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Science 294 (5545): 1337-1340

Copyright © 2001 by the American Association for the Advancement of Science

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}

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J. Immunol. 184, 4062-4068
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Genome-wide identification of hypoxia-inducible factor binding sites and target genes by a probabilistic model integrating transcription-profiling data and in silico binding site prediction.
A. Ortiz-Barahona, D. Villar, N. Pescador, J. Amigo, and L. del Peso (2010)
Nucleic Acids Res. 38, 2332-2345
   Abstract »    Full Text »    PDF »
Nickel Ions Inhibit Histone Demethylase JMJD1A and DNA Repair Enzyme ABH2 by Replacing the Ferrous Iron in the Catalytic Centers.
H. Chen, N. C. Giri, R. Zhang, K. Yamane, Y. Zhang, M. Maroney, and M. Costa (2010)
J. Biol. Chem. 285, 7374-7383
   Abstract »    Full Text »    PDF »
Complex Regulation of the Transactivation Function of Hypoxia-inducible Factor-1{alpha} by Direct Interaction with Two Distinct Domains of the CREB-binding Protein/p300.
J. L. Ruas, U. Berchner-Pfannschmidt, S. Malik, K. Gradin, J. Fandrey, R. G. Roeder, T. Pereira, and L. Poellinger (2010)
J. Biol. Chem. 285, 2601-2609
   Abstract »    Full Text »    PDF »
Prolyl Hydroxylases 2 and 3 Act in Gliomas as Protective Negative Feedback Regulators of Hypoxia-Inducible Factors.
A.-T. Henze, J. Riedel, T. Diem, J. Wenner, I. Flamme, J. Pouyseggur, K. H. Plate, and T. Acker (2010)
Cancer Res. 70, 357-366
   Abstract »    Full Text »    PDF »
Structure Activity Analysis of 2-Methoxyestradiol Analogues Reveals Targeting of Microtubules as the Major Mechanism of Antiproliferative and Proapoptotic Activity.
Y. S. Chua, Y. L. Chua, and T. Hagen (2010)
Mol. Cancer Ther. 9, 224-235
   Abstract »    Full Text »    PDF »
Inhibition of Prolyl Hydroxylase Domain-Containing Protein Suppressed Lipopolysaccharide-Induced TNF-{alpha} Expression.
K. Takeda, T. Ichiki, E. Narabayashi, K. Inanaga, R. Miyazaki, T. Hashimoto, H. Matsuura, J. Ikeda, T. Miyata, and K. Sunagawa (2009)
Arterioscler Thromb Vasc Biol 29, 2132-2137
   Abstract »    Full Text »    PDF »
Hypoxia-induced pathological angiogenesis mediates tumor cell dissemination, invasion, and metastasis in a zebrafish tumor model.
S. L. C. Lee, P. Rouhi, L. D. Jensen, D. Zhang, H. Ji, G. Hauptmann, P. Ingham, and Y. Cao (2009)
PNAS 106, 19485-19490
   Abstract »    Full Text »    PDF »
A Feedback Loop Involving the Phd3 Prolyl Hydroxylase Tunes the Mammalian Hypoxic Response In Vivo.
Y. A. Minamishima, J. Moslehi, R. F. Padera, R. T. Bronson, R. Liao, and W. G. Kaelin Jr. (2009)
Mol. Cell. Biol. 29, 5729-5741
   Abstract »    Full Text »    PDF »

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