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The transcription factor HIF-1 plays a critical role in the growth factor-dependent regulation of both aerobic and anaerobic glycolysis

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

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-1) mRNA. Growth factor-deprived hematopoietic cells do not engage in glucose-dependent anabolic synthesis and neither express Hif-1 mRNA nor require HIF-1 protein to regulate cell survival in response to hypoxia. However, HIF-1 is adaptive for the survival of growth factor-stimulated cells, as suppression of HIF-1 results in death when growing cells are exposed to hypoxia. Growth factor-dependent HIF-1 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-1 protein is stabilized by hypoxia. Together, these data suggest that HIF-1 contributes to the regulation of growth factor-stimulated glucose metabolism even in the absence of hypoxia.

[Keywords: HIF-1; hypoxia; growth factor signaling; glucose metabolism; cell survival]

Received January 8, 2007; revised version accepted March 8, 2007.

E-MAIL craig{at}mail.med.upenn.edu; FAX (215) 746-5511.

Supplemental material is available at http://www.genesdev.org.

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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