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Genes & Dev. 15 (20): 2675-2686

Copyright © 2001 by Cold Spring Harbor Laboratory Press.

Vol. 15, No. 20, pp. 2675-2686, October 15, 2001

RESEARCH PAPER
FIH-1: a novel protein that interacts with HIF-1alpha and VHL to mediate repression of HIF-1 transcriptional activity

Patrick C. Mahon,1,3 Kiichi Hirota,1,2,3 and Gregg L. Semenza1,4

1 Institute of Genetic Medicine, Departments of Pediatrics and Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287-3914, USA; 2 Department of Anesthesia, Kyoto University Hospital, Kyoto University, Kyoto, 606-8507, Japan

Hypoxia-inducible factor 1 (HIF-1) is a master regulator of oxygen homeostasis that controls angiogenesis, erythropoiesis, and glycolysis via transcriptional activation of target genes under hypoxic conditions. O2-dependent binding of the von Hippel-Lindau (VHL) tumor suppressor protein targets the HIF-1alpha subunit for ubiquitination and proteasomal degradation. The activity of the HIF-1alpha transactivation domains is also O2 regulated by a previously undefined mechanism. Here, we report the identification of factor inhibiting HIF-1 (FIH-1), a protein that binds to HIF-1alpha and inhibits its transactivation function. In addition, we demonstrate that FIH-1 binds to VHL and that VHL also functions as a transcriptional corepressor that inhibits HIF-1alpha transactivation function by recruiting histone deacetylases. Involvement of VHL in association with FIH-1 provides a unifying mechanism for the modulation of HIF-1alpha protein stabilization and transcriptional activation in response to changes in cellular O2 concentration.

[Key Words: Corepressor; histone deacetylase; hypoxia; transactivation]

3 These authors contributed equally to this work.

4 Corresponding author.

GENES & DEVELOPMENT 15:2675-2686 © 2001 by Cold Spring Harbor Laboratory Press  ISSN 0890-9369/01 $5.00

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   Abstract »    Full Text »    PDF »
Spermidine/Spermine-N1-Acetyltransferase 2 Is an Essential Component of the Ubiquitin Ligase Complex That Regulates Hypoxia-inducible Factor 1{alpha}.
J. H. Baek, Y. V. Liu, K. R. McDonald, J. B. Wesley, M. E. Hubbi, H. Byun, and G. L. Semenza (2007)
J. Biol. Chem. 282, 23572-23580
   Abstract »    Full Text »    PDF »
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
   Abstract »    Full Text »    PDF »
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
   Abstract »    Full Text »    PDF »
Glycogen Synthase Kinase 3 Phosphorylates Hypoxia-Inducible Factor 1{alpha} and Mediates Its Destabilization in a VHL-Independent Manner.
D. Flugel, A. Gorlach, C. Michiels, and T. Kietzmann (2007)
Mol. Cell. Biol. 27, 3253-3265
   Abstract »    Full Text »    PDF »
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
   Abstract »    Full Text »    PDF »
Histone Deacetylase Inhibitors Synergize p300 Autoacetylation that Regulates Its Transactivation Activity and Complex Formation.
D. P. Stiehl, D. M. Fath, D. Liang, Y. Jiang, and N. Sang (2007)
Cancer Res. 67, 2256-2264
   Abstract »    Full Text »    PDF »
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
   Abstract »    Full Text »    PDF »
Nitric Oxide Modulates Oxygen Sensing by Hypoxia-inducible Factor 1-dependent Induction of Prolyl Hydroxylase 2.
U. Berchner-Pfannschmidt, H. Yamac, B. Trinidad, and J. Fandrey (2007)
J. Biol. Chem. 282, 1788-1796
   Abstract »    Full Text »    PDF »
Role of hypoxia-inducible factor-1{alpha} as a cancer therapy target.
S. Patiar and A. L Harris (2006)
Endocr. Relat. Cancer 13, S61-S75
   Abstract »    Full Text »    PDF »
Clioquinol, a Cu(II)/Zn(II) Chelator, Inhibits Both Ubiquitination and Asparagine Hydroxylation of Hypoxia-inducible Factor-1{alpha}, Leading to Expression of Vascular Endothelial Growth Factor and Erythropoietin in Normoxic Cells.
S. M. Choi, K.-O. Choi, Y.-K. Park, H. Cho, E. G. Yang, and H. Park (2006)
J. Biol. Chem. 281, 34056-34063
   Abstract »    Full Text »    PDF »
Hypoxia-Inducible Factor-1 (HIF-1).
Q. Ke and M. Costa (2006)
Mol. Pharmacol. 70, 1469-1480
   Abstract »    Full Text »    PDF »
Posttranslational hydroxylation of ankyrin repeats in I{kappa}B proteins by the hypoxia-inducible factor (HIF) asparaginyl hydroxylase, factor inhibiting HIF (FIH).
M. E. Cockman, D. E. Lancaster, I. P. Stolze, K. S. Hewitson, M. A. McDonough, M. L. Coleman, C. H. Coles, X. Yu, R. T. Hay, S. C. Ley, et al. (2006)
PNAS 103, 14767-14772
   Abstract »    Full Text »    PDF »

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