The transcription factor HIF-1alpha plays a critical role in the growth factor-dependent regulation of both aerobic and anaerobic glycolysis.
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-1alpha) mRNA. Growth factor-deprived hematopoietic cells do not engage in glucose-dependent anabolic synthesis and neither express Hif-1alpha mRNA nor require HIF-1alpha protein to regulate cell survival in response to hypoxia. However, HIF-1alpha is adaptive for the survival of growth factor-stimulated cells, as suppression of HIF-1alpha results in death when growing cells are exposed to hypoxia. Growth factor-dependent HIF-1alpha 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-1alpha protein is stabilized by hypoxia. Together, these data suggest that HIF-1alpha contributes to the regulation of growth factor-stimulated glucose metabolism even in the absence of hypoxia.
Lum
Julian J
JJ
Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Bui
Thi
T
Gruber
Michaela
M
Gordan
John D
JD
DeBerardinis
Ralph J
RJ
Covello
Kelly L
KL
Simon
M Celeste
MC
Thompson
Craig B
CB
D000332:Aerobiosis; D000693:Anaerobiosis; D000818:Animals; D001483:Base Sequence; D015687:Cell Hypoxia; D002460:Cell Line; D049109:Cell Proliferation; D002470:Cell Survival; D017353:Gene Deletion; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis / Q000235:genetics* / Q000502:physiology*; D006133:Growth Substances / Q000378:metabolism; D006413:Hematopoietic System / Q000166:cytology / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics* / Q000378:metabolism*; D007377:Interleukin-3 / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D008954:Models, Biological; D041681:NIH 3T3 Cells; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
D006133:Growth Substances; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007377:Interleukin-3; D012333:RNA, Messenger; D005947:Glucose