Outcompeting p53-Mutant Cells in the Normal Esophagus by Redox Manipulation.
Cell stem cell
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Fernandez-Antoran, D., Piedrafita, G., Murai, K., Ong, S. H., Herms, A., Frezza, C., & Jones, P. (2019). Outcompeting p53-Mutant Cells in the Normal Esophagus by Redox Manipulation.. Cell stem cell, 25 (3), 329-341.e6. https://doi.org/10.1016/j.stem.2019.06.011
As humans age, normal tissues, such as the esophageal epithelium, become a patchwork of mutant clones. Some mutations are under positive selection, conferring a competitive advantage over wild-type cells. We speculated that altering the selective pressure on mutant cell populations may cause them to expand or contract. We tested this hypothesis by examining the effect of oxidative stress from low-dose ionizing radiation (LDIR) on wild-type and p53 mutant cells in the transgenic mouse esophagus. We found that LDIR drives wild-type cells to stop proliferating and differentiate. p53 mutant cells are insensitive to LDIR and outcompete wild-type cells following exposure. Remarkably, combining antioxidant treatment and LDIR reverses this effect, promoting wild-type cell proliferation and p53 mutant differentiation, reducing the p53 mutant population. Thus, p53- mutant cells can be depleted from the normal esophagus by redox manipulation, showing that external interventions may be used to alter the mutational landscape of an aging tissue.
Esophagus, Cells, Cultured, Epithelial Cells, Animals, Mice, Transgenic, Humans, Mice, Receptors, Estrogen, Antioxidants, Cell Differentiation, Cell Proliferation, Oxidation-Reduction, Oxidative Stress, Aging, Mutation, Radiation, Ionizing, Tumor Suppressor Protein p53, NF-E2-Related Factor 2
EC FP7 CP (323267)
Cancer Research UK (C609/A17257)
Medical Research Council (MC_UU_12022/3)
Medical Research Council (MC_UU_12022/6)
External DOI: https://doi.org/10.1016/j.stem.2019.06.011
This record's URL: https://www.repository.cam.ac.uk/handle/1810/294829
Attribution 4.0 International
Licence URL: https://creativecommons.org/licenses/by/4.0/