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.
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Abbreviations
- NHE-1:
-
Na+/H+ exchanger 1
- O2•−:
-
superoxide
- H2O2:
-
hydrogen peroxide
- pHi:
-
Intracellular pH
- βgal:
-
βgalactosidase protein
- CAT:
-
chloramphenicol acetyl transferase gene
- DPI:
-
diphenyleneiodonium
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Acknowledgements
This work was supported by Grant R-183-000-084-213 from The National Medical Research Council of Singapore to MVC, R-185-000-072-305 from the Biomedical Research Council of Singapore to MVC and SP and the Canadian Institute of Health Research to LF.
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Akram, S., Teong, H., Fliegel, L. et al. Reactive oxygen species-mediated regulation of the Na+–H+ exchanger 1 gene expression connects intracellular redox status with cells' sensitivity to death triggers. Cell Death Differ 13, 628–641 (2006). https://doi.org/10.1038/sj.cdd.4401775
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DOI: https://doi.org/10.1038/sj.cdd.4401775
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