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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 |
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author | 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. |
author_facet | 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. |
author_sort | Murai, Kasumi |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-6224607 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Cell Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-62246072018-11-13 Epidermal Tissue Adapts to Restrain Progenitors Carrying Clonal p53 Mutations 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. Cell Stem Cell Article 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. Cell Press 2018-11-01 /pmc/articles/PMC6224607/ /pubmed/30269904 http://dx.doi.org/10.1016/j.stem.2018.08.017 Text en © 2018 The Author(s) http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article 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. Epidermal Tissue Adapts to Restrain Progenitors Carrying Clonal p53 Mutations |
title | Epidermal Tissue Adapts to Restrain Progenitors Carrying Clonal p53 Mutations |
title_full | Epidermal Tissue Adapts to Restrain Progenitors Carrying Clonal p53 Mutations |
title_fullStr | Epidermal Tissue Adapts to Restrain Progenitors Carrying Clonal p53 Mutations |
title_full_unstemmed | Epidermal Tissue Adapts to Restrain Progenitors Carrying Clonal p53 Mutations |
title_short | Epidermal Tissue Adapts to Restrain Progenitors Carrying Clonal p53 Mutations |
title_sort | epidermal tissue adapts to restrain progenitors carrying clonal p53 mutations |
topic | Article |
url | 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 |
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