Endogenous 2-oxoacids differentially regulate expression of oxygen sensors.
Adaptations to change in oxygen availability are crucial for survival of multi-cellular organisms and are also implicated in several disease states. Such adaptations rely upon gene expression regulated by the heterodimeric transcription factors HIFs (hypoxia-inducible factors). Enzymes that link changes in oxygen tensions with the stability and transcriptional activity of HIFs are considered as oxygen sensors. These enzymes are oxygen-, iron- and 2-oxoglutarate-dependent dioxygenases that hydroxylate key proline and asparagine residues in HIFalpha subunits. The constitutive inhibitory action of these enzymes on HIFs is relieved by hypoxia and by agents that displace iron or 2-oxoglutarate. Two of the enzymes, HPH (HIF prolyl hydroxylase)-1 and HPH-2, are known to be inducible by hypoxia in a HIF-dependent manner. This suggests the existence of a novel feedback loop for adjusting hypoxia-regulated gene expression. We have recently shown that HIF-1alpha stability, HIF-1 nuclear translocation and HIF-mediated gene expression in human glioma cell lines can be stimulated by pyruvate independently of hypoxia. In the present study we show that the endogenous 2-oxoacid oxaloacetate can also activate HIF-mediated gene expression. Pyruvate and oxaloacetate treatment of cells also up-regulates HPH-1 and HPH-2, but not HPH-3 or the HIF asparaginyl hydroxylase FIH-1 (factor inhibiting HIF). Regulation of HIF-1 and the expression of HPH homologue genes can thus be influenced by specific glycolytic and tricarboxylic acid cycle metabolites. These findings may underlie important interactions between oxygen homoeostasis, glycolysis, the tricarboxylic acid cycle and gluconeogenesis.
Department of Neurology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, USA.
Clifton Lee
CL
Dalgard
Huasheng
H
Lu
Ahmed
A
Mohyeldin
Ajay
A
Verma
D045744:Cell Line, Tumor; D016543:Central Nervous System Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D002952:Citric Acid Cycle / Q000502:physiology; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology*; D005909:Glioblastoma / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D006019:Glycolysis / Q000502:physiology; D006801:Humans; D000860:Hypoxia / Q000201:enzymology / Q000378:metabolism; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007651:Keto Acids / Q000378:metabolism*; D006899:Mixed Function Oxygenases / Q000096:biosynthesis; D009687:Nuclear Proteins / Q000378:metabolism / Q000502:physiology; D062907:Oxaloacetic Acid / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism*; D019289:Pyruvic Acid / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007651:Keto Acids; D009687:Nuclear Proteins; D014157:Transcription Factors; D062907:Oxaloacetic Acid; D019289:Pyruvic Acid; D006899:Mixed Function Oxygenases; D010100:Oxygen