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Originally published in Science Express on 11 October 2001
Science 9 November 2001:
Vol. 294. no. 5545, pp. 1337 - 1340
DOI: 10.1126/science.1066373
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Reports

A Conserved Family of Prolyl-4-Hydroxylases That Modify HIF

Richard K. Bruick, Steven L. McKnight*

Mammalian cells respond to changes in oxygen availability through a conserved pathway that is regulated by the hypoxia-inducible factor (HIF). The alpha subunit of HIF is targeted for degradation under normoxic conditions by a ubiquitin-ligase complex that recognizes a hydroxylated proline residue in HIF. We identified a conserved family of HIF prolyl hydoxylase (HPH) enzymes that appear to be responsible for this posttranslational modification. In cultured mammalian cells, inappropriate accumulation of HIF caused by forced expression of the HIF-1alpha subunit under normoxic conditions was attenuated by coexpression of HPH. Suppression of HPH in cultured Drosophila melanogaster cells by RNA interference resulted in elevated expression of a hypoxia-inducible gene (LDH, encoding lactate dehydrogenase) under normoxic conditions. These findings indicate that HPH is an essential component of the pathway through which cells sense oxygen.

Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard L3.124, Dallas, TX 75390-9152, USA.
*   To whom correspondence should be addressed. E-mail: smckni{at}biochem.swmed.edu

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The Qo site of the mitochondrial complex III is required for the transduction of hypoxic signaling via reactive oxygen species production.
E. L. Bell, T. A. Klimova, J. Eisenbart, C. T. Moraes, M. P. Murphy, G.R. S. Budinger, and N. S. Chandel (2007)
J. Cell Biol. 177, 1029-1036
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Neuron-Specific Inactivation of the Hypoxia Inducible Factor 1{alpha} Increases Brain Injury in a Mouse Model of Transient Focal Cerebral Ischemia.
O. Baranova, L. F. Miranda, P. Pichiule, I. Dragatsis, R. S. Johnson, and J. C. Chavez (2007)
J. Neurosci. 27, 6320-6332
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In Cultured Astrocytes, p53 and MDM2 Do Not Alter Hypoxia-inducible Factor-1{alpha} Function Regardless of the Presence of DNA Damage.
D. A. Rempe, K. M. Lelli, G. Vangeison, R. S. Johnson, and H. J. Federoff (2007)
J. Biol. Chem. 282, 16187-16201
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Quercetin Activates an Angiogenic Pathway, Hypoxia Inducible Factor (HIF)-1-Vascular Endothelial Growth Factor, by Inhibiting HIF-Prolyl Hydroxylase: a Structural Analysis of Quercetin for Inhibiting HIF-Prolyl Hydroxylase.
H. Jeon, H. Kim, D. Choi, D. Kim, S.-Y. Park, Y.-J. Kim, Y. M. Kim, and Y. Jung (2007)
Mol. Pharmacol. 71, 1676-1684
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Human Placental Hypoxia-Inducible Factor-1{alpha} Expression Correlates with Clinical Outcomes in Chronic Hypoxia in Vivo.
S. Zamudio, Y. Wu, F. Ietta, A. Rolfo, A. Cross, T. Wheeler, M. Post, N. P. Illsley, and I. Caniggia (2007)
Am. J. Pathol. 170, 2171-2179
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Constitutive/Hypoxic Degradation of HIF-{alpha} Proteins by the Proteasome Is Independent of von Hippel Lindau Protein Ubiquitylation and the Transactivation Activity of the Protein.
X. Kong, B. Alvarez-Castelao, Z. Lin, J. G. Castano, and J. Caro (2007)
J. Biol. Chem. 282, 15498-15505
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The Peptidyl Prolyl cis/trans Isomerase FKBP38 Determines Hypoxia-Inducible Transcription Factor Prolyl-4-Hydroxylase PHD2 Protein Stability.
S. Barth, J. Nesper, P. A. Hasgall, R. Wirthner, K. J. Nytko, F. Edlich, D. M. Katschinski, D. P. Stiehl, R. H. Wenger, and G. Camenisch (2007)
Mol. Cell. Biol. 27, 3758-3768
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Mammalian Tumor Suppressor Int6 Specifically Targets Hypoxia Inducible Factor 2{alpha} for Degradation by Hypoxia- and pVHL-independent Regulation.
L. Chen, K. Uchida, A. Endler, and F. Shibasaki (2007)
J. Biol. Chem. 282, 12707-12716
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EGLN3 Prolyl Hydroxylase Regulates Skeletal Muscle Differentiation and Myogenin Protein Stability.
J. Fu, K. Menzies, R. S. Freeman, and M. B. Taubman (2007)
J. Biol. Chem. 282, 12410-12418
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Hypoxia-inducible Factor 2{alpha} Regulates Expression of the Mitochondrial Aconitase Chaperone Protein Frataxin.
Y. Oktay, E. Dioum, S. Matsuzaki, K. Ding, L.-J. Yan, R. G. Haller, L. I. Szweda, and J. A. Garcia (2007)
J. Biol. Chem. 282, 11750-11756
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Hypoxia-inducible factor 1{alpha} stabilization by carbon monoxide results in cytoprotective preconditioning.
B. Y. Chin, G. Jiang, B. Wegiel, H. J. Wang, T. MacDonald, X. C. Zhang, D. Gallo, E. Cszimadia, F. H. Bach, P. J. Lee, et al. (2007)
PNAS 104, 5109-5114
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The Hypoxia-Inducible Factor 2{alpha} N-Terminal and C-Terminal Transactivation Domains Cooperate To Promote Renal Tumorigenesis In Vivo.
Q. Yan, S. Bartz, M. Mao, L. Li, and W. G. Kaelin Jr. (2007)
Mol. Cell. Biol. 27, 2092-2102
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Molecular regulation of the PAI-1 gene by hypoxia: contributions of Egr-1, HIF-1{alpha}, and C/EBP{alpha}.
H. Liao, M. C. Hyman, D. A. Lawrence, and D. J. Pinsky (2007)
FASEB J 21, 935-949
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ATP6V0C Competes with Von Hippel-Lindau Protein in Hypoxia-Inducible Factor 1{alpha} (HIF-1{alpha}) Binding and Mediates HIF-1{alpha} Expression by Bafilomycin A1.
J.-H. Lim, J.-W. Park, S. J. Kim, M.-S. Kim, S.-K. Park, R. S. Johnson, and Y.-S. Chun (2007)
Mol. Pharmacol. 71, 942-948
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Inhibition of Hypoxia-inducible Factor (HIF) Hydroxylases by Citric Acid Cycle Intermediates: POSSIBLE LINKS BETWEEN CELL METABOLISM AND STABILIZATION OF HIF.
P. Koivunen, M. Hirsila, A. M. Remes, I. E. Hassinen, K. I. Kivirikko, and J. Myllyharju (2007)
J. Biol. Chem. 282, 4524-4532
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Suppression of the Hypoxia-Inducible Factor-1 Response in Cervical Carcinoma Xenografts by Proteasome Inhibitors.
D. C. Birle and D. W. Hedley (2007)
Cancer Res. 67, 1735-1743
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Structural and Mechanistic Studies on the Inhibition of the Hypoxia-inducible Transcription Factor Hydroxylases by Tricarboxylic Acid Cycle Intermediates.
K. S. Hewitson, B. M. R. Lienard, M. A. McDonough, I. J. Clifton, D. Butler, A. S. Soares, N. J. Oldham, L. A. McNeill, and C. J. Schofield (2007)
J. Biol. Chem. 282, 3293-3301
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Multiple Factors Affecting Cellular Redox Status and Energy Metabolism Modulate Hypoxia-Inducible Factor Prolyl Hydroxylase Activity In Vivo and In Vitro.
Y. Pan, K. D. Mansfield, C. C. Bertozzi, V. Rudenko, D. A. Chan, A. J. Giaccia, and M. C. Simon (2007)
Mol. Cell. Biol. 27, 912-925
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The prolyl hydroxylase oxygen-sensing pathway is cytoprotective and allows maintenance of mitochondrial membrane potential during metabolic inhibition.
V. Sridharan, J. Guichard, R. M. Bailey, H. Kasiganesan, C. Beeson, and G. L. Wright (2007)
Am J Physiol Cell Physiol 292, C719-C728
   Abstract »    Full Text »    PDF »


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