Reactive oxygen species-mediated regulation of the Na+-H+ exchanger 1 gene expression connects intracellular redox status with cells' sensitivity to death triggers.
We have previously demonstrated that a slight increase in intracellular superoxide (O2*-) anion confers resistance to death stimuli. Using pharmacological and molecular approaches to manipulate intracellular O2*-, here we report that an increase in intracellular O2*- anion induces Na+/H+ exchanger 1 (NHE-1) gene promoter activity resulting in increased NHE-1 protein expression, which strongly correlates with the resistance of cells to death stimuli. In contrast, exposure to exogenous hydrogen peroxide suppressed NHE-1 promoter activity and gene expression, and increased cell sensitivity to death triggers. Furthermore, the increase in cell sensitivity to death upon downregulation of NHE-1 gene expression correlates with reduced capacity of cells to recover from an acid load, while survival upon overexpression of NHE-1 appears independent of its pump activity. These findings indicate that NHE-1 is a redox-regulated gene, and provide a novel intracellular target for the redox control of cell death sensitivity.
Akram
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Department of Biochemistry, The Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
Teong
H F C
HF
Fliegel
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Pervaiz
S
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Clément
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MV
D000818:Animals; D017209:Apoptosis; D027682:Cation Transport Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004050:Ditiocarb / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D041681:NIH 3T3 Cells; D010084:Oxidation-Reduction; D011401:Promoter Regions, Genetic / Q000187:drug effects; D034622:RNA Interference; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000037:antagonists & inhibitors; D013481:Superoxides / Q000378:metabolism*; D014162:Transfection; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
D027682:Cation Transport Proteins; D004791:Enzyme Inhibitors; D008565:Membrane Proteins; C490997:Slc9a1 protein, mouse; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers; D013481:Superoxides; D004050:Ditiocarb; D006861:Hydrogen Peroxide; D013482:Superoxide Dismutase; D020830:rac1 GTP-Binding Protein