HIF1 and oxygen sensing in the brain

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.

[1]  G. Semenza,et al.  Hypoxia induces type II NOS gene expression in pulmonary artery endothelial cells via HIF-1. , 1998, American journal of physiology. Lung cellular and molecular physiology.

[2]  M. Marber,et al.  Hypoxic preconditioning of ischaemic myocardium. , 1992, Cardiovascular research.

[3]  F. Agani,et al.  Expression of hypoxia-inducible factor-1alpha in the brain of rats during chronic hypoxia. , 2000, Journal of applied physiology.

[4]  G. Semenza,et al.  Transcriptional regulation of genes encoding glycolytic enzymes by hypoxia-inducible factor 1. , 1994, The Journal of biological chemistry.

[5]  R. R. Lonser,et al.  von Hippel-Lindau disease , 2003, The Lancet.

[6]  D. Millhorn,et al.  Hypoxia Induces Phosphorylation of the Cyclic AMP Response Element-binding Protein by a Novel Signaling Mechanism* , 1998, The Journal of Biological Chemistry.

[7]  E. Morishita,et al.  In vivo evidence that erythropoietin protects neurons from ischemic damage. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[8]  W. Swann The known and the unknown , 1955 .

[9]  N. Jones,et al.  Hypoxic Preconditioning Induces Changes in HIF-1 Target Genes in Neonatal Rat Brain , 2001, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[10]  K. Seta,et al.  Hypoxia-induced Regulation of MAPK Phosphatase-1 as Identified by Subtractive Suppression Hybridization and cDNA Microarray Analysis* , 2001, The Journal of Biological Chemistry.

[11]  B. Aronow,et al.  Genomic responses of the brain to ischemic stroke, intracerebral haemorrhage, kainate seizures, hypoglycemia, and hypoxia , 2002, The European journal of neuroscience.

[12]  Christopher J. Schofield,et al.  Structural basis for the recognition of hydroxyproline in HIF-1α by pVHL , 2002, Nature.

[13]  L. Conforti,et al.  Regulation of gene expression for tyrosine hydroxylase in oxygen sensitive cells by hypoxia. , 1997, Kidney international.

[14]  M. van Buchem,et al.  Nitric oxide mediates hypoxia-induced cerebral vasodilation in humans. , 2002, Journal of applied physiology.

[15]  Michael I. Wilson,et al.  C. elegans EGL-9 and Mammalian Homologs Define a Family of Dioxygenases that Regulate HIF by Prolyl Hydroxylation , 2001, Cell.

[16]  J. Peng,et al.  The transcription factor EPAS-1/hypoxia-inducible factor 2alpha plays an important role in vascular remodeling. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[17]  M. Gassmann,et al.  Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1 alpha. , 1998, Genes & development.

[18]  G. Semenza,et al.  Induction of hypoxia‐inducible factor‐1 (HIF‐1) and its target genes following focal ischaemia in rat brain , 1999, The European journal of neuroscience.

[19]  P. Carmeliet,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 , 2002, Nature Medicine.

[20]  D. Livingston,et al.  Structural basis for recruitment of CBP/p300 by hypoxia-inducible factor-1α , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[21]  N. Chandel,et al.  Reactive Oxygen Species Generated at Mitochondrial Complex III Stabilize Hypoxia-inducible Factor-1α during Hypoxia , 2000, The Journal of Biological Chemistry.

[22]  A. Kibel,et al.  Binding of the von Hippel-Lindau tumor suppressor protein to Elongin B and C , 1995, Science.

[23]  E. Mackenzie,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 , 2002, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[24]  J. LaManna,et al.  Hypoxic Regulation of Angiopoietin-2 Expression in Endothelial Cells* , 2004, Journal of Biological Chemistry.

[25]  Jessica Lo,et al.  HIF‐1α is required for solid tumor formation and embryonic vascularization , 1998 .

[26]  U. Dirnagl,et al.  Desferrioxamine Induces Delayed Tolerance against Cerebral Ischemia in Vivo and in Vitro , 2002, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[27]  Moon-Kyoung Bae,et al.  Regulation and Destabilization of HIF-1α by ARD1-Mediated Acetylation , 2002, Cell.

[28]  M. Takayasu,et al.  Adrenomedullin Reduces Ischemic Brain Injury after Transient Middle Cerebral Artery Occlusion in Rats , 2001, Acta Neurochirurgica.

[29]  Y. Itoyama,et al.  Rapid induction of vascular endothelial growth factor gene expression after transient middle cerebral artery occlusion in rats. , 1997, Stroke.

[30]  P. Ratcliffe,et al.  Oxygen sensing, hypoxia-inducible factor-1 and the regulation of mammalian gene expression. , 1998, The Journal of experimental biology.

[31]  R. Rickert,et al.  Hypoxia-Inducible Factor 1 (cid:2) Is Essential for Cell Cycle Arrest during Hypoxia , 2002 .

[32]  L. Wartman,et al.  Molecular characterization and chromosomal localization of a third alpha-class hypoxia inducible factor subunit, HIF3alpha. , 1998, Gene expression.

[33]  T Kobayashi,et al.  Hypoxia in cartilage: HIF-1alpha is essential for chondrocyte growth arrest and survival. , 2001, Genes & development.

[34]  Y Fujii-Kuriyama,et al.  A novel bHLH-PAS factor with close sequence similarity to hypoxia-inducible factor 1alpha regulates the VEGF expression and is potentially involved in lung and vascular development. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[35]  P. Ratcliffe,et al.  Regulation of hypoxia-inducible factor is preserved in the absence of a functioning mitochondrial respiratory chain. , 2001, Blood.

[36]  E. Mackenzie,et al.  A Potential Role for Erythropoietin in Focal Permanent Cerebral Ischemia in Mice , 1999, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[37]  G. Semenza,et al.  FIH-1: a novel protein that interacts with HIF-1alpha and VHL to mediate repression of HIF-1 transcriptional activity. , 2001 .

[38]  W. Claycomb,et al.  Adrenomedullin Gene Expression Is Developmentally Regulated and Induced by Hypoxia in Rat Ventricular Cardiac Myocytes* , 1998, The Journal of Biological Chemistry.

[39]  R. Schmidt-Kastner,et al.  Differential changes of bax, caspase-3 and p21 mRNA expression after transient focal brain ischemia in the rat. , 2000, Brain Research. Molecular Brain Research.

[40]  T. Beaty,et al.  Impaired physiological responses to chronic hypoxia in mice partially deficient for hypoxia-inducible factor 1alpha. , 1999, The Journal of clinical investigation.

[41]  J. Faber,et al.  Characterization of the α1B-adrenergic receptor gene promoter region and hypoxia regulatory elements in vascular smooth muscle , 1997 .

[42]  F. Sharp,et al.  Blood Genomic Expression Profile for Neuronal Injury , 2003, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[43]  M. Moskowitz,et al.  Dual role of nitric oxide in focal cerebral ischemia , 1994, Neuropharmacology.

[44]  J. Encinas,et al.  Adrenomedullin over-expression in the caudate-putamen of the adult rat brain after ischaemia–reperfusion injury , 2002, Neuroscience Letters.

[45]  A. Harris,et al.  HIF-1-dependent regulation of hypoxic induction of the cell death factors BNIP3 and NIX in human tumors. , 2001, Cancer research.

[46]  G. Semenza,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* , 1996, The Journal of Biological Chemistry.

[47]  F. Agani,et al.  HIF-1α and VEGF Expression after Transient Global Cerebral Ischemia , 2003 .

[48]  Christopher J Schofield,et al.  Hypoxia-inducible Factor (HIF) Asparagine Hydroxylase Is Identical to Factor Inhibiting HIF (FIH) and Is Related to the Cupin Structural Family* , 2002, The Journal of Biological Chemistry.

[49]  M. Buemi,et al.  Erythropoietin and the brain: from neurodevelopment to neuroprotection. , 2002, Clinical science.

[50]  R. Johnson,et al.  A Novel Role for the Hypoxia Inducible Transcription Factor HIF-1alpha: Critical Regulation of Inflammatory Cell Function , 2003, Cell cycle.

[51]  J. Marshall,et al.  Interactions of adenosine, prostaglandins and nitric oxide in hypoxia‐induced vasodilatation: in vivo and in vitro studies , 2002, The Journal of physiology.

[52]  F. Agani,et al.  The Role of Mitochondria in the Regulation of Hypoxia-inducible Factor 1 Expression during Hypoxia* , 2000, The Journal of Biological Chemistry.

[53]  Yunjuan Sun,et al.  Neuroglobin is up-regulated by and protects neurons from hypoxic-ischemic injury , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[54]  Kan Ding,et al.  Multiple organ pathology, metabolic abnormalities and impaired homeostasis of reactive oxygen species in Epas1−/− mice , 2003, Nature Genetics.

[55]  M. Ollerenshaw,et al.  Expression of hypoxia‐inducible factor 1α in tumours of patients with glioblastoma , 2002, Neuropathology and applied neurobiology.

[56]  M. Ivan,et al.  The von Hippel-Lindau tumor suppressor protein. , 2001, Current opinion in genetics & development.

[57]  M. Bernaudin,et al.  Hypoxia-induced vascular endothelial growth factor expression precedes neovascularization after cerebral ischemia. , 2000, The American journal of pathology.

[58]  A. Larsson,et al.  VEGF is increased in serum but not in spinal cord from patients with amyotrophic lateral sclerosis , 2002, Neuroreport.

[59]  R. Klausner,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. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[60]  Martin S. Taylor,et al.  Characterization and comparative analysis of the EGLN gene family. , 2001, Gene.

[61]  M. Halterman,et al.  Hypoxia-Inducible Factor-1α Mediates Hypoxia-Induced Delayed Neuronal Death That Involves p53 , 1999, The Journal of Neuroscience.

[62]  M. Gassmann,et al.  Defective Brain Development in Mice Lacking the Hif-1α Gene in Neural Cells , 2003, Molecular and Cellular Biology.

[63]  S. K. Park,et al.  Angiogenic role of adrenomedullin through activation of Akt, mitogen‐activated protein kinase, and focal adhesion kinase in endothelial cells , 2003, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[64]  L. Giudice,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. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[65]  P. Ratcliffe,et al.  Hypoxia response elements. , 1997, Oncology research.

[66]  G. Stancel,et al.  Identification of functional estrogen response elements in the gene coding for the potent angiogenic factor vascular endothelial growth factor. , 2000, Cancer research.

[67]  M. Taubman,et al.  Mammalian EGLN genes have distinct patterns of mRNA expression and regulation. , 2002, Biochemistry and cell biology = Biochimie et biologie cellulaire.

[68]  W. Jelkmann,et al.  Intracellular localisation of human HIF-1α hydroxylases: implications for oxygen sensing , 2003, Journal of Cell Science.

[69]  G. Semenza,et al.  Desferrioxamine induces erythropoietin gene expression and hypoxia-inducible factor 1 DNA-binding activity: implications for models of hypoxia signal transduction. , 1993, Blood.

[70]  Till Acker,et al.  Deletion of the hypoxia-response element in the vascular endothelial growth factor promoter causes motor neuron degeneration , 2001, Nature Genetics.

[71]  Huasheng Lu,et al.  Hypoxia-inducible Factor 1 Activation by Aerobic Glycolysis Implicates the Warburg Effect in Carcinogenesis* , 2002, The Journal of Biological Chemistry.

[72]  D. Rosenbaum,et al.  Erythropoietin administration protects retinal neurons from acute ischemia-reperfusion injury , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[73]  M. Trese,et al.  Management of retinopathy of prematurity. , 1991, Current opinion in ophthalmology.

[74]  C. Peers Oxygen-sensitive ion channels. , 1997, Trends in pharmacological sciences.

[75]  M. Gassmann,et al.  Oxygen-regulated expression of TGF-beta 3, a growth factor involved in trophoblast differentiation. , 2003, Placenta.

[76]  Till Acker,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 , 2002, Nature Medicine.

[77]  Peter Carmeliet,et al.  Abnormal B lymphocyte development and autoimmunity in hypoxia-inducible factor 1α-deficient chimeric mice , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[78]  Dena Leshkowitz,et al.  Identification of a Novel Hypoxia-Inducible Factor 1-Responsive Gene, RTP801, Involved in Apoptosis , 2002, Molecular and Cellular Biology.

[79]  P. Ratcliffe,et al.  Identification of hypoxically inducible mRNAs in HeLa cells using differential-display PCR. Role of hypoxia-inducible factor-1. , 1996, European journal of biochemistry.

[80]  Yuichi Makino,et al.  Inhibitory PAS Domain Protein (IPAS) Is a Hypoxia-inducible Splicing Variant of the Hypoxia-inducible Factor-3α Locus* , 2002, The Journal of Biological Chemistry.

[81]  L. Huang,et al.  Regulation of hypoxia-inducible factor 1α is mediated by an O2-dependent degradation domain via the ubiquitin-proteasome pathway , 1998 .

[82]  Napoleone Ferrara,et al.  Role of vascular endothelial growth factor in physiologic and pathologic angiogenesis: therapeutic implications. , 2002, Seminars in oncology.

[83]  Andrew L. Kung,et al.  Suppression of tumor growth through disruption of hypoxia-inducible transcription , 2000, Nature Medicine.

[84]  I. Silver,et al.  Oxygen and ion concentrations in normoxic and hypoxic brain cells. , 1998, Advances in experimental medicine and biology.

[85]  J. Howell,et al.  A Novel Hypoxia-inducible Factor-independent Hypoxic Response Regulating Mammalian Target of Rapamycin and Its Targets* , 2003, Journal of Biological Chemistry.

[86]  H. Mitsumoto,et al.  Identification of a novel mutation in Cu/Zn superoxide dismutase gene associated with familial amyotrophic lateral sclerosis , 2002, Journal of Neurological Sciences.

[87]  P. Ratcliffe,et al.  Independent function of two destruction domains in hypoxia‐inducible factor‐α chains activated by prolyl hydroxylation , 2001, The EMBO journal.

[88]  L. Huang,et al.  Hypoxia-inducible Factor and Its Biomedical Relevance* , 2003, Journal of Biological Chemistry.

[89]  J. Elkins,et al.  Structure of Factor-inhibiting Hypoxia-inducible Factor (HIF) Reveals Mechanism of Oxidative Modification of HIF-1α* , 2003, The Journal of Biological Chemistry.

[90]  P. Carmeliet,et al.  Role of HIF-1α in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis , 1998, Nature.

[91]  N. Aiyar,et al.  Discovery of adrenomedullin in rat ischemic cortex and evidence for its role in exacerbating focal brain ischemic damage. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[92]  R. Hammer,et al.  The hypoxia-responsive transcription factor EPAS1 is essential for catecholamine homeostasis and protection against heart failure during embryonic development. , 1998, Genes & development.

[93]  S. Bhattacharya,et al.  Functional role of p35srj, a novel p300/CBP binding protein, during transactivation by HIF-1. , 1999, Genes & development.

[94]  A. Shah,et al.  Nitric Oxide Mediates Cerebral Ischemic Tolerance in a Neonatal Rat Model of Hypoxic Preconditioning , 1999, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[95]  M. Ivan,et al.  Structure of an HIF-1α-pVHL Complex: Hydroxyproline Recognition in Signaling , 2002, Science.

[96]  J. Drazen,et al.  Egr-1 and Sp1 interact functionally with the 5-lipoxygenase promoter and its naturally occurring mutants. , 1998, American journal of respiratory cell and molecular biology.

[97]  Matthias Schramm,et al.  Overexpression of PH-4, a novel putative proline 4-hydroxylase, modulates activity of hypoxia-inducible transcription factors. , 2002, Biochemical and biophysical research communications.

[98]  Christine C. Hudson,et al.  Regulation of Hypoxia-Inducible Factor 1α Expression and Function by the Mammalian Target of Rapamycin , 2002, Molecular and Cellular Biology.

[99]  K. Jungermann,et al.  HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY 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 , 2016 .

[100]  R. Sapolsky,et al.  Herpes simplex virus vectors overexpressing the glucose transporter gene protect against seizure-induced neuron loss. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[101]  G. Semenza,et al.  Role of hypoxia‐inducible factor‐1 in hypoxia‐induced ischemic tolerance in neonatal rat brain , 2000, Annals of neurology.

[102]  M. Lerman,et al.  Lowered oxygen tension induces expression of the hypoxia marker MN/carbonic anhydrase IX in the absence of hypoxia-inducible factor 1 alpha stabilization: a role for phosphatidylinositol 3'-kinase. , 2002, Cancer research.

[103]  Liliana Attisano,et al.  Synergistic Cooperation between Hypoxia and Transforming Growth Factor-β Pathways on Human Vascular Endothelial Growth Factor Gene Expression* , 2001, The Journal of Biological Chemistry.

[104]  G. Semenza Signal transduction to hypoxia-inducible factor 1. , 2002, Biochemical pharmacology.

[105]  C. Marra,et al.  Cognitive impairment in chronic obstructive pulmonary disease--a neuropsychological and spect study. , 2003, Journal of neurology.

[106]  Thomas Hankeln,et al.  A vertebrate globin expressed in the brain , 2000, Nature.

[107]  T. Sick,et al.  Anoxic preconditioning in hippocampal slices: role of adenosine , 1996, Neuroscience.

[108]  R. Bruick Expression of the gene encoding the proapoptotic Nip3 protein is induced by hypoxia. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[109]  Robert D. Barber,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 , 2004 .

[110]  R. Gill,et al.  Increased expression of cyclin G1 and p21WAF1/CIP1 in neurons following transient forebrain ischemia: Comparison with early DNA damage , 1998, Journal of neuroscience research.

[111]  G. Semenza,et al.  Hypoxia-inducible factor 1: oxygen homeostasis and disease pathophysiology. , 2001, Trends in molecular medicine.

[112]  S. Antonarakis,et al.  Hypoxia-inducible nuclear factors bind to an enhancer element located 3' to the human erythropoietin gene. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[113]  D. Gozal,et al.  Excitotoxic preconditioning elicited by both glutamate and hypoxia and abolished by lactate transport inhibition in rat hippocampal slices , 2001, Neuroscience Letters.

[114]  N. Hayward,et al.  Analysis of the promoter region of the human VEGF-related factor gene. , 1997, Biochemical and biophysical research communications.

[115]  Nigel Mackman,et al.  Egr-1, a master switch coordinating upregulation of divergent gene families underlying ischemic stress , 2000, Nature Medicine.

[116]  G. Semenza,et al.  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 , 2001, Molecular and Cellular Biology.

[117]  H. Simon,et al.  Regulation of Eosinophil Apoptosis: Transduction of Survival and Death Signals , 1999, International Archives of Allergy and Immunology.

[118]  George M. Hilliard,et al.  Cobalt Inhibits the Interaction between Hypoxia-inducible Factor-α and von Hippel-Lindau Protein by Direct Binding to Hypoxia-inducible Factor-α* , 2003, The Journal of Biological Chemistry.

[119]  E. Mackenzie,et al.  Transforming growth factor‐βl as a regulator of the serpins/t‐PA axis in cerebral ischemia , 1999, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[120]  R. Jaenisch,et al.  HIF-1α Is Essential for Myeloid Cell-Mediated Inflammation , 2003, Cell.

[121]  D. Vordermark Expression of hypoxia‐inducible factor‐1α in oligodendrogliomas , 2002 .

[122]  M. Bernaudin,et al.  Brain Genomic Response following Hypoxia and Re-oxygenation in the Neonatal Rat , 2002, The Journal of Biological Chemistry.

[123]  Thilo Hagen,et al.  Redistribution of Intracellular Oxygen in Hypoxia by Nitric Oxide: Effect on HIF1α , 2003, Science.

[124]  R. Keep,et al.  The role of thrombin and thrombin receptors in ischemic, hemorrhagic and traumatic brain injury: deleterious or protective? , 2002, Journal of neurochemistry.

[125]  G. Semenza,et al.  Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1 , 1996, Molecular and cellular biology.

[126]  Jianhe Huang,et al.  Sequence Determinants in Hypoxia-inducible Factor-1α for Hydroxylation by the Prolyl Hydroxylases PHD1, PHD2, and PHD3* , 2002, The Journal of Biological Chemistry.

[127]  D. Dressman,et al.  Overexpression of the EGFR/FKBP12/HIF-2alpha pathway identified in childhood astrocytomas by angiogenesis gene profiling. , 2003, Cancer research.

[128]  Michael I. Wilson,et al.  Targeting of HIF-α to the von Hippel-Lindau Ubiquitylation Complex by O2-Regulated Prolyl Hydroxylation , 2001, Science.

[129]  R. Mulhern,et al.  Cognitive impairment in children with hemoglobin SS sickle cell disease: relationship to MR imaging findings and hematocrit. , 2003, AJNR. American journal of neuroradiology.

[130]  G. Semenza,et al.  Reciprocal positive regulation of hypoxia-inducible factor 1alpha and insulin-like growth factor 2. , 1999, Cancer research.

[131]  C. Wykoff,et al.  The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis , 1999, Nature.

[132]  D. Davies,et al.  The Interaction of an Epidermal Growth Factor/Transforming Growth Factor α Tail Chimera with the Human Epidermal Growth Factor Receptor Reveals Unexpected Complexities* , 1996, The Journal of Biological Chemistry.

[133]  B. Brüne,et al.  Nitric oxide impairs normoxic degradation of HIF-1alpha by inhibition of prolyl hydroxylases. , 2003, Molecular biology of the cell.

[134]  T. Hunter,et al.  Phosphatidylinositol 3-kinase signaling controls levels of hypoxia-inducible factor 1. , 2001, Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.

[135]  C. Dalgard,et al.  Endogenous 2-oxoacids differentially regulate expression of oxygen sensors. , 2004, The Biochemical journal.

[136]  P. Carmeliet,et al.  Hypoxia-inducible Factor-2α (HIF-2α) Is Involved in the Apoptotic Response to Hypoglycemia but Not to Hypoxia* , 2001, The Journal of Biological Chemistry.

[137]  S. McKnight,et al.  A Conserved Family of Prolyl-4-Hydroxylases That Modify HIF , 2001, Science.

[138]  M. Schindl,et al.  Expression of hypoxia‐inducible factor–1α in oligodendrogliomas , 2001 .

[139]  T. Kawamoto,et al.  Identification of Functional Hypoxia Response Elements in the Promoter Region of the DEC1 and DEC2 Genes* , 2002, The Journal of Biological Chemistry.

[140]  D. Peet,et al.  FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor. , 2002, Genes & development.

[141]  S. Takahashi,et al.  Hypoxic Induction of Prolyl 4-Hydroxylase α(I) in Cultured Cells* , 2000, The Journal of Biological Chemistry.

[142]  R. Vannucci,et al.  Hypoxic Preconditioning and Hypoxic‐Ischemic Brain Damage in the Immature Rat: Pathologic and Metabolic Correlates , 1998, Journal of neurochemistry.

[143]  P. Campochiaro,et al.  Hypoxia inducible factor-1alpha is increased in ischemic retina: temporal and spatial correlation with VEGF expression. , 1999, Investigative ophthalmology & visual science.

[144]  Yuichi Makino,et al.  Inhibitory PAS domain protein is a negative regulator of hypoxia-inducible gene expression , 2001, Nature.

[145]  K. Jin,et al.  Neuroglobin protects the brain from experimental stroke in vivo , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[146]  O. Hankinson,et al.  The Role of the Aryl Hydrocarbon Receptor Nuclear Translocator (ARNT) in Hypoxic Induction of Gene Expression , 1996, The Journal of Biological Chemistry.

[147]  B. Mazumder,et al.  Role of Hypoxia-inducible Factor-1 in Transcriptional Activation of Ceruloplasmin by Iron Deficiency* , 2000, The Journal of Biological Chemistry.

[148]  L. Neckers,et al.  Hsp90 Regulates a von Hippel Lindau-independent Hypoxia-inducible Factor-1α-degradative Pathway* , 2002, The Journal of Biological Chemistry.

[149]  R. Crowder,et al.  Expression of the SM‐20 Gene Promotes Death in Nerve Growth Factor‐Dependent Sympathetic Neurons , 1999, Journal of neurochemistry.

[150]  J. Dichgans,et al.  Neuroprotection by Hypoxic Preconditioning Requires Sequential Activation of Vascular Endothelial Growth Factor Receptor and Akt , 2002, The Journal of Neuroscience.

[151]  A. Giaccia,et al.  Activation of metallothionein gene expression by hypoxia involves metal response elements and metal transcription factor-1. , 1999, Cancer research.

[152]  P. Lewczuk,et al.  Erythropoietin Therapy for Acute Stroke Is Both Safe and Beneficial , 2002, Molecular medicine.

[153]  K. Webster,et al.  Hypoxia regulates expression of the endothelin-1 gene through a proximal hypoxia-inducible factor-1 binding site on the antisense strand. , 1998, Biochemical and biophysical research communications.

[154]  R. Klausner,et al.  Identification of the von Hippel-lindau tumor-suppressor protein as part of an active E3 ubiquitin ligase complex. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[155]  D. Mottet,et al.  Is HIF-1α a pro- or an anti-apoptotic protein? ☆ , 2002 .

[156]  L. Neckers,et al.  Stabilization of wild-type p53 by hypoxia-inducible factor 1α , 1998, Nature.

[157]  J. Powell,et al.  Mutations in all five exons of SOD‐1 may cause ALS , 1998, Annals of neurology.

[158]  Brandon A. Miller,et al.  Cerebral protection by hypoxic preconditioning in a murine model of focal ischemia-reperfusion , 2001, Neuroreport.

[159]  L. Ellis,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* , 2002, The Journal of Biological Chemistry.

[160]  Q. Yu,et al.  Identification of an oxygen responsive enhancer element in the glyceraldehyde-3-phosphate dehydrogenase gene. , 1999, Biochimica et biophysica acta.

[161]  R. Wenger,et al.  Cellular adaptation to hypoxia: O2‐sensing protein hydroxylases, hypoxia‐inducible transcription factors, and O2‐regulated gene expression , 2002, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[162]  B. Ebert,et al.  Hypoxia and Mitochondrial Inhibitors Regulate Expression of Glucose Transporter-1 via Distinct Cis-acting Sequences (*) , 1995, The Journal of Biological Chemistry.

[163]  D. Maysinger,et al.  MKP-1 as a target for pharmacological manipulations in PC12 cell survival , 2001, Neurochemistry International.

[164]  Kai-Uwe Eckardt,et al.  The FASEB Journal express article 10.1096/fj.02-0445fje. Published online December 17, 2002. Widespread, hypoxia-inducible expression of HIF-2α in distinct cell populations of different organs , 2022 .

[165]  S. McKnight,et al.  Endothelial PAS domain protein 1 (EPAS1), a transcription factor selectively expressed in endothelial cells. , 1997, Genes & development.

[166]  M. Ross,et al.  Inducible Nitric Oxide Synthase Gene Expression in Brain following Cerebral Ischemia , 1995, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[167]  G. Semenza,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, p21waf1/cip1, and Erythropoietin , 1999, The Journal of Neuroscience.

[168]  S. Kumar,et al.  Role of Angiogenesis in Patients With Cerebral Ischemic Stroke , 1994, Stroke.

[169]  A. Shah,et al.  Neuroprotection from ischemic brain injury by hypoxic preconditioning in the neonatal rat , 1994, Neuroscience Letters.

[170]  P. Ratcliffe,et al.  Regulation of HIF by the von Hippel‐Lindau Tumour Suppressor: Implications for Cellular Oxygen Sensing , 2001, IUBMB life.

[171]  G. Semenza,et al.  Hypoxia-inducible Factor-1 Mediates Transcriptional Activation of the Heme Oxygenase-1 Gene in Response to Hypoxia* , 1997, The Journal of Biological Chemistry.

[172]  B. Ebert,et al.  Hypoxic Regulation of Lactate Dehydrogenase A , 1995, The Journal of Biological Chemistry.

[173]  M. Gassmann,et al.  Oxygen-regulated Transferrin Expression Is Mediated by Hypoxia-inducible Factor-1* , 1997, The Journal of Biological Chemistry.

[174]  N. Ferrara,et al.  Differential Transcriptional Regulation of the Two Vascular Endothelial Growth Factor Receptor Genes , 1997, The Journal of Biological Chemistry.

[175]  A. Dogan,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 , 1997, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[176]  R. Simon Hypoxia versus ischemia , 1999, Neurology.

[177]  G. Greeley,et al.  Hypoxia‐induced mitochondrial and nuclear DNA damage in the rat brain , 1999, Journal of neuroscience research.

[178]  G. Semenza,et al.  Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[179]  J. LaManna,et al.  Activation of Hypoxia-Inducible Factor-1 in the Rat Cerebral Cortex after Transient Global Ischemia: Potential Role of Insulin-Like Growth Factor-1 , 2002, The Journal of Neuroscience.

[180]  G. Semenza,et al.  Hypoxia-inducible factor 1 levels vary exponentially over a physiologically relevant range of O2 tension. , 1996, The American journal of physiology.

[181]  U. Dirnagl,et al.  Induction of hypoxia inducible factor 1 by oxygen glucose deprivation is attenuated by hypoxic preconditioning in rat cultured neurons , 1998, Neuroscience Letters.

[182]  D. Vordermark Expression of hypoxia-inducible factor-1alpha in oligodendrogliomas: its impact on prognosis and on neoangiogenesis. , 2002, Cancer.

[183]  D. Peet,et al.  Asparagine Hydroxylation of the HIF Transactivation Domain: A Hypoxic Switch , 2002, Science.

[184]  M. Lazdunski,et al.  Activation of the Nuclear Factor-κB Is a Key Event in Brain Tolerance , 2001, The Journal of Neuroscience.

[185]  C. Iadecola,et al.  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 , 1994, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[186]  T. Clanton,et al.  Physiological and Genomic Consequences of Intermittent Hypoxia Invited Review : Adaptive responses of skeletal muscle to intermittent hypoxia : the known and the unknown , 2001 .

[187]  J. LaManna,et al.  Angiopoietin-2 and rat brain capillary remodeling during adaptation and deadaptation to prolonged mild hypoxia. , 2002, Journal of applied physiology.

[188]  F. Cuttitta,et al.  Adrenomedullin expression is up-regulated by ischemia–reperfusion in the cerebral cortex of the adult rat , 2002, Neuroscience.

[189]  P. Ratcliffe,et al.  New insights into an enigmatic tumour suppressor , 2003, Nature Cell Biology.

[190]  P Ghezzi,et al.  Erythropoietin crosses the blood-brain barrier to protect against experimental brain injury. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[191]  P. Campochiaro,et al.  Upregulation of vascular endothelial growth factor in ischemic and non-ischemic human and experimental retinal disease. , 1997, Histology and histopathology.

[192]  G. Semenza,et al.  Characterization of hypoxia-inducible factor 1 and regulation of DNA binding activity by hypoxia. , 1993, The Journal of biological chemistry.

[193]  Y. Olsson,et al.  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 , 1998, Journal of neuropathology and experimental neurology.

[194]  N. van Bruggen,et al.  Evidence for a protective role of metallothionein-1 in focal cerebral ischemia. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[195]  R. Freeman,et al.  SM-20 Is a Novel Mitochondrial Protein That Causes Caspase-dependent Cell Death in Nerve Growth Factor-dependent Neurons* , 2001, The Journal of Biological Chemistry.

[196]  M. Ivan,et al.  HIFα Targeted for VHL-Mediated Destruction by Proline Hydroxylation: Implications for O2 Sensing , 2001, Science.