Transcriptional regulation of genes encoding glycolytic enzymes by hypoxia-inducible factor 1.
Hypoxia-inducible factor 1 (HIF-1) activates erythropoietin gene transcription in Hep3B cells subjected to hypoxia. HIF-1 activity is also induced by hypoxia in non-erythropoietin-producing cells, suggesting a more general regulatory role. We now report that RNAs encoding the glycolytic enzymes aldolase A (ALDA), phosphoglycerate kinase 1 (PGK1), and pyruvate kinase M were induced by exposure of Hep3B or HeLa cells to inducers of HIF-1 (1% O2, cobalt chloride, or desferrioxamine), whereas cycloheximide blocked induction of glycolytic RNAs and HIF-1 activity. Oligonucleotides from the ALDA, PGK1, enolase 1, lactate dehydrogenase A, and phosphofructokinase L (PFKL) genes, containing sequences similar to the HIF-1 binding site in the erythropoietin enhancer, specifically bound HIF-1 present in crude nuclear extracts or affinity-purified preparations. Sequences from the ALDA, PFKL, and PGK1 genes containing HIF-1 binding sites mediated hypoxia-inducible transcription in transient expression assays. These results support the role of HIF-1 as a mediator of adaptive responses to hypoxia that underlie cellular and systemic oxygen homeostasis.
Semenza
G L
GL
Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287-3914.
Roth
P H
PH
Fang
H M
HM
Wang
G L
GL
D001483:Base Sequence; D016384:Consensus Sequence; D017931:DNA Primers / Q000737:chemistry; D004268:DNA-Binding Proteins / Q000502:physiology*; D005634:Fructose-Bisphosphate Aldolase / Q000235:genetics; D006019:Glycolysis; D006367:HeLa Cells; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000502:physiology*; D010733:Phosphoglucomutase / Q000235:genetics; D010735:Phosphoglycerate Kinase / Q000235:genetics; D011401:Promoter Regions, Genetic; D014157:Transcription Factors / Q000502:physiology*; D014158:Transcription, Genetic
D017931:DNA Primers; D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; D014157:Transcription Factors; D010735:Phosphoglycerate Kinase; D005634:Fructose-Bisphosphate Aldolase; D010733:Phosphoglucomutase