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dc.contributor.authorMurai, Kasumi
dc.contributor.authorSkrupskelyte, Greta
dc.contributor.authorPiedrafita, Gabriel
dc.contributor.authorHall, Michael
dc.contributor.authorKostiou, Vasiliki
dc.contributor.authorOng, Swee Hoe
dc.contributor.authorNagy, Tibor
dc.contributor.authorCagan, Alex
dc.contributor.authorGoulding, David
dc.contributor.authorKlein, Allon M
dc.contributor.authorHall, Benjamin
dc.contributor.authorJones, Philip
dc.date.accessioned2018-11-20T00:30:23Z
dc.date.available2018-11-20T00:30:23Z
dc.date.issued2018-11-01
dc.identifier.issn1934-5909
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/285437
dc.description.abstractAging 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.
dc.description.sponsorshipThis 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).
dc.format.mediumPrint-Electronic
dc.languageeng
dc.publisherElsevier BV
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectEpidermis
dc.subjectCells, Cultured
dc.subjectClone Cells
dc.subjectStem Cells
dc.subjectAnimals
dc.subjectMice, Inbred C57BL
dc.subjectMice
dc.subjectUltraviolet Rays
dc.subjectMutation
dc.subjectFemale
dc.subjectMale
dc.subjectTumor Suppressor Protein p53
dc.subjectEpidermal Cells
dc.titleEpidermal Tissue Adapts to Restrain Progenitors Carrying Clonal p53 Mutations.
dc.typeArticle
prism.endingPage699.e8
prism.issueIdentifier5
prism.publicationDate2018
prism.publicationNameCell Stem Cell
prism.startingPage687
prism.volume23
dc.identifier.doi10.17863/CAM.32797
dcterms.dateAccepted2018-08-28
rioxxterms.versionofrecord10.1016/j.stem.2018.08.017
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2018-11
dc.contributor.orcidHall, Benjamin [0000-0003-0355-2946]
dc.contributor.orcidJones, Philip [0000-0002-5904-795X]
dc.identifier.eissn1875-9777
rioxxterms.typeJournal Article/Review
pubs.funder-project-idMRC (unknown)
pubs.funder-project-idCancer Research UK (C609/A17257)
pubs.funder-project-idMedical Research Council (MC_UU_12022/3)
pubs.funder-project-idRoyal Society (Paul Instrument Fund) (UF130039)
pubs.funder-project-idMedical Research Council (MC_UU_12022/9)
pubs.funder-project-idMRC (MR/N501876/1)
pubs.funder-project-idMRC
cam.issuedOnline2018-09-27


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International