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 HIFα 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-1α 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.
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Research Article|
June 01 2004
Endogenous 2-oxoacids differentially regulate expression of oxygen sensors
Clifton Lee DALGARD;
Clifton Lee DALGARD
1
Department of Neurology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, U.S.A.
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Huasheng LU;
Huasheng LU
1
Department of Neurology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, U.S.A.
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Ahmed MOHYELDIN;
Ahmed MOHYELDIN
Department of Neurology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, U.S.A.
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Ajay VERMA
Ajay VERMA
2
Department of Neurology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, U.S.A.
2To whom correspondence should be addressed (e-mail averma@usuhs.mil).
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Publisher: Portland Press Ltd
Received:
October 28 2003
Revision Received:
February 20 2004
Accepted:
February 25 2004
Accepted Manuscript online:
February 25 2004
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London ©2004
2004
Biochem J (2004) 380 (2): 419–424.
Article history
Received:
October 28 2003
Revision Received:
February 20 2004
Accepted:
February 25 2004
Accepted Manuscript online:
February 25 2004
Citation
Clifton Lee DALGARD, Huasheng LU, Ahmed MOHYELDIN, Ajay VERMA; Endogenous 2-oxoacids differentially regulate expression of oxygen sensors. Biochem J 1 June 2004; 380 (2): 419–424. doi: https://doi.org/10.1042/bj20031647
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