Oxygen is essential to the life of all aerobic organisms. Virtually every cell type is able to sense a limited oxygen supply (hypoxia) and specifically to induce a set of oxygen-regulated genes. This review summarizes current concepts of mammalian oxygen-sensing and signal-transduction pathways. Since the discovery of the hypoxia-inducible factors (HIFs), a great deal of progress has been made in our comprehension of how hypoxia induces the expression of oxygen-regulated genes. The alpha subunit of the heterodimeric transcription factors HIF-1, 2 and 3 is unstable under normoxia but is rapidly stabilized upon exposure to hypoxic conditions. Following heterodimerization with the constitutively expressed beta subunit, HIFs activate the transcription of an increasing number of genes involved in maintaining oxygen homeostasis at the cellular, local and systemic levels.
REFERENCES
Acker
H.
, Dufau
E.
, Huber
J.
, Sylvester
D.
(1989
). Indications to an NADPH oxidase as a possible P Osensor in the rat carotid body
. FEBS Lett
256
, 75
–.Agani
F.
, Semenza
G. L.
(1998
). Mersalyl is a novel inducer of vascular endothelial growth factor gene expression and hypoxia-inducible factor 1 activity
. Mol. Pharmac
54
, 749
–.Arany
Z.
, Huang
L. E.
, Eckner
R.
, Bhattacharya
S.
, Jiang
C.
, Goldberg
M. A.
, Bunn
H. F.
, Livingston
D. M.
(1996
). An essential role for p300/CBP in the cellular response to hypoxia
. Proc. Natl. Acad. Sci. USA
93
, 12969
–.Archer
S. L.
, Reeve
H. L.
, Michelakis
E.
, Puttagunta
L.
, Waite
R.
, Nelson
D. P.
, Dinauer
M. C.
, Weir
E. K.
(1999
). O2sensing is preserved in mice lacking the gp91phoxsubunit of NADPH oxidase
. Proc. Natl. Acad. Sci. USA
96
, 7944
–.Bhattacharya
S.
, Michels
C. L.
, Leung
M. K.
, Arany
Z. P.
, Kung
A. L.
, Livingston
D. M.
(1999
). Functional role of p35srj, a novel p300/CBP binding protein, during transactivation by HIF-1
. Genes Dev
13
, 64
–.Budinger
G. R.
, Duranteau
J.
, Chandel
N. S.
, Schumacker
P. T.
(1998
). Hibernation during hypoxia in cardiomyocytes. Role of mitochondria as the O2sensor
. J. Biol. Chem
273
, 3320
–.Bunn
H. F.
, Poyton
R. O.
(1996
). Oxygen sensing and molecular adaptation to hypoxia
. Physiol. Rev
76
, 839
–.Canbolat
O.
, Fandrey
J.
, Jelkmann
W.
(1998
). Effects of modulators of the production and degradation of hydrogen peroxide on erythropoietin synthesis
. Respir. Physiol
114
, 175
–.Carrero
P.
, Okamoto
K.
, Coumailleau
P.
, O'Brien
S.
, Tanaka
H.
, Poellinger
L.
(2000
). Redox-regulated recruitment of the transcriptional coactivators CREB-binding protein and SRC-1 to hypoxia-inducible factor 1
. Mol. Cell. Biol
20
, 402
–.Chandel
N. S.
, Budinger
G. R.
, Choe
S. H.
, Schumacker
P. T.
(1997
). Cellular respiration during hypoxia. Role of cytochrome oxidase as the oxygen sensor in hepatocytes
. J. Biol. Chem
272
, 18808
–.Chandel
N. S.
, Maltepe
E.
, Goldwasser
E.
, Mathieu
C. E.
, Simon
M. C.
, Schumacker
P. T.
(1998
). Mitochondrial reactive oxygen species trigger hypoxia-induced transcription
. Proc. Natl. Acad. Sci. USA
95
, 11715
–.Chilov
D.
, Camenisch
G.
, Kvietikova
I.
, Ziegler
U.
, Gassmann
M.
, Wenger
R. H.
(1999
). Induction and nuclear translocation of hypoxia-inducible factor-1 (HIF-1): heterodimerization with ARNT is not necessary for nuclear accumulation of HIF-1
. J. Cell Sci
112
, 1203
–.Conrad
P. W.
, Freeman
T. L.
, Beitner-Johnson
D.
, Millhorn
D. E.
(1999
). EPAS1 trans -activation during hypoxia requires p42/p44 MAPK
. J. Biol. Chem
274
, 33709
–.Cross
A. R.
, Henderson
L.
, Jones
O. T.
, Delpiano
M. A.
, Hentschel
J.
, Acker
H.
(1990
). Involvement of an NAD(P)H oxidase as a P Osensor protein in the rat carotid body
. Biochem. J
272
, 743
–.Damert
A.
, Ikeda
E.
, Risau
W.
(1997
). Activator-protein-1 binding potentiates the hypoxia-inducible factor-1-mediated hypoxia-induced transcriptional activation of vascular-endothelial growth factor expression in C6 glioma cells
. Biochem. J
327
, 419
–.Duranteau
J.
, Chandel
N. S.
, Kulisz
A.
, Shao
Z.
, Schumacker
P. T.
(1998
). Intracellular signaling by reactive oxygen species during hypoxia in cardiomyocytes
. J. Biol. Chem
273
, 11619
–.Ebert
B. L.
, Bunn
H. F.
(1998
). Regulation of transcription by hypoxia requires a multiprotein complex that includes hypoxia-inducible factor 1, an adjacent transcription factor and p300/CREB binding protein
. Mol. Cell. Biol
18
, 4089
–.Ebert
B. L.
, Firth
J. D.
, Ratcliffe
P. J.
(1995
). Hypoxia and mitochondrial inhibitors regulate expression of glucose transporter-1 via distinct cis -acting sequences
. J. Biol. Chem
270
, 29083
–.Eckhart
A. D.
, Yang
N.
, Xin
X.
, Faber
J. E.
(1997
). Characterization of the1B-adrenergic receptor gene promoter region and hypoxia regulatory elements in vascular smooth muscle
. Proc. Natl. Acad. Sci. USA
94
, 9487
–.Ehleben
W.
, Porwol
T.
, Fandrey
J.
, Acker
H.
(1998
). The influence of phenobarbital on cytochromes and reactive oxygen species in erythropoietin producing HepG2 cells
. FEBS Lett
440
, 343
–.Ema
M.
, Hirota
K.
, Mimura
J.
, Abe
H.
, Yodoi
J.
, Sogawa
K.
, Poellinger
L.
, Fujii-Kuriyama
Y.
(1999
). Molecular mechanisms of transcription activation by HLF and HIF1-inresponse to hypoxia: their stabilization and redox signal-induced interaction with CBP/p300
. EMBO J
18
, 1905
–.Ema
M.
, Taya
S.
, Yokotani
N.
, Sogawa
K.
, Matsuda
Y.
, Fujii-Kuriyama
Y.
(1997
). A novel bHLH-PAS factor with close sequence similarity to hypoxia-inducible factor 1regulates the VEGF expression and is potentially involved in lung and vascular development
. Proc. Natl. Acad. Sci. USA
94
, 4273
–.Estes
S. D.
, Stoler
D. L.
, Anderson
G. R.
(1995
). Anoxic induction of a sarcoma virus-related VL30 retrotransposon is mediated by a cis-acting element which binds hypoxia-inducible factor 1 and an anoxia-inducible factor
. J. Virol
69
, 6335
–.Fandrey
J.
, Frede
S.
, Ehleben
W.
, Porwol
T.
, Acker
H.
, Jelkmann
W.
(1997
). Cobalt chloride and desferrioxamine antagonize the inhibition of erythropoietin production by reactive oxygen species
. Kidney Int
51
, 492
–.Fandrey
J.
, Frede
S.
, Jelkmann
W.
(1994
). Role of hydrogen peroxide in hypoxia-induced erythropoietin production
. Biochem. J
303
, 507
–.Fandrey
J.
, Seydel
F. P.
, Siegers
C. P.
, Jelkmann
W.
(1990
). Role of cytochrome P450 in the control of the production of erythropoietin
. Life Sci
47
, 127
–.Feldser
D.
, Agani
F.
, Iyer
N. V.
, Pak
B.
, Ferreira
G.
, Semenza
G. L.
(1999
). Reciprocal positive regulation of hypoxia-inducible factor 1and insulin-like growth factor 2
. Cancer Res
59
, 3915
–.Firth
J. D.
, Ebert
B. L.
, Pugh
C. W.
, Ratcliffe
P. J.
(1994
). Oxygen-regulated control elements in the phosphoglycerate kinase 1 and lactate dehydrogenase A genes: similarities with the erythropoietin 3enhancer
. Proc. Natl. Acad. Sci. USA
91
, 6496
–.Firth
J. D.
, Ebert
B. L.
, Ratcliffe
P. J.
(1995
). Hypoxic regulation of lactate dehydrogenase A. Interaction between hypoxia-inducible factor 1 and cyclic AMP response elements
. J. Biol. Chem
270
, 21021
–.Flamme
I.
, Frohlich
T.
, von Reutern
M.
, Kappel
A.
, Damert
A.
, Risau
W.
(1997
). HRF, a putative basic helix—loop—helix-PAS-domain transcription factor is closely related to hypoxia-inducible factor-1and developmentally expressed in blood vessels
. Mech. Dev
63
, 51
–.Forsythe
J. A.
, Jiang
B. H.
, Iyer
N. V.
, Agani
F.
, Leung
S. W.
, Koos
R. D.
, Semenza
G. L.
(1996
). Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1
. Mol. Cell. Biol
16
, 4604
–.Galson
D. L.
, Tsuchiya
T.
, Tendler
D. S.
, Huang
L. E.
, Ren
Y.
, Ogura
T.
, Bunn
H. F.
(1995
). The orphan receptor hepatic nuclear factor 4 functions as a transcriptional activator fortissue-specific and hypoxia-specific erythropoietin gene expression and is antagonized by EAR3/COUP-TF1
. Mol. Cell. Biol
15
, 2135
–.Gassmann
M.
, Kvietikova
I.
, Rolfs
A.
, Wenger
R. H.
(1997
). Oxygen-and dioxin-regulated gene expression in mouse hepatoma cells
. Kidney Int
51
, 567
–.Gerber
H. P.
, Condorelli
F.
, Park
J.
, Ferrara
N.
(1997
). 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
–.Gleadle
J. M.
, Ebert
B. L.
, Ratcliffe
P. J.
(1995
). Diphenylene iodonium inhibits the induction of erythropoietin and other mammalian genes by hypoxia. Implications for the mechanism of oxygen sensing
. Eur. J. Biochem
234
, 92
–.Goldberg
M. A.
, Dunning
S. P.
, Bunn
H. F.
(1988
). R. H. WENGER1260Regulation of the erythropoietin gene: evidence that the oxygen sensor is a heme protein
. Science
242
, 1412
–.Goldwasser
E.
, Alibali
P.
, Gardner
A.
(1995
). Differential inhibition by iodonium compounds of induced erythropoietin expression
. J. Biol. Chem
270
, 2628
–.Gong
W.
, Hao
B.
, Mansy
S. S.
, Gonzalez
G.
, Gilles-Gonzalez
M. A.
, Chan
M. K.
(1998
). Structure of a biological oxygen sensor: a new mechanism for heme-driven signal transduction
. Proc. Natl. Acad. Sci. USA
95
, 15177
–.Görlach
A.
, Fandrey
J.
, Holtermann
G.
, Acker
H.
(1994
). Effects of cobalt on haem proteins of erythropoietin-producing HepG2 cells in multicellular spheroid culture
. FEBS Lett
348
, 216
–.Görlach
A.
, Holtermann
G.
, Jelkmann
W.
, Hancock
J. T.
, Jones
S. A.
, Jones
O. T.
, Acker
H.
(1993
). Photometric characteristics of haem proteins in erythropoietin-producing hepatoma cells (HepG2)
. Biochem. J
290
, 771
–.Gradin
K.
, McGuire
J.
, Wenger
R. H.
, Kvietikova
I.
, Whitelaw
M. L.
, Toftgård
R.
, Tora
L.
, Gassmann
M.
, Poellinger
L.
(1996
). Functional interference between hypoxia and dioxin signal transduction pathways: competition for recruitment of the Arnt transcription factor
. Mol. Cell. Biol
16
, 5221
–.Graven
K. K.
, Yu
Q.
, Pan
D.
, Roncarati
J. S.
, Farber
H. W.
(1999
). Identification of an oxygen responsive enhancer element in the glyceraldehyde-3-phosphate dehydrogenase gene
. Biochim. Biophys. Acta
1447
, 208
–.Gu
Y. Z.
, Moran
S. M.
, Hogenesch
J. B.
, Wartman
L.
, Bradfield
C. A.
(1998
). Molecular characterization and chromosomal localization of a third-class hypoxia inducible factor subunit, HIF3
. Gene Expr
7
, 205
–.Harder
D. R.
, Narayanan
J.
, Birks
E. K.
, Liard
J. F.
, Imig
J. D.
, Lombard
J. H.
, Lange
A. R.
, Roman
R. J.
(1996
). Identification of a putative microvascular oxygen sensor
. Circ. Res
79
, 54
–.Hellwig-Burgel
T.
, Rutkowski
K.
, Metzen
E.
, Fandrey
J.
, Jelkmann
W.
(1999
). Interleukin-1and tumor necrosis factor- stimulate DNA binding of hypoxia-inducible factor-1
. Blood
94
, 1561
–.Ho
V. T.
, Bunn
H. F.
(1996
). Effects of transition metals on the expression of the erythropoietin gene: further evidence that the oxygen sensor is a heme protein
. Biochem. Biophys. Res. Commun
223
, 175
–.Hoffman
E. C.
, Reyes
H.
, Chu
F. F.
, Sander
F.
, Conley
L. H.
, Brooks
B. A.
, Hankinson
O.
(1991
). Cloning of a factor required for activity of the Ah (dioxin) receptor
. Science
252
, 954
–.Hogenesch
J. B.
, Chan
W. K.
, Jackiw
V. H.
, Brown
R. C.
, Gu
Y. Z.
, Pray-Grant
M.
, Perdew
G. H.
, Bradfield
C. A.
(1997
). Characterization of a subset of the basic-helix—loop—helix-PAS superfamily that interacts with components of the dioxin signaling pathway
. J. Biol. Chem
272
, 8581
–.Hogenesch
J. B.
, Gu
Y. Z.
, Jain
S. J.
, Bradfield
C. A.
(1998
). The basic-helix—loop—helix-PAS orphan MOP3 forms transcriptionally active complexes with circadian and hypoxia factors
. Proc. Natl. Acad. Sci. USA
95
, 5474
–.Hohler
B.
, Lange
B.
, Holzapfel
B.
, Goldenberg
A.
, Hanze
J.
, Sell
A.
, Testan
H.
, Moller
W.
, Kummer
W.
(1999
). Hypoxic upregulation of tyrosine hydroxylase gene expression is paralleled, but not induced, by increased generation of reactive oxygen species in PC12 cells
. FEBS Lett
457
, 53
–.Hu
B.
, Wright
E.
, Campbell
L.
, Blanchard
K. L.
(1997
). Invivo analysis of DNA—protein interactions on the human erythropoietin enhancer
. Mol. Cell. Biol
17
, 851
–.Hu
J.
, Discher
D. J.
, Bishopric
N. H.
, Webster
K. A.
(1998
). 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
–.Huang
L. E.
, Gu
J.
, Schau
M.
, Bunn
H. F.
(1998
). Regulation of hypoxia-inducible factor 1is mediated by an O2-dependent degradation domain via the ubiquitin—proteasome pathway
. Proc. Natl. Acad. Sci. USA
95
, 7987
–.Huang
L. E.
, Arany
Z.
, Livingston
D. M.
, Bunn
H. F.
(1996
). Activation of hypoxia-inducible transcription factor depends primarily upon redox-sensitive stabilization of itssubunit
. J. Biol. Chem
271
, 32253
–.Iwai
K.
, Drake
S. K.
, Wehr
N. B.
, Weissman
A. M.
, LaVaute
T.
, Minato
N.
, Klausner
R. D.
, Levine
R. L.
, Rouault
T. A.
(1998
). Iron-dependent oxidation, ubiquitination and degradation of iron regulatory protein 2: implications for degradation of oxidized proteins
. Proc. Natl. Acad. Sci. USA
95
, 4924
–.Iyer
N. V.
, Kotch
L. E.
, Agani
F.
, Leung
S. W.
, Laughner
E.
, Wenger
R. H.
, Gassmann
M.
, Gearhart
J. D.
, Lawler
A. M.
, Yu
A. Y.
, Semenza
G. L.
(1998
). Cellular and developmental control of O2homeostasis by hypoxia-inducible factor 1
. Genes Dev
12
, 149
–.Jiang
B. H.
, Semenza
G. L.
, Bauer
C.
, Marti
H. H.
(1996
). Hypoxia-inducible factor 1 levels vary exponentially over a physiologically relevant range of O2tension
. Am. J. Physiol
271
, 1172
–.Jiang
B. H.
, Zheng
J. Z.
, Leung
S. W.
, Roe
R.
, Semenza
G. L.
(1997
). Transactivation and inhibitory domains of hypoxia-inducible factor 1. Modulation of transcriptional activity by oxygen tension
. J. Biol. Chem
272
, 19253
–.Kallio
P. J.
, Okamoto
K.
, O'Brien
S.
, Carrero
P.
, Makino
Y.
, Tanaka
H.
, Poellinger
L.
(1998
). Signal transduction in hypoxic cells: inducible nuclear translocation and recruitment of the CBP/p300 coactivator by the hypoxia-inducible factor-1
. EMBO J
17
, 6573
–.Kallio
P. J.
, Pongratz
I.
, Gradin
K.
, McGuire
J.
, Poellinger
L.
(1997
). Activation of hypoxia-inducible factor 1: posttranscriptional regulation and conformational change by recruitment of the Arnt transcription factor
. Proc. Natl. Acad. Sci. USA
94
, 5667
–.Kallio
P. J.
, Wilson
W. J. S. O. B.
, Makino
Y.
, Poellinger
L.
(1999
). Regulation of the hypoxia-inducible transcription factor 1by the ubiquitin-proteasome pathway
. J. Biol. Chem
274
, 6519
–.Kietzmann
T.
, Freimann
S.
, Bratke
J.
, Jungermann
K.
(1996
). Regulation of the gluconeogenic phosphoenolpyruvate carboxykinase and glycolytic aldolase A gene expression by O2in rat hepatocyte cultures. Involvement of hydrogen peroxide as mediator in the response to O2
. FEBS Lett
388
, 228
–.Kietzmann
T.
, Porwol
T.
, Zierold
K.
, Jungermann
K.
, Acker
H.
(1998
). Involvement of a local Fenton reaction in the reciprocal modulation by O2of the glucagon-dependent activation of the phosphoenolpyruvate carboxykinase gene and the insulin-dependent activation of the glucokinase gene in rat hepatocytes
. Biochem. J
335
, 425
–.Kietzmann
T.
, Roth
U.
, Freimann
S.
, Jungermann
K.
(1997
). Arterial oxygen partial pressures reduce the insulin-dependent induction of the perivenously located glucokinase in rat Mammalian oxygen homeostasis 1261hepatocyte cultures: mimicry of arterial oxygen pressures by H2O2
. Biochem. J
321
, 17
–.Kietzmann
T.
, Roth
U.
, Jungermann
K.
(1999
). 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
–.Kotch
L. E.
, Iyer
N. V.
, Laughner
E.
, Semenza
G. L.
(1999
). Defective vascularization of HIF-1-null embryos is not associated with VEGF deficiency but with mesenchymal cell death
. Dev. Biol
209
, 254
–.Kroll
S. L.
, Czyzyk-Krzeska
M. F.
(1998
). Role of H2O2and heme-containing O2sensors in hypoxic regulation of tyrosine hydroxylase gene expression
. Am. J. Physiol
274
, 167
–.Kummer
W.
, Acker
H.
(1995
). Immunohistochemical demonstration of four subunits of neutrophil NAD(P)H oxidase in type I cells of carotid body
. J. Appl. Physiol
78
, 1904
–.Kvietikova
I.
, Wenger
R. H.
, Marti
H. H.
, Gassmann
M.
(1995
). The transcription factors ATF-1 and CREB-1 bind constitutively to the hypoxia-inducible factor-1 (HIF-1) DNA recognition site
. Nucleic Acids Res
23
, 4542
–.Kvietikova
I.
, Wenger
R. H.
, Marti
H. H.
, Gassmann
M.
(1997
). The hypoxia-inducible factor-1 DNA recognition site is cAMP-responsive
. Kidney Int
51
, 564
–.Lahiri
S.
, Buerk
D. G.
, Chugh
D.
, Osanai
S.
, Mokashi
A.
(1995
). Reciprocal photolabile O2consumption and chemoreceptor excitation by carbon monoxide in the cat carotid body: evidence for cytochrome a3 as the primary O2sensor
. Brain Res
684
, 194
–.Lahiri
S.
, Ehleben
W.
, Acker
H.
(1999
). Chemoreceptor discharges and cytochrome redox changes of the rat carotid body: role of heme ligands
. Proc. Natl. Acad. Sci. USA
96
, 9427
–.Lee
P. J.
, Jiang
B. H.
, Chin
B. Y.
, Iyer
N. V.
, Alam
J.
, Semenza
G. L.
, Choi
A. M.
(1997
). Hypoxia-inducible factor-1 mediates transcriptional activation of the heme oxygenase-1 gene in response to hypoxia
. J. Biol. Chem
272
, 5375
–.Levy
A. P.
, Levy
N. S.
, Wegner
S.
, Goldberg
M. A.
(1995
). Transcriptional regulation of the rat vascular endothelial growth factor gene by hypoxia
. J. Biol. Chem
270
, 13333
–.Li
H.
, Ko
H. P.
, Whitlock
J. P.
(1996
). Induction of phosphoglycerate kinase 1 gene expression by hypoxia. Roles of ARNT and HIF1
. J. Biol. Chem
271
, 21262
–.Liu
Y.
, Cox
S. R.
, Morita
T.
, Kourembanas
S.
(1995
). Hypoxia regulates vascular endothelial growth factor gene expression in endothelial cells. Identification of a 5enhancer
. Circ. Res
77
, 638
–.Lok
C. N.
, Ponka
P.
(1999
). Identification of a hypoxia response element in the transferrin receptor gene
. J. Biol. Chem
274
, 24147
–.Maxwell
P. H.
, Wiesener
M. S.
, Chang
G. W.
, Clifford
S. C.
, Vaux
E. C.
, Cockman
M. E.
, Wykoff
C. C.
, Pugh
C. W.
, Maher
E. R.
, Ratcliffe
P. J.
(1999
). The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis
. Nature
399
, 271
–.Melillo
G.
, Musso
T.
, Sica
A.
, Taylor
L. S.
, Cox
G. W.
, Varesio
L.
(1995
). A hypoxia-responsive element mediates a novel pathway of activation of the inducible nitric oxide synthase promoter
. J. Exp. Med
182
, 1683
–.Nguyen
S. V.
, Claycomb
W. C.
(1999
). Hypoxia regulates the expression of the adrenomedullin and HIF-1 genes in cultured HL-1 cardiomyocytes
. Biochem. Biophys. Res. Commun
265
, 382
–.Okino
S. T.
, Chichester
C. H.
, Whitlock
J. P.
Jr. (1998
). Hypoxia-inducible mammalian gene expression analyzed in vivo at a TATA-driven promoter and at an initiator-driven promoter
. J. Biol. Chem
273
, 23837
–.O'Rourke
J. F.
, Tian
Y. M.
, Ratcliffe
P. J.
, Pugh
C. W.
(1999
). Oxygen-regulated and transactivating domains in endothelial PAS protein 1: comparison with hypoxia-inducible factor-1
. J. Biol. Chem
274
, 2060
–.Palmer
L. A.
, Semenza
G. L.
, Stoler
M. H.
, Johns
R. A.
(1998
). Hypoxia induces type II NOS gene expression in pulmonary artery endothelial cells via HIF-1
. Am. J. Physiol
274
, 212
–.Porwol
T.
, Ehleben
W.
, Zierold
K.
, Fandrey
J.
, Acker
H.
(1998
). The influence of nickel and cobalt on putative members of the oxygen-sensing pathway of erythropoietin-producing HepG2 cells
. Eur. J. Biochem
256
, 16
–.Pugh
C. W.
, O'Rourke
J. F.
, Nagao
M.
, Gleadle
J. M.
, Ratcliffe
P. J.
(1997
). Activation of hypoxia-inducible factor-1; definition of regulatory domains within thesubunit
. J. Biol. Chem
272
, 11205
–.Qi
Y.
, Jamindar
T. M.
, Dawson
G.
(1995
). Hypoxia alters iron homeostasis and induces ferritin synthesis in oligodendrocytes
. J. Neurochem
64
, 2458
–.Richard
D. E.
, Berra
E.
, Gothie
E.
, Roux
D.
, Pouyssegur
J.
(1999
). p42/p44 mitogen-activated protein kinases phosphorylate hypoxia-inducible factor 1(HIF-1) and enhance the transcriptional activity of HIF-1
. J. Biol. Chem
274
, 32631
–.Rolfs
A.
, Kvietikova
I.
, Gassmann
M.
, Wenger
R. H.
(1997
). Oxygen-regulated transferrin expression is mediated by hypoxia-inducible factor-1
. J. Biol. Chem
272
, 20055
–.Ryan
H. E.
, Lo
J.
, Johnson
R. S.
(1998
). HIF-1is required for solid tumor formation and embryonic vascularization
. EMBO J
17
, 3005
–.Salceda
S.
, Beck
I.
, Caro
J.
(1996
). Absolute requirement of aryl hydrocarbon receptor nuclear translocator protein for gene activation by hypoxia
. Arch. Biochem. Biophys
334
, 389
–.Salceda
S.
, Beck
I.
, Srinivas
V.
, Caro
J.
(1997
). Complex role of protein phosphorylation in gene activation by hypoxia
. Kidney Int
51
, 556
–.Salceda
S.
, Caro
J.
(1997
). Hypoxia-inducible factor 1(HIF-1) protein is rapidly degraded by the ubiquitin—proteasome system under normoxic conditions. Its stabilization by hypoxia depends on redox-induced changes
. J. Biol. Chem
272
, 22642
–.Schmaltz
C.
, Hardenbergh
P. H.
, Wells
A.
, Fisher
D. E.
(1998
). Regulation of proliferation—survival decisions during tumor cell hypoxia
. Mol. Cell. Biol
18
, 2845
–.Semenza
G. L.
(1998
). Hypoxia-inducible factor 1: master regulator of O2homeostasis
. Curr. Opin. Genet. Dev
8
, 588
–.Semenza
G. L.
, Jiang
B. H.
, Leung
S. W.
, Passantino
R.
, Concordet
J. P.
, Maire
P.
, Giallongo
A.
(1996
). 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
–.Semenza
G. L.
, Roth
P. H.
, Fang
H. M.
, Wang
G. L.
(1994
). Transcriptional regulation of genes encoding glycolytic enzymes by hypoxia-inducible factor 1
. J. Biol. Chem
269
, 23757
–.Srinivas
V.
, Zhang
L. P.
, Zhu
X. H.
, Caro
J.
(1999
). Characterization of an oxygen/redox-dependent degradation domain of hypoxia-inducible factor(HIF-) proteins
. Biochem. Biophys. Res. Commun
260
, 557
–.Srinivas
V.
, Zhu
X.
, Salceda
S.
, Nakamura
R.
, Caro
J.
(1999
). Hypoxia-inducible factor 1 (HIF-1) is a non-heme iron protein. Implications for oxygen sensing [retraction of V. Srinivas, X. Zhu, S. Salceda, R. Nakamura and J. Caro (1998). J. Biol. Chem. 273, 18019—18022]
. J. Biol. Chem
274
, 1180
.Suzuki
Y. J.
, Forman
H. J.
, Sevanian
A.
(1997
). Oxidants as stimulators of signal transduction
. Free Radical Biol. Med
22
, 269
–.Tacchini
L.
, Bianchi
L.
, Bernelli-Zazzera
A.
, Cairo
G.
(1999
). Transferrin receptor induction by hypoxia. HIF-1-mediated transcriptional activation and cell-specific post-transcriptional regulation
. J. Biol. Chem
274
, 24142
–.Tan
C. C.
, Ratcliffe
P. J.
(1991
). Effect of inhibitors of oxidative phosphorylation on erythropoietin mRNA in isolated perfused rat kidneys
. Am. J. Physiol
261
, 982
–.Taylor
C. T.
, Lisco
S. J.
, Awtrey
C. S.
, Colgan
S. P.
(1998
). Hypoxia inhibits cyclic nucleotide-stimulated epithelial ion transport: role for nucleotide cyclases as oxygen sensors
. J. Pharmac. Exp. Ther
284
, 568
–.Tazuke
S. I.
, Mazure
N. M.
, Sugawara
J.
, Carland
G.
, Faessen
G. H.
, Suen
L. F.
, Irwin
J. C.
, Powell
D. R.
, Giaccia
A. J.
, Giudice
L. C.
(1998
). 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
–.Tian
H.
, Hammer
R. E.
, Matsumoto
A. M.
, Russell
D. W.
, McKnight
S. L.
(1998
). The hypoxia-responsive transcription factor EPAS1 is essential for catecholamine homeostasis and protection against heart failure during embryonic development
. Genes Dev
12
, 3320
–.Tian
H.
, McKnight
S. L.
, Russell
D. W.
(1997
). Endothelial PAS domain protein 1 (EPAS1), a transcription factor selectively expressed in endothelial cells
. Genes Dev
11
, 72
–.Vanden Hoek
T. L.
, Becker
L. B.
, Shao
Z.
, Li
C.
, Schumacker
P. T.
(1998
). Reactive oxygen species released from mitochondria during brief hypoxia induce preconditioning in cardiomyocytes
. J. Biol. Chem
273
, 18092
–.Wang
D.
, Youngson
C.
, Wong
V.
, Yeger
H.
, Dinauer
M. C.
, Vega-Saenz Miera
E.
, Rudy
B.
, Cutz
E.
(1996
). NADPH-oxidase and a hydrogen peroxide-sensitive K+channel may function as an oxygen sensor complex in airway chemoreceptors and small cell lung carcinoma cell lines
. Proc. Natl. Acad. Sci. USA
93
, 13182
–.Wang
G. L.
, Jiang
B. H.
, Rue
E. A.
, Semenza
G. L.
(1995
). Hypoxia-inducible factor 1 is a basic-helix—loop—helix-PAS heterodimer regulated by cellular O2tension
. Proc. Natl. Acad. Sci. USA
92
, 5510
–.Wang
G. L.
, Jiang
B. H.
, Semenza
G. L.
(1995
). Effect of protein kinase and phosphatase inhibitors on expression of hypoxia-inducible factor 1
. Biochem. Biophys. Res. Commun
216
, 669
–.Wang
G. L.
, Semenza
G. L.
(1993
). Characterization of hypoxia-inducible factor 1 and regulation of DNA binding activity by hypoxia
. J. Biol. Chem
268
, 21513
–.Wang
G. L.
, Semenza
G. L.
(1993
). Desferrioxamine induces erythropoietin gene expression and hypoxia-inducible factor 1 DNA-binding activity: implications for models of hypoxia signal transduction
. Blood
82
, 3610
–.Wenger
R. H.
, Gassmann
M.
(1997
). Oxygen(es) and the hypoxia-inducible factor-1
. Biol. Chem
378
, 609
–.Wenger
R. H.
, Kvietikova
I.
, Rolfs
A.
, Camenisch
G.
, Gassmann
M.
(1998
). Oxygen-regulated erythropoietin gene expression is dependent on a CpG methylation-free hypoxia-inducible factor-1 DNA-binding site
. Eur. J. Biochem
253
, 771
–.Wenger
R. H.
, Marti
H. H.
, Schuerer-Maly
C. C.
, Kvietikova
I.
, Bauer
C.
, Gassmann
M.
, Maly
F. E.
(1996
). Hypoxic induction of gene expression in chronic granulomatous disease-derived B-cell lines: oxygen sensing is independent of the cytochrome b558-containing nicotinamide adenine dinucleotide phosphate oxidase
. Blood
87
, 756
–.Wenger
R. H.
, Rolfs
A.
, Kvietikova
I.
, Spielmann
P.
, Zimmermann
D. R.
, Gassmann
M.
(1997
). The mouse gene for hypoxia-inducible factor-1. Genomic organization, expression and characterization of an alternative first exon and 5 flanking sequence
. Eur. J. Biochem
246
, 155
–.Wenger
R. H.
, Rolfs
A.
, Spielmann
P.
, Zimmermann
D. R.
, Gassmann
M.
(1998
). Mouse hypoxia-inducible factor-1is encoded by two different mRNA isoforms — expression from a tissue-specific and a housekeeping-type promoter
. Blood
91
, 3471
–.Wiesener
M. S.
, Turley
H.
, Allen
W. E.
, Willam
C.
, Eckardt
K. U.
, Talks
K. L.
, Wood
S. M.
, Gatter
K. C.
, Harris
A. L.
, Pugh
C. W.
, Ratcliffe
P. J.
, Maxwell
P. H.
(1998
). Induction of endothelial PAS domain protein-1 by hypoxia: Characterization and comparison with hypoxia-inducible factor-1
. Blood
92
, 2260
–.Wilson
D. F.
, Mokashi
A.
, Chugh
D.
, Vinogradov
S.
, Osanai
S.
, Lahiri
S.
(1994
). The primary oxygen sensor of the cat carotid body is cytochrome a3 of the mitochondrial respiratory chain
. FEBS Lett
351
, 370
–.Wood
S. M.
, Gleadle
J. M.
, Pugh
C. W.
, Hankinson
O.
, Ratcliffe
P. J.
(1996
). 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
–.Wood
S. M.
, Wiesener
M. S.
, Yeates
K. M.
, Okada
N.
, Pugh
C. W.
, Maxwell
P. H.
, Ratcliffe
P. J.
(1998
). Selection and analysis of a mutant cell line defective in the hypoxia-inducible factor-1-subunit (HIF-1). Characterization of HIF-1-dependent and-independent hypoxia-inducible gene expression
. J. Biol. Chem
273
, 8360
–.Youngson
C.
, Nurse
C.
, Yeger
H.
, Curnutte
J. T.
, Vollmer
C.
, Wong
V.
, Cutz
E.
(1997
). Immunocytochemical localization on O2-sensing protein (NADPH oxidase) in chemoreceptor cells
. Microsc. Res. Tech
37
, 101
–.Youngson
C.
, Nurse
C.
, Yeger
H.
, Cutz
E.
(1993
). Oxygen sensing in airway chemoreceptors
. Nature
365
, 153
–.Yu
A. Y.
, Shimoda
L. A.
, Iyer
N. V.
, Huso
D. L.
, Sun
X.
, McWilliams
R.
, Beaty
T.
, Sham
J. S.
, Wiener
C. M.
, Sylvester
J. T.
, Semenza
G. L.
(1999
). Impaired physiological responses to chronic hypoxia in mice partially deficient for hypoxia-inducible factor 1
. J. Clin. Invest
103
, 691
–.Zelzer
E.
, Levy
Y.
, Kahana
C.
, Shilo
B. Z.
, Rubinstein
M.
, Cohen
B.
(1998
). Insulin induces transcription of target genes through the hypoxia-inducible factor HIF-1/ARNT
. EMBO J
17
, 5085
–.
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