolds, J. D. The management of retinopathy of prematurity. Paediatr. Drugs 3, 263–272 (2001).

    Article  CAS  PubMed  Google Scholar 

  168. Antonelli Incalzi, R. et al. Cognitive impairment in chronic obstructive pulmonary disease — a neuropsychological and spect study. J. Neurol. 250, 325–332 (2003).

    Article  PubMed  Google Scholar 

  169. Steen, R. G. et al. Cognitive impairment in children with hemoglobin SS sickle cell disease: relationship to MR imaging findings and hematocrit. Am. J. Neuroradiol. 24, 382–389 (2003).

    PubMed  Google Scholar 

  170. Scortegagna, M. et al. Multiple organ pathology, metabolic abnormalities and impaired homeostasis of reactive oxygen species in Epas1−/− mice. Nature Genet. 35, 331–340 (2003).

    Article  CAS  PubMed  Google Scholar 

  171. Cramer, T. & Johnson, R. S. A novel role for the hypoxia inducible transcription factor HIF-1α: critical regulation of inflammatory cell function. Cell Cycle 2, 192–193 (2003).

    Article  CAS  PubMed  Google Scholar 

  172. Piret, J. P., Mottet, D., Raes, M. & Michiels, C. Is HIF-1α a pro- or an anti-apoptotic protein? Biochem. Pharmacol. 64, 889–892 (2002).

    Article  CAS  PubMed  Google Scholar 

  173. Shaw, C. E. et al. Mutations in all five exons of SOD-1 may cause ALS. Ann. Neurol. 43, 390–394 (1998).

    Article  CAS  PubMed  Google Scholar 

  174. Naini, A. et al. Identification of a novel mutation in Cu/Zn superoxide dismutase gene associated with familial amyotrophic lateral sclerosis. J. Neurol. Sci. 198, 17–19 (2002).

    Article  CAS  PubMed  Google Scholar 

  175. Oosthuyse, B. et al. Deletion of the hypoxia-response element in the vascular endothelial growth factor promoter causes motor neuron degeneration. Nature Genet. 28, 131–138 (2001).

    Article  CAS  PubMed  Google Scholar 

  176. Nygren, I., Larsson, A., Johansson, A. & Askmark, H. VEGF is increased in serum but not in spinal cord from patients with amyotrophic lateral sclerosis. Neuroreport 13, 2199–2201 (2002).

    Article  CAS  PubMed  Google Scholar 

  177. Millhorn, D. E. et al. Regulation of gene expression for tyrosine hydroxylase in oxygen sensitive cells by hypoxia. Kidney Int. 51, 527–535 (1997).

    Article  CAS  PubMed  Google Scholar 

  178. Maher, E. R. & Kaelin, W. G. Jr. von Hippel-Lindau disease. Medicine (Baltimore) 76, 381–391 (1997).

    Article  CAS  Google Scholar 

  179. Ivan, M. & Kaelin, W. G. Jr. The von Hippel-Lindau tumor suppressor protein. Curr. Opin. Genet. Dev. 11, 27–34 (2001).

    Article  CAS  PubMed  Google Scholar 

  180. Ratcliffe, P. J. New insights into an enigmatic tumour suppressor. Nature Cell Biol. 5, 7–8 (2003).

    Article  CAS  PubMed  Google Scholar 

  181. Kung, A. L., Wang, S., Klco, J. M., Kaelin, W. G. & Livingston, D. M. Suppression of tumor growth through disruption of hypoxia-inducible transcription. Nature Med. 6, 1335–1340 (2000). This study gives clear evidence that disrupting the interaction of HIF1 and p300/CBP has an anti-tumoral effect.

    Article  CAS  PubMed  Google Scholar 

  182. Birner, P. et al. Expression of hypoxia-inducible factor-1α in oligodendrogliomas: its impact on prognosis and on neoangiogenesis. Cancer 92, 165–171 (2001).

    Article  CAS  PubMed  Google Scholar 

  183. Sondergaard, K. L., Hilton, D. A., Penney, M., Ollerenshaw, M. & Demaine, A. G. Expression of hypoxia-inducible factor 1α in tumours of patients with glioblastoma. Neuropathol. Appl. Neurobiol. 28, 210–217 (2002).

    Article  CAS  PubMed  Google Scholar 

  184. Khatua, S. et al. Overexpression of the EGFR/FKBP12/HIF-2α pathway identified in childhood astrocytomas by angiogenesis gene profiling. Cancer Res. 63, 1865–1870 (2003).

    CAS  PubMed  Google Scholar 

  185. Ferrara, N. Role of vascular endothelial growth factor in physiologic and pathologic angiogenesis: therapeutic implications. Semin. Oncol. 29, 10–14 (2002).

    Article  CAS  PubMed  Google Scholar 

  186. An, W. G. et al. Stabilization of wild-type p53 by hypoxia-inducible factor 1α. Nature 392, 405–408 (1998).

    Article  CAS  PubMed  Google Scholar 

  187. Brusselmans, K. et al. Hypoxia-inducible factor-2α (HIF-2α) is involved in the apoptotic response to hypoglycemia but not to hypoxia. J. Biol. Chem. 276, 39192–39196 (2001).

    Article  CAS  PubMed  Google Scholar 

  188. Carmeliet, P. et al. Role of HIF-1α in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis. Nature 394, 485–490 (1998).

    Article  CAS  PubMed  Google Scholar 

  189. Halterman, M. W., Miller, C. C. & Federoff, H. J. Hypoxia-inducible factor-1α mediates hypoxia-induced delayed neuronal death that involves p53. J. Neurosci. 19, 6818–6824 (1999).

    Article  CAS  PubMed  Google Scholar 

  190. Goda, N. et al. Hypoxia-inducible factor 1α is essential for cell cycle arrest during hypoxia. Mol. Cell. Biol. 23, 359–369 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We would like to thank J. Gidday, J. LaManna, E. Petit and S. Vannucci for their comments on the manuscript. We are supported by NINDS/National Institutes of Health grants, the CNRS and the University of Caen.

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Authors and Affiliations

  1. Department of Neurology, Pediatrics and Neuroscience Program, Vontz Center for Molecular Studies, Room 2327, 3125 Eden Avenue

    Frank R. Sharp

  2. University of Cincinnati, Cincinnati, 45267-0536, Ohio, USA

    Frank R. Sharp

  3. The MIND Institute and Department of Neurology, University of California at Davis, Davis, 95616, California, USA

    Frank R. Sharp

  4. UMR-CNRS 6185, Université de CAEN, Centre Cyceron, Boulevard Henri Becquerel, BP5229, F-14074 CAEN, cedex, France

    Myriam Bernaudin

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DATABASES

Entrez Gene

adrenomedullin

ANG2

ARD1

CELF

COX2

CREB

Cullin 2

DEC1

DEC2

EGL-9

EGR1

elongin B

elongin C

EPO

FIH1

FLT1

FRAP

GLUT1

heregulin

HIF1α

HIF1β

HIF2α

HIF3α

HPH1

HPH2

HPH3

HSP90

IGF1

IL-1β

insulin

MKP1

MT1

MTF1

neuroglobin

NF-κB

NOS2

p21

p300/CBP

PAI1

RBX1

RTP801

SM-20

TGFβ

TH

TNFα

VEGF

VHL

OMIM

von Hippel-Lindau disease

FURTHER INFORMATION

Encyclopedia of Life Sciences

hypoxia

Sharp's homepage

Glossary

BARORECEPTORS

Cells, located in the arteries, that monitor blood pressure.

BASIC HELIX–LOOP–HELIX

(bHLH). A structural motif present in many transcription factors that is characterized by two α-helices separated by a loop. The helices mediate dimerization, and the adjacent basic region is required for DNA binding.

NORMOXIC

At or containing a normal level of oxygen.

EPENDYMAL CELLS

A layer of cells that line the large fluid-filled cavities in the brain, the ventricles.

PURKINJE CELLS

Inhibitory neurons in the cerebellum that use GABA (γ-aminobutyric acid) as their neurotransmitter. Their cell bodies are situated beneath the molecular layer, and their dendrites branch extensively in this layer. Their axons project into the underlying white matter, and they provide the only output from the cerebellar cortex.

HYDROCEPHALUS

A condition, marked by an expansion of the cerebral ventricles and a compression of neural structures, that is caused by a block in the flow of cerebral spinal fluid or by its overproduction.

MYELOID

In the haematopoietic system, myeloid refers to granulocytes and monocytes/macrophages and their precursors.

ANGIOGENESIS

The formation of blood vessels, such as occurs during embryogenesis, tissue repair or tumorigenesis.

PROTEASOMAL

A term that refers to a protein complex that is responsible for degrading intracellular proteins that have been tagged for destruction by the addition of ubiquitin.

ERYTHROPOIETIN

(EPO). A renal hormone that is induced by anaemia and that activates haemoglobin synthesis by bone-marrow red-cell precursors.

ANTISENSE

Oligonucleotides with a sequence that is complementary to the mRNA of a given molecule can be used to block its translation. The subsequent temporary elimination of the protein of interest often provides useful information on its biological function.

SMALL INHIBITORY RNA

A small RNA molecule that interferes with normal RNA processing, causing rapid degradation of the endogenous RNA and thereby precluding translation. This provides a simple way of studying the effects of the absence of a gene product in simple organisms and in cells.

SICKLE CELL DISEASE

A red blood cell disorder that is caused by a point mutation in the gene that codes for the oxygen-transport protein haemoglobin. In the homozygous state, this mutation causes haemoglobin molecules to aggregate and form long chains when they release oxygen, causing the red blood cell to adopt the characteristic sickle shape. These sickle-shaped cells can cause blockages in blood vessels. There is also an increase in red blood cell destruction, leading to anaemia.

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Sharp, F., Bernaudin, M. HIF1 and oxygen sensing in the brain. Nat Rev Neurosci 5, 437–448 (2004). https://doi.org/10.1038/nrn1408

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