Epidermal Tissue Adapts to Restrain Progenitors Carrying Clonal p53 Mutations.
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Authors
Murai, Kasumi
Skrupskelyte, Greta
Piedrafita, Gabriel
Hall, Michael
Kostiou, Vasiliki
Ong, Swee Hoe
Nagy, Tibor
Cagan, Alex
Goulding, David
Klein, Allon M
Hall, Benjamin A
Jones, Philip H
Publication Date
2018-11-01Journal Title
Cell Stem Cell
ISSN
1934-5909
Publisher
Elsevier BV
Volume
23
Issue
5
Pages
687-699.e8
Language
eng
Type
Article
Physical Medium
Print-Electronic
Metadata
Show full item recordCitation
Murai, K., Skrupskelyte, G., Piedrafita, G., Hall, M., Kostiou, V., Ong, S. H., Nagy, T., et al. (2018). Epidermal Tissue Adapts to Restrain Progenitors Carrying Clonal p53 Mutations.. Cell Stem Cell, 23 (5), 687-699.e8. https://doi.org/10.1016/j.stem.2018.08.017
Abstract
Aging human tissues, such as sun-exposed epidermis, accumulate a high burden of progenitor cells that carry oncogenic mutations. However, most progenitors carrying such mutations colonize and persist in normal tissue without forming tumors. Here, we investigated tissue-level constraints on clonal progenitor behavior by inducing a single-allele p53 mutation (Trp53R245W; p53∗/wt), prevalent in normal human epidermis and squamous cell carcinoma, in transgenic mouse epidermis. p53∗/wt progenitors initially outcompeted wild-type cells due to enhanced proliferation, but subsequently reverted toward normal dynamics and homeostasis. Physiological doses of UV light accelerated short-term expansion of p53∗/wt clones, but their frequency decreased with protracted irradiation, possibly due to displacement by UV-induced mutant clones with higher competitive fitness. These results suggest multiple mechanisms restrain the proliferation of p53∗/wt progenitors, thereby maintaining epidermal integrity.
Keywords
Epidermis, Cells, Cultured, Clone Cells, Stem Cells, Animals, Mice, Inbred C57BL, Mice, Ultraviolet Rays, Mutation, Female, Male, Tumor Suppressor Protein p53, Epidermal Cells
Sponsorship
This work was supported by a Medical Research Council Grant-in-Aid to the MRC Cancer unit, and a core grant from the Wellcome Trust to the Wellcome Sanger Institute. PHJ acknowledges support from a Cancer Research UK Programme Grant 18 (C609/A17257). BH acknowledges support from the Royal Society (UF130039).
Funder references
MRC (unknown)
Cancer Research UK (C609/A17257)
Medical Research Council (MC_UU_12022/3)
Royal Society (Paul Instrument Fund) (UF130039)
Medical Research Council (MC_UU_12022/9)
MRC (MR/N501876/1)
MRC
Identifiers
External DOI: https://doi.org/10.1016/j.stem.2018.08.017
This record's URL: https://www.repository.cam.ac.uk/handle/1810/285437
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