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J Appl Physiol 88: 1474-1480, 2000;
8750-7587/00 $5.00
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Vol. 88, Issue 4, 1474-1480, April 2000

INVITED REVIEW
HIF-1: mediator of physiological and pathophysiological responses to hypoxia

Gregg L. Semenza

Institute of Genetic Medicine, Departments of Pediatrics and Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287-3914

All organisms can sense O2 concentration and respond to hypoxia with adaptive changes in gene expression. The large body size of mammals necessitates the development of multiple complex physiological systems to ensure adequate O2 delivery to all cells under normal conditions. The transcriptional regulator hypoxia-inducible factor 1 (HIF-1) is an essential mediator of O2 homeostasis. HIF-1 is required for the establishment of key physiological systems during development and their subsequent utilization in fetal and postnatal life. HIF-1 also appears to play a key role in the pathophysiology of cancer, cardiovascular disease, and chronic lung disease, which represent the major causes of mortality among industrialized societies. Genetic or pharmacological modulation of HIF-1 activity in vivo may represent a novel therapeutic approach to these disorders.

angiogenesis; glycolysis; ischemia; pulmonary hypertension; vascular endothelial growth factor; hypoxia-inducible factor 1


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EndocrinologyHome page
H. O. D. Critchley, J. Osei, T. A. Henderson, L. Boswell, K. J. Sales, H. N. Jabbour, and N. Hirani
Hypoxia-Inducible Factor-1{alpha} Expression in Human Endometrium and Its Regulation by Prostaglandin E-Series Prostanoid Receptor 2 (EP2)
Endocrinology, February 1, 2006; 147(2): 744 - 753.
[Abstract] [Full Text] [PDF]


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Exp PhysiolHome page
N. R Prabhakar
O2 sensing at the mammalian carotid body: why multiple O2 sensors and multiple transmitters?
Exp Physiol, January 1, 2006; 91(1): 17 - 23.
[Abstract] [Full Text] [PDF]


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J. Biol. Chem.Home page
R. D. Lester, M. Jo, W. M. Campana, and S. L. Gonias
Erythropoietin Promotes MCF-7 Breast Cancer Cell Migration by an ERK/Mitogen-activated Protein Kinase-dependent Pathway and Is Primarily Responsible for the Increase in Migration Observed in Hypoxia
J. Biol. Chem., November 25, 2005; 280(47): 39273 - 39277.
[Abstract] [Full Text] [PDF]


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Am. J. Respir. Crit. Care Med.Home page
E. M. Mercken, G. J. Hageman, A. M. W. J. Schols, M. A. Akkermans, A. Bast, and E. F. M. Wouters
Rehabilitation Decreases Exercise-induced Oxidative Stress in Chronic Obstructive Pulmonary Disease
Am. J. Respir. Crit. Care Med., October 15, 2005; 172(8): 994 - 1001.
[Abstract] [Full Text] [PDF]


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Nucleic Acids ResHome page
K.-F. Chen, Y.-Y. Lai, H. S. Sun, and S.-J. Tsai
Transcriptional repression of human cad gene by hypoxia inducible factor-1{alpha}
Nucleic Acids Res., September 9, 2005; 33(16): 5190 - 5198.
[Abstract] [Full Text] [PDF]


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JGPHome page
D. F. Pisani and C. A. Dechesne
Skeletal Muscle HIF-1{alpha} Expression Is Dependent on Muscle Fiber Type
J. Gen. Physiol., July 25, 2005; 126(2): 173 - 178.
[Abstract] [Full Text] [PDF]


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J. Biol. Chem.Home page
E. Temes, S. Martin-Puig, B. Acosta-Iborra, M. C. Castellanos, M. Feijoo-Cuaresma, G. Olmos, J. Aragones, and M. O. Landazuri
Activation of HIF-prolyl Hydroxylases by R59949, an Inhibitor of the Diacylglycerol Kinase
J. Biol. Chem., June 24, 2005; 280(25): 24238 - 24244.
[Abstract] [Full Text] [PDF]


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J. Clin. Endocrinol. Metab.Home page
A. Grimberg, C. M. Coleman, T. F. Burns, B. P. Himelstein, C. J. Koch, P. Cohen, and W. S. El-Deiry
p53-Dependent and p53-Independent Induction of Insulin-Like Growth Factor Binding Protein-3 by Deoxyribonucleic Acid Damage and Hypoxia
J. Clin. Endocrinol. Metab., June 1, 2005; 90(6): 3568 - 3574.
[Abstract] [Full Text] [PDF]


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Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
J. Wang, L. Weigand, W. Wang, J. T. Sylvester, and L. A. Shimoda
Chronic hypoxia inhibits Kv channel gene expression in rat distal pulmonary artery
Am J Physiol Lung Cell Mol Physiol, June 1, 2005; 288(6): L1049 - L1058.
[Abstract] [Full Text] [PDF]


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J. Biol. Chem.Home page
T. S. Fisher, S. D. Etages, L. Hayes, K. Crimin, and B. Li
Analysis of ARD1 Function in Hypoxia Response Using Retroviral RNA Interference
J. Biol. Chem., May 6, 2005; 280(18): 17749 - 17757.
[Abstract] [Full Text] [PDF]


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Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
M. Nikinmaa and B. B. Rees
Oxygen-dependent gene expression in fishes
Am J Physiol Regulatory Integrative Comp Physiol, May 1, 2005; 288(5): R1079 - R1090.
[Abstract] [Full Text] [PDF]


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Exp PhysiolHome page
A. Wagatsuma, H. Tamaki, and F. Ogita
Capillary supply and gene expression of angiogenesis-related factors in murine skeletal muscle following denervation
Exp Physiol, May 1, 2005; 90(3): 403 - 409.
[Abstract] [Full Text] [PDF]


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Jpn J Clin OncolHome page
W.-T. Chen, C.-J. Huang, M.-T. Wu, S.-F. Yang, Y.-C. Su, and C.-Y. Chai
Hypoxia-inducible Factor-1{alpha} is Associated with Risk of Aggressive Behavior and Tumor Angiogenesis in Gastrointestinal Stromal Tumor
Jpn. J. Clin. Oncol., April 1, 2005; 35(4): 207 - 213.
[Abstract] [Full Text] [PDF]


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IOVSHome page
P. van Wijngaarden, D. J. Coster, H. M. Brereton, I. L. Gibbins, and K. A. Williams
Strain-Dependent Differences in Oxygen-Induced Retinopathy in the Inbred Rat
Invest. Ophthalmol. Vis. Sci., April 1, 2005; 46(4): 1445 - 1452.
[Abstract] [Full Text] [PDF]


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Proc Am Thorac SocHome page
E. F. M. Wouters
Local and Systemic Inflammation in Chronic Obstructive Pulmonary Disease
Proceedings of the ATS, April 1, 2005; 2(1): 26 - 33.
[Abstract] [Full Text] [PDF]


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Cardiovasc ResHome page
Y. Cao, A. Hong, H. Schulten, and M. J. Post
Update on therapeutic neovascularization
Cardiovasc Res, February 15, 2005; 65(3): 639 - 648.
[Abstract] [Full Text] [PDF]


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J. Appl. Physiol.Home page
M. F. Banks, E. V. Gerasimovskaya, D. A. Tucker, M. G. Frid, T. C. Carpenter, and K. R. Stenmark
Egr-1 antisense oligonucleotides inhibit hypoxia-induced proliferation of pulmonary artery adventitial fibroblasts
J Appl Physiol, February 1, 2005; 98(2): 732 - 738.
[Abstract] [Full Text] [PDF]


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J. Appl. Physiol.Home page
G. B. Waypa and P. T. Schumacker
Hypoxic pulmonary vasoconstriction: redox events in oxygen sensing
J Appl Physiol, January 1, 2005; 98(1): 404 - 414.
[Abstract] [Full Text] [PDF]


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EndocrinologyHome page
U. Meissner, C. Hanisch, I. Ostreicher, I. Knerr, K.-H. Hofbauer, W. F. Blum, I. Allabauer, W. Rascher, and J. Dotsch
Differential Regulation of Leptin Synthesis in Rats during Short-Term Hypoxia and Short-Term Carbon Monoxide Inhalation
Endocrinology, January 1, 2005; 146(1): 215 - 220.
[Abstract] [Full Text] [PDF]


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Reproductive SciencesHome page
T. L. Van Natta, J. C. Ralphe, C. E. Mascio, K. A. Bedell, T. D. Scholz, and J. L. Segar
Ontogeny of Vascular Growth Factors in Perinatal Sheep Myocardium
Reproductive Sciences, December 1, 2004; 11(8): 503 - 510.
[Abstract] [PDF]


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Am. J. Pathol.Home page
T. Tanaka, T. Miyata, R. Inagi, T. Fujita, and M. Nangaku
Hypoxia in Renal Disease with Proteinuria and/or Glomerular Hypertension
Am. J. Pathol., December 1, 2004; 165(6): 1979 - 1992.
[Abstract] [Full Text] [PDF]


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Am. J. Physiol. Endocrinol. Metab.Home page
N. Morita, K. Iizuka, K. Okita, T. Oikawa, K. Yonezawa, T. Nagai, Y. Tokumitsu, T. Murakami, A. Kitabatake, and H. Kawaguchi
Exposure to pressure stimulus enhances succinate dehydrogenase activity in L6 myoblasts
Am J Physiol Endocrinol Metab, December 1, 2004; 287(6): E1064 - E1069.
[Abstract] [Full Text] [PDF]


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Mol Cancer ResHome page
W. H. Dragowska, C. Warburton, D. T.T. Yapp, A. I. Minchinton, Y. Hu, D. N. Waterhouse, K. Gelmon, K. Skov, J. Woo, D. Masin, et al.
HER-2/neu Overexpression Increases the Viable Hypoxic Cell Population within Solid Tumors without Causing Changes in Tumor Vascularization
Mol. Cancer Res., November 1, 2004; 2(11): 606 - 619.
[Abstract] [Full Text] [PDF]


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Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
K. K. K. Sheares, T. K. Jeffery, L. Long, X. Yang, and N. W. Morrell
Differential effects of TGF-{beta}1 and BMP-4 on the hypoxic induction of cyclooxygenase-2 in human pulmonary artery smooth muscle cells
Am J Physiol Lung Cell Mol Physiol, November 1, 2004; 287(5): L919 - L927.
[Abstract] [Full Text] [PDF]


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Br Med BullHome page
H. K. Eltzschig and C. D. Collard
Vascular ischaemia and reperfusion injury
Br. Med. Bull., October 19, 2004; 70(1): 71 - 86.
[Abstract] [Full Text] [PDF]


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J. Biol. Chem.Home page
K. Hirota, R. Fukuda, S. Takabuchi, S. Kizaka-Kondoh, T. Adachi, K. Fukuda, and G. L. Semenza
Induction of Hypoxia-inducible Factor 1 Activity by Muscarinic Acetylcholine Receptor Signaling
J. Biol. Chem., October 1, 2004; 279(40): 41521 - 41528.
[Abstract] [Full Text] [PDF]


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Cancer Res.Home page
I. Serganova, M. Doubrovin, J. Vider, V. Ponomarev, S. Soghomonyan, T. Beresten, L. Ageyeva, A. Serganov, S. Cai, J. Balatoni, et al.
Molecular Imaging of Temporal Dynamics and Spatial Heterogeneity of Hypoxia-Inducible Factor-1 Signal Transduction Activity in Tumors in Living Mice
Cancer Res., September 1, 2004; 64(17): 6101 - 6108.
[Abstract] [Full Text] [PDF]


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Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
M. C. Tissot van Patot, J. Bendrick-Peart, V. E. Beckey, N. Serkova, and L. Zwerdlinger
Greater vascularity, lowered HIF-1/DNA binding, and elevated GSH as markers of adaptation to in vivo chronic hypoxia
Am J Physiol Lung Cell Mol Physiol, September 1, 2004; 287(3): L525 - L532.
[Abstract] [Full Text] [PDF]




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