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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}adelaide.edu.au

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   Abstract »    Full Text »    PDF »
Up-Regulation of c-met Protooncogene Product Expression through Hypoxia-Inducible Factor-1{alpha} Is Involved in Trophoblast Invasion under Low-Oxygen Tension.
M. Hayashi, M. Sakata, T. Takeda, M. Tahara, T. Yamamoto, Y. Okamoto, R. Minekawa, A. Isobe, M. Ohmichi, K. Tasaka, et al. (2005)
Endocrinology 146, 4682-4689
   Abstract »    Full Text »    PDF »
The Androgen Receptor Is Significantly Associated with Vascular Endothelial Growth Factor and Hypoxia Sensing via Hypoxia-Inducible Factors HIF-1a, HIF-2a, and the Prolyl Hydroxylases in Human Prostate Cancer.
J. L. Boddy, S. B. Fox, C. Han, L. Campo, H. Turley, S. Kanga, P. R. Malone, and A. L. Harris (2005)
Clin. Cancer Res. 11, 7658-7663
   Abstract »    Full Text »    PDF »
Functions of the Per/ARNT/Sim Domains of the Hypoxia-inducible Factor.
J. Yang, L. Zhang, P. J. A. Erbel, K. H. Gardner, K. Ding, J. A. Garcia, and R. K. Bruick (2005)
J. Biol. Chem. 280, 36047-36054
   Abstract »    Full Text »    PDF »
Integration of Oxygen Signaling at the Consensus HRE.
R. H. Wenger, D. P. Stiehl, and G. Camenisch (2005)
Sci. STKE 2005, re12
   Abstract »    Full Text »    PDF »
Inhibition of mitochondrial respiration elevates oxygen concentration but leaves regulation of hypoxia-inducible factor (HIF) intact.
K. Doege, S. Heine, I. Jensen, W. Jelkmann, and E. Metzen (2005)
Blood 106, 2311-2317
   Abstract »    Full Text »    PDF »
Coordinate Regulation of the Oxygen-Dependent Degradation Domains of Hypoxia-Inducible Factor 1{alpha}.
D. A. Chan, P. D. Sutphin, S.-E. Yen, and A. J. Giaccia (2005)
Mol. Cell. Biol. 25, 6415-6426
   Abstract »    Full Text »    PDF »
Activation of hypoxia-inducible factors in hyperoxia through prolyl 4-hydroxylase blockade in cells and explants of primate lung.
T. M. Asikainen, B. K. Schneider, N. S. Waleh, R. I. Clyman, W.-B. Ho, L. A. Flippin, V. Gunzler, and C. W. White (2005)
PNAS 102, 10212-10217
   Abstract »    Full Text »    PDF »
Hypoxia inducible factor (HIF) in rheumatology: low O2! See what HIF can do!.
T Gaber, R Dziurla, R Tripmacher, G R Burmester, and F Buttgereit (2005)
Ann Rheum Dis 64, 971-980
   Abstract »    Full Text »    PDF »
Activation of HIF-prolyl Hydroxylases by R59949, an Inhibitor of the Diacylglycerol Kinase.
E. Temes, S. Martin-Puig, B. Acosta-Iborra, M. C. Castellanos, M. Feijoo-Cuaresma, G. Olmos, J. Aragones, and M. O. Landazuri (2005)
J. Biol. Chem. 280, 24238-24244
   Abstract »    Full Text »    PDF »
Oxygen Sensing: Getting Pumped by Sterols.
B. M. Emerling and N. S. Chandel (2005)
Sci. STKE 2005, pe30
   Abstract »    Full Text »    PDF »
Mitochondrial Reactive Oxygen Species Activation of p38 Mitogen-Activated Protein Kinase Is Required for Hypoxia Signaling.
B. M. Emerling, L. C. Platanias, E. Black, A. R. Nebreda, R. J. Davis, and N. S. Chandel (2005)
Mol. Cell. Biol. 25, 4853-4862
   Abstract »    Full Text »    PDF »
Antitumor Activity of Rapamycin in a Transgenic Mouse Model of ErbB2-Dependent Human Breast Cancer.
M. Liu, A. Howes, J. Lesperance, W. B. Stallcup, C. A. Hauser, K. Kadoya, R. G. Oshima, and R. T. Abraham (2005)
Cancer Res. 65, 5325-5336
   Abstract »    Full Text »    PDF »
BMK1/ERK5 Is a Novel Regulator of Angiogenesis by Destabilizing Hypoxia Inducible Factor 1{alpha}.
X. Pi, G. Garin, L. Xie, Q. Zheng, H. Wei, J.-i. Abe, C. Yan, and B. C. Berk (2005)
Circ. Res. 96, 1145-1151
   Abstract »    Full Text »    PDF »
The Proinflammatory Cytokine Interleukin 1{beta} and Hypoxia Cooperatively Induce the Expression of Adrenomedullin in Ovarian Carcinoma Cells through Hypoxia Inducible Factor 1 Activation.
S. Frede, P. Freitag, T. Otto, C. Heilmaier, and J. Fandrey (2005)
Cancer Res. 65, 4690-4697
   Abstract »    Full Text »    PDF »
The candidate tumor suppressor ING4 represses activation of the hypoxia inducible factor (HIF).
A. Ozer, L. C. Wu, and R. K. Bruick (2005)
PNAS 102, 7481-7486
   Abstract »    Full Text »    PDF »
Analysis of ARD1 Function in Hypoxia Response Using Retroviral RNA Interference.
T. S. Fisher, S. D. Etages, L. Hayes, K. Crimin, and B. Li (2005)
J. Biol. Chem. 280, 17749-17757
   Abstract »    Full Text »    PDF »
Oxidation by 2-oxoglutarate oxygenases: non-haem iron systems in catalysis and signalling.
K.S Hewitson, N Granatino, R.W.D Welford, M.A McDonough, and C.J Schofield (2005)
Phil Trans R Soc A 363, 807-828
   Abstract »    Full Text »    PDF »

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