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J. Biol. Chem., Vol. 280, Issue 51, 41928-41939, December 23, 2005
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Reversible Inactivation of HIF-1 Prolyl Hydroxylases Allows Cell Metabolism to Control Basal HIF-1*
From the Department of Neurology, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814
Continuous hydroxylation of the HIF-1 transcription factor 
subunit by oxygen and 2-oxoglutarate-dependent dioxygenases promotes decay of this protein and thus prevents the transcriptional activation of many genes involved in energy metabolism, angiogenesis, cell survival, and matrix modification. Hypoxia blocks HIF-1 hydroxylation and thus activates HIF-1-mediated gene expression. Several nonhypoxic stimuli can also activate HIF-1, although the mechanisms involved are not well known. Here we show that the glucose metabolites pyruvate and oxaloacetate inactivate HIF-1 decay in a manner selectively reversible by ascorbate, cysteine, histidine, and ferrous iron but not by 2-oxoglutarate or oxygen. Pyruvate and oxaloacetate bind to the 2-oxoglutarate site of HIF-1 prolyl hydroxylases, but their effects on HIF-1 are not mimicked by other Krebs cycle intermediates, including succinate and fumarate. We show that inactivation of HIF-1 hydroxylation by glucose-derived 2-oxoacids underlies the prominent basal HIF-1 activity commonly seen in many highly glycolytic cancer cells. Since HIF-1 itself promotes glycolytic metabolism, enhancement of HIF-1 by glucose metabolites may constitute a novel feed-forward signaling mechanism involved in malignant progression.
Received for publication, August 8, 2005 , and in revised form, October 13, 2005.
* This work was supported by National Institutes of Health Grant NS37814 and Department of Defense Grants MDA-905-02-2-0005 and MDA-905-03-2-0001 (to A. V.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. 1.
1 These authors contributed equally to this work.
2 Recipient of a fellowship from the Henry Jackson Foundation.
3 To whom correspondence should be addressed: Dept. of Neurology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Rd., Bethesda, MD 20814. Tel.: 301-295-3840; Fax: 301-295-3825; E-mail: averma{at}usuhs.mil.
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