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A more recent version of this article appeared on February 15, 2002
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Papers In Press, published online ahead of print December 14, 2001
J. Biol. Chem, 10.1074/jbc.M110978200
Submitted on November 15, 2001
Revised on December 12, 2001
Accepted on December 13, 2001

Hypoxia-inducible factor-1 (HIF-1) mediated expression of the 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKBF3) gene: its possible role in the Warburg effect

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

medicine, thomas jefferson univ, philadelphia, PA 19107

Corresponding Author: jaime.caro{at}mail.tju.edu

One of the key mediators of the hypoxic response in animal cells is the HIF-1 transcription factor complex, whose alpha subunit is highly susceptible to oxygen-dependent degradation. During hypoxia, cells shift to a primarily glycolytic metabolic mode for their energetic needs. 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 (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 PFK1. Steady state levels of F-2,6-P2 are maintained by the bifunctional enzyme PFK-2/F2,6-BPase that has both kinase and phosphatase activities. Herein, we show that one isozyme, PFKBF3, 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 VHL-dependent destabilization and tagging of HIF-1a. The absolute dependence of the PFKBF3 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-1a.


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