Outcompeting p53-Mutant Cells in the Normal Esophagus by Redox Manipulation.
Aging
/ physiology
Animals
Antioxidants
Cell Differentiation
Cell Proliferation
Cells, Cultured
Epithelial Cells
/ physiology
Esophagus
/ physiology
Humans
Mice
Mice, Transgenic
Mutation
/ genetics
NF-E2-Related Factor 2
/ metabolism
Oxidation-Reduction
Oxidative Stress
Radiation, Ionizing
Receptors, Estrogen
/ genetics
Tumor Suppressor Protein p53
/ genetics
NFE2L2
TP53
cell competition
cell tracing
differentiation
ionizing radiation
mitochondria
oxidative stress
somatic mutation
stem cell
Journal
Cell stem cell
ISSN: 1875-9777
Titre abrégé: Cell Stem Cell
Pays: United States
ID NLM: 101311472
Informations de publication
Date de publication:
05 09 2019
05 09 2019
Historique:
received:
12
03
2019
revised:
14
05
2019
accepted:
14
06
2019
pubmed:
23
7
2019
medline:
22
9
2020
entrez:
23
7
2019
Statut:
ppublish
Résumé
As humans age, normal tissues, such as the esophageal epithelium, become a patchwork of mutant clones. Some mutations are under positive selection, conferring a competitive advantage over wild-type cells. We speculated that altering the selective pressure on mutant cell populations may cause them to expand or contract. We tested this hypothesis by examining the effect of oxidative stress from low-dose ionizing radiation (LDIR) on wild-type and p53 mutant cells in the transgenic mouse esophagus. We found that LDIR drives wild-type cells to stop proliferating and differentiate. p53 mutant cells are insensitive to LDIR and outcompete wild-type cells following exposure. Remarkably, combining antioxidant treatment and LDIR reverses this effect, promoting wild-type cell proliferation and p53 mutant differentiation, reducing the p53 mutant population. Thus, p53-mutant cells can be depleted from the normal esophagus by redox manipulation, showing that external interventions may be used to alter the mutational landscape of an aging tissue.
Identifiants
pubmed: 31327664
pii: S1934-5909(19)30275-9
doi: 10.1016/j.stem.2019.06.011
pmc: PMC6739485
pii:
doi:
Substances chimiques
Antioxidants
0
NF-E2-Related Factor 2
0
Receptors, Estrogen
0
Tumor Suppressor Protein p53
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
329-341.e6Subventions
Organisme : Cancer Research UK
ID : C609/A17257
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_12022/3
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 296194
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_12022/6
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 098051
Pays : United Kingdom
Organisme : Wellcome Trust
Pays : United Kingdom
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.
Références
Carcinogenesis. 2002 Sep;23(9):1541-7
pubmed: 12189199
J Biol Chem. 2002 Nov 8;277(45):42769-74
pubmed: 12198130
Am J Anat. 1965 Jul;117:73-87
pubmed: 14345836
Nat Genet. 2003 Nov;35(3):238-45
pubmed: 14517554
Proc Natl Acad Sci U S A. 2004 Apr 27;101(17):6379-84
pubmed: 15087497
Nature. 2007 Mar 8;446(7132):185-9
pubmed: 17330052
Nat Cell Biol. 2007 May;9(5):573-80
pubmed: 17417627
Nat Methods. 2008 Jun;5(6):553-9
pubmed: 18469822
Trends Cell Biol. 2011 May;21(5):312-9
pubmed: 21354798
Cancer Lett. 2012 Dec 31;327(1-2):48-60
pubmed: 22182453
Cochrane Database Syst Rev. 2012 Mar 14;(3):CD007176
pubmed: 22419320
OMICS. 2012 May;16(5):284-7
pubmed: 22455463
Science. 2012 Aug 31;337(6098):1091-3
pubmed: 22821983
Bioinformatics. 2013 Jan 1;29(1):15-21
pubmed: 23104886
Sci Signal. 2013 Feb 05;6(261):ra8
pubmed: 23386745
Nat Rev Cancer. 2013 Mar;13(3):161-71
pubmed: 23388619
Nat Cell Biol. 2014 Jun;16(6):615-22
pubmed: 24814514
Bioinformatics. 2015 Jan 15;31(2):166-9
pubmed: 25260700
Genome Biol. 2014;15(12):550
pubmed: 25516281
Cell Cycle. 2015;14(1):9-17
pubmed: 25551772
J Clin Invest. 2015 Apr;125(4):1557-68
pubmed: 25774506
Science. 2015 May 22;348(6237):880-6
pubmed: 25999502
Nat Rev Mol Cell Biol. 2015 Jul;16(7):393-405
pubmed: 26122615
Lancet. 2015 Aug 1;386(9992):479-88
pubmed: 26251393
Dev Cell. 2015 Nov 23;35(4):444-57
pubmed: 26609959
Nat Cell Biol. 2016 Sep;18(9):967-78
pubmed: 27548914
Nature. 2017 Jan 12;541(7636):169-175
pubmed: 28052061
Science. 2017 Feb 24;355(6327):842-847
pubmed: 28104796
Hum Mol Genet. 2017 Jul 15;26(14):2591-2602
pubmed: 28369373
JAMA Intern Med. 2017 Jun 1;177(6):810-817
pubmed: 28395000
Blood. 2017 Aug 10;130(6):742-752
pubmed: 28483762
Cell Rep. 2017 Sep 26;20(13):3199-3211
pubmed: 28954235
Cell Rep. 2018 Aug 14;24(7):1777-1789
pubmed: 30110635
Cell Stem Cell. 2018 Nov 1;23(5):677-686.e4
pubmed: 30269903
Cell Stem Cell. 2018 Nov 1;23(5):687-699.e8
pubmed: 30269904
Science. 2018 Nov 23;362(6417):911-917
pubmed: 30337457
Nature. 2019 Jan;565(7739):312-317
pubmed: 30602793
Science. 2019 Jun 7;364(6444):
pubmed: 31171663
J R Soc Interface. 2019 Jul 26;16(156):20190230
pubmed: 31362624
Proc Natl Acad Sci U S A. 1996 Nov 26;93(24):13943-8
pubmed: 8943040