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Epidermal Tissue Adapts to Restrain Progenitors Carrying Clonal p53 Mutations
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 pr...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cell Press
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6224607/ https://www.ncbi.nlm.nih.gov/pubmed/30269904 http://dx.doi.org/10.1016/j.stem.2018.08.017 |
Sumario: | 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 (Trp53(R245W); 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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