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Epidermal Tissue Adapts to Restrain Progenitors Carrying Clonal p53 Mutations.

Published version
Peer-reviewed

Type

Article

Change log

Authors

Murai, Kasumi 
Skrupskelyte, Greta 
Piedrafita, Gabriel 
Hall, Michael 
Kostiou, Vasiliki 

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.

Description

Keywords

Cdh1, Trp53, carcinogenesis, cell adhesion, cell competition, desmosome, differentiation, stem cell, transgenic mice, ultraviolet light, Animals, Cells, Cultured, Clone Cells, Epidermal Cells, Epidermis, Female, Male, Mice, Mice, Inbred C57BL, Mutation, Stem Cells, Tumor Suppressor Protein p53, Ultraviolet Rays

Journal Title

Cell Stem Cell

Conference Name

Journal ISSN

1934-5909
1875-9777

Volume Title

23

Publisher

Elsevier BV
Sponsorship
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
Medical Research Council (MC_UU_12022/5)
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).