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Originally published In Press as doi:10.1074/jbc.M110978200 on December 14, 2001

J. Biol. Chem., Vol. 277, Issue 8, 6183-6187, February 22, 2002
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Hypoxia-inducible Factor-1-mediated Expression of the 6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3) Gene
ITS POSSIBLE ROLE IN THE WARBURG EFFECT*

Alexander Minchenko, Irene Leshchinsky, Irina Opentanova, Nianli Sang, Vickram Srinivas, Valerie Armstead, and Jaime CaroDagger

From the Department of Anesthesiology/Physiology and the Cardeza Foundation for Hematologic Research, Department of Medicine, Jefferson Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania 19107

One of the key mediators of the hypoxic response in animal cells is the hypoxia-inducible transcription factor-1 (HIF-1) complex, in which the alpha -subunit is highly susceptible to oxygen-dependent degradation. The hypoxic response is manifested in many pathophysiological processes such as tumor growth and metastasis. During hypoxia, cells shift to a primarily glycolytic metabolic mode for their energetic needs. This is also manifested in the HIF-1-dependent up-regulation of many glycolytic genes. Paradoxically, tumor cells growing under conditions of normal oxygen tension also show elevated glycolytic rates that correlate with the increased expression of glycolytic enzymes and glucose transporters (the Warburg effect). A key regulator of glycolytic flux is the relatively recently discovered fructose-2,6-bisphosphate (F-2,6-P2), an allosteric activator of 6-phosphofructo-1-kinase (PFK-1). Steady state levels of F-2,6-P2 are maintained by the bifunctional enzyme PFK-2/F2,6-Bpase, which has both kinase and phosphatase activities. Herein, we show that one isozyme, PFKFB3, is highly induced by hypoxia and the hypoxia mimics cobalt and desferrioxamine. This induction could be replicated by the use of an inhibitor of the prolyl hydroxylase enzymes responsible for the von Hippel Lindau (VHL)-dependent destabilization and tagging of HIF-1alpha . The absolute dependence of the PFKFB3 gene on HIF-1 was confirmed by its overexpression in VHL-deficient cells and by the lack of hypoxic induction in mouse embryonic fibroblasts conditionally nullizygous for HIF-1alpha .

* Supported in part by National Institutes of Health Grants RO1 CA089212 (to J. C.), KO-8 GM00686 (to V. A.), AHA 0060194U (to V. S.), and 9950122N (to J. C.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger To whom correspondence should be addressed: Cardeza Foundation for Hematologic Research, 1015 Walnut St., Philadelphia, PA 19107-509. Tel.: 215-955-7775; Fax: 215-923-3836; E-mail: Jaime.Caro@mail.tju.edu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.


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