Epidermal Tissue Adapts to Restrain Progenitors Carrying Clonal p53 Mutations.
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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.
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1875-9777
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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)
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Medical Research Council (MC_UU_12022/5)
MRC (MR/N501876/1)