Abstract
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.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis*
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Cation Transport Proteins / biosynthesis
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Cation Transport Proteins / genetics
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Cation Transport Proteins / metabolism*
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Cell Line, Tumor
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Ditiocarb / pharmacology
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Dose-Response Relationship, Drug
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Enzyme Inhibitors / pharmacology
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Gene Expression Regulation / drug effects
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Humans
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Hydrogen Peroxide / pharmacology
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Hydrogen-Ion Concentration
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Membrane Proteins / biosynthesis
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Membrane Proteins / genetics
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Membrane Proteins / metabolism*
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Mice
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NIH 3T3 Cells
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Oxidation-Reduction
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Promoter Regions, Genetic* / drug effects
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RNA Interference
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Sodium-Hydrogen Exchanger 1
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Sodium-Hydrogen Exchangers / biosynthesis
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Sodium-Hydrogen Exchangers / genetics
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Sodium-Hydrogen Exchangers / metabolism*
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Superoxide Dismutase / antagonists & inhibitors
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Superoxides / metabolism*
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Transfection
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rac1 GTP-Binding Protein / genetics
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rac1 GTP-Binding Protein / metabolism
Substances
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Cation Transport Proteins
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Enzyme Inhibitors
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Membrane Proteins
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Slc9a1 protein, mouse
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Sodium-Hydrogen Exchanger 1
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Sodium-Hydrogen Exchangers
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Superoxides
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Ditiocarb
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Hydrogen Peroxide
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Superoxide Dismutase
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rac1 GTP-Binding Protein