The transcription factor HIF-1α plays a critical role in the growth factor-dependent regulation of both aerobic and anaerobic glycolysis
- Julian J. Lum1,2,
- Thi Bui1,2,
- Michaela Gruber1,
- John D. Gordan1,
- Ralph J. DeBerardinis1,2,3,
- Kelly L. Covello1,
- M. Celeste Simon1,4, and
- Craig B. Thompson1,2,5
- 1 Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA;
- 2 Department of Cancer Biology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA;
- 3 Division of Child Development, Rehabilitation Medicine and Metabolic Disease, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA;
- 4 Howard Hughes Medical Institute, Philadelphia, Pennsylvania 19104, USA
Abstract
Mammalian cells are believed to have a cell-intrinsic ability to increase glucose metabolism in response to hypoxia. Here we show that the ability of hematopoietic cells to up-regulate anaerobic glycolysis in response to hypoxia is dependent on receptor-mediated signal transduction. In the absence of growth factor signaling, hematopoietic cells fail to express hypoxia-inducible transcription factor (Hif-1α) mRNA. Growth factor-deprived hematopoietic cells do not engage in glucose-dependent anabolic synthesis and neither express Hif-1α mRNA nor require HIF-1α protein to regulate cell survival in response to hypoxia. However, HIF-1α is adaptive for the survival of growth factor-stimulated cells, as suppression of HIF-1α results in death when growing cells are exposed to hypoxia. Growth factor-dependent HIF-1α expression reprograms the intracellular fate of glucose, resulting in decreased glucose-dependent anabolic synthesis and increased lactate production, an effect that is enhanced when HIF-1α protein is stabilized by hypoxia. Together, these data suggest that HIF-1α contributes to the regulation of growth factor-stimulated glucose metabolism even in the absence of hypoxia.
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Footnotes
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↵5 Corresponding author.
↵5 E-MAIL craig{at}mail.med.upenn.edu; FAX (215) 746-5511.
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Supplemental material is available at http://www.genesdev.org.
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Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.1529107
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- Received January 8, 2007.
- Accepted March 8, 2007.
- Copyright © 2007, Cold Spring Harbor Laboratory Press