p53 dynamics vary between tissues and are linked with radiation sensitivity.
Animals
Antineoplastic Agents
/ pharmacology
Cell Line, Tumor
Cell Survival
/ drug effects
Humans
Mice
Neoplasms
/ drug therapy
Protein Binding
/ drug effects
Proto-Oncogene Proteins c-mdm2
/ antagonists & inhibitors
Radiation Tolerance
/ drug effects
Tissue Distribution
/ drug effects
Tumor Burden
/ drug effects
Tumor Suppressor Protein p53
/ metabolism
Xenograft Model Antitumor Assays
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
09 02 2021
09 02 2021
Historique:
received:
16
09
2019
accepted:
21
12
2020
entrez:
10
2
2021
pubmed:
11
2
2021
medline:
24
2
2021
Statut:
epublish
Résumé
Radiation sensitivity varies greatly between tissues. The transcription factor p53 mediates the response to radiation; however, the abundance of p53 protein does not correlate well with the extent of radiosensitivity across tissues. Given recent studies showing that the temporal dynamics of p53 influence the fate of cultured cells in response to irradiation, we set out to determine the dynamic behavior of p53 and its impact on radiation sensitivity in vivo. We find that radiosensitive tissues show prolonged p53 signaling after radiation, while more resistant tissues show transient p53 activation. Sustaining p53 using a small molecule (NMI801) that inhibits Mdm2, a negative regulator of p53, reduced viability in cell culture and suppressed tumor growth. Our work proposes a mechanism for the control of radiation sensitivity and suggests tools to alter the dynamics of p53 to enhance tumor clearance. Similar approaches can be used to enhance killing of cancer cells or reduce toxicity in normal tissues following genotoxic therapies.
Identifiants
pubmed: 33563973
doi: 10.1038/s41467-021-21145-z
pii: 10.1038/s41467-021-21145-z
pmc: PMC7873198
doi:
Substances chimiques
Antineoplastic Agents
0
Trp53 protein, mouse
0
Tumor Suppressor Protein p53
0
Mdm2 protein, mouse
EC 2.3.2.27
Proto-Oncogene Proteins c-mdm2
EC 2.3.2.27
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
898Subventions
Organisme : NCI NIH HHS
ID : R00 CA207727
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM083303
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM116864
Pays : United States
Références
Acta Crystallogr D Biol Crystallogr. 1994 Sep 1;50(Pt 5):760-3
pubmed: 15299374
Cell Stem Cell. 2008 Jun 5;2(6):576-83
pubmed: 18522850
Ann N Y Acad Sci. 1955 Feb 3;59(4):649-64
pubmed: 14362308
J Clin Oncol. 2017 Apr 20;35(12):1304-1311
pubmed: 28240971
Science. 1998 Sep 11;281(5383):1674-7
pubmed: 9733514
Science. 2012 Jun 15;336(6087):1440-4
pubmed: 22700930
Nature. 1993 Apr 29;362(6423):847-9
pubmed: 8479522
Proc Natl Acad Sci U S A. 1993 Jun 15;90(12):5742-6
pubmed: 8516323
Front Oncol. 2016 Jan 27;6:7
pubmed: 26858935
Bioorg Med Chem Lett. 2012 May 15;22(10):3498-502
pubmed: 22507962
Science. 2017 Aug 18;357(6352):
pubmed: 28818916
Acta Crystallogr D Biol Crystallogr. 2004 Dec;60(Pt 12 Pt 1):2126-32
pubmed: 15572765
Acta Crystallogr D Biol Crystallogr. 2010 Feb;66(Pt 2):125-32
pubmed: 20124692
Cancer Res. 2006 Aug 1;66(15):7482-9
pubmed: 16885345
Cancer Res. 2018 Sep 1;78(17):5084-5093
pubmed: 30026328
BMC Mol Cell Biol. 2020 Feb 18;21(1):5
pubmed: 32070277
Cancer Res. 2002 Dec 15;62(24):7316-27
pubmed: 12499275
J Mol Cell Biol. 2019 Jul 19;11(7):586-599
pubmed: 31310659
Nat Rev Cancer. 2003 Feb;3(2):117-29
pubmed: 12563311
Sci Transl Med. 2017 May 31;9(392):
pubmed: 28566423
Proc Natl Acad Sci U S A. 2000 Oct 10;97(21):11250-5
pubmed: 11016968
J Cell Sci. 1995 May;108 ( Pt 5):1843-8
pubmed: 7657708
Science. 1956 Jun 8;123(3206):1020-2
pubmed: 13324136
Nature. 2007 Feb 8;445(7128):661-5
pubmed: 17251932
Proc Natl Acad Sci U S A. 2020 Sep 22;117(38):23663-23673
pubmed: 32900967
Oncogene. 2000 Feb 3;19(5):649-60
pubmed: 10698510
Oncogene. 2004 Apr 22;23(19):3265-71
pubmed: 15064735
Blood. 2010 Apr 29;115(17):3472-80
pubmed: 20177048
Cell. 2009 May 1;137(3):413-31
pubmed: 19410540
J Hematol Oncol. 2017 Jul 3;10(1):133
pubmed: 28673313
Cell. 2016 Apr 21;165(3):631-42
pubmed: 27062928
Gastroenterology. 2012 Nov;143(5):1266-1276
pubmed: 22841781
Cell Death Differ. 2017 Nov;24(11):1853-1860
pubmed: 28686579
EMBO J. 1997 Mar 17;16(6):1391-400
pubmed: 9135154
Oncogene. 1996 Dec 19;13(12):2575-87
pubmed: 9000131
Sci Rep. 2015 Apr 10;5:8566
pubmed: 25858503
Science. 2016 Mar 11;351(6278):1204-8
pubmed: 26965628
Sci Signal. 2017 Apr 25;10(476):
pubmed: 28442631