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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
Journal article   Open access   Peer reviewed

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 Caro
The Journal of biological chemistry, v 277(8), pp 6183-6187
22 Feb 2002
DOI: https://doi.org/10.1074/jbc.M110978200
PMID: 11744734
Featured in Collection :   UN Sustainable Development Goals @ Drexel
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https://doi.org/10.1074/jbc.M110978200View
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Abstract

Deferoxamine - pharmacology Gene Expression Regulation, Enzymologic - drug effects Hypoxia-Inducible Factor 1 Humans Nuclear Proteins - metabolism Gene Expression Regulation, Enzymologic - physiology Liver Neoplasms Hypoxia-Inducible Factor 1, alpha Subunit Cell Hypoxia DNA-Binding Proteins - metabolism Transcription Factors - metabolism Cobalt - pharmacology Transcription, Genetic Carcinoma, Hepatocellular Gene Expression Regulation, Neoplastic - drug effects Tumor Cells, Cultured Gene Expression Regulation, Neoplastic - physiology
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-1 alpha. 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-1 alpha.

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Web of Science research areas
Biochemistry & Molecular Biology
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