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Science 295 (5556): 858-861

Copyright © 2002 by the American Association for the Advancement of Science

Asparagine Hydroxylation of the HIF Transactivation Domain: A Hypoxic Switch

David Lando,1 Daniel J. Peet,1 Dean A. Whelan,2 Jeffrey J. Gorman,2 Murray L. Whitelaw1*

The hypoxia-inducible factors (HIFs) 1alpha and 2alpha are key mammalian transcription factors that exhibit dramatic increases in both protein stability and intrinsic transcriptional potency during low-oxygen stress. This increased stability is due to the absence of proline hydroxylation, which in normoxia promotes binding of HIF to the von Hippel-Lindau (VHL tumor suppressor) ubiquitin ligase. We now show that hypoxic induction of the COOH-terminal transactivation domain (CAD) of HIF occurs through abrogation of hydroxylation of a conserved asparagine in the CAD. Inhibitors of Fe(II)- and 2-oxoglutarate-dependent dioxygenases prevented hydroxylation of the Asn, thus allowing the CAD to interact with the p300 transcription coactivator. Replacement of the conserved Asn by Ala resulted in constitutive p300 interaction and strong transcriptional activity. Full induction of HIF-1alpha and -2alpha , therefore, relies on the abrogation of both Pro and Asn hydroxylation, which during normoxia occur at the degradation and COOH-terminal transactivation domains, respectively.

1 Department of Molecular Biosciences (Biochemistry), Adelaide University, SA 5005, Australia.
2 CSIRO Health Sciences and Nutrition, 343 Royal Parade, Parkville, VIC 3052, Australia.
*   To whom correspondence should be addressed. E-mail: murray.whitelaw{at}

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Mol. Cancer Res. 5, 383-391
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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
   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 »
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
   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 »
Mucin 1 Oncoprotein Blocks Hypoxia-inducible Factor 1{alpha} Activation in a Survival Response to Hypoxia.
L. Yin, S. Kharbanda, and D. Kufe (2007)
J. Biol. Chem. 282, 257-266
   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 »
Prolyl hydroxylase-1 negatively regulates I{kappa}B kinase-beta, giving insight into hypoxia-induced NF{kappa}B activity.
E. P. Cummins, E. Berra, K. M. Comerford, A. Ginouves, K. T. Fitzgerald, F. Seeballuck, C. Godson, J. E. Nielsen, P. Moynagh, J. Pouyssegur, et al. (2006)
PNAS 103, 18154-18159
   Abstract »    Full Text »    PDF »
Carbamylated erythropoietin ameliorates the metabolic stress induced in vivo by severe chronic hypoxia.
M. Fantacci, P. Bianciardi, A. Caretti, T. R. Coleman, A. Cerami, M. Brines, and M. Samaja (2006)
PNAS 103, 17531-17536
   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 »
Identification of MAPK Phosphorylation Sites and Their Role in the Localization and Activity of Hypoxia-inducible Factor-1{alpha}.
I. Mylonis, G. Chachami, M. Samiotaki, G. Panayotou, E. Paraskeva, A. Kalousi, E. Georgatsou, S. Bonanou, and G. Simos (2006)
J. Biol. Chem. 281, 33095-33106
   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 »
Enhancement of angiogenic effectors through hypoxia-inducible factor in preterm primate lung in vivo.
T. M. Asikainen, N. S. Waleh, B. K. Schneider, R. I. Clyman, and C. W. White (2006)
Am J Physiol Lung Cell Mol Physiol 291, L588-L595
   Abstract »    Full Text »    PDF »

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