Truncated PPM1D impairs stem cell response to genotoxic stress and promotes growth of APC-deficient tumors in the mouse colon.
Adenomatous Polyposis Coli Protein
/ genetics
Animals
Carcinogenesis
/ drug effects
Cell Cycle Checkpoints
/ genetics
Cell Proliferation
/ drug effects
Chromatin
/ drug effects
Colonic Neoplasms
/ drug therapy
DNA Damage
/ drug effects
DNA Repair
/ drug effects
Exons
/ genetics
Fluorouracil
/ pharmacology
Gene Expression Regulation, Neoplastic
/ drug effects
Humans
Mice
Mutation
/ genetics
Protein Phosphatase 2C
/ genetics
Tumor Suppressor Protein p53
/ genetics
Journal
Cell death & disease
ISSN: 2041-4889
Titre abrégé: Cell Death Dis
Pays: England
ID NLM: 101524092
Informations de publication
Date de publication:
28 10 2019
28 10 2019
Historique:
received:
06
07
2019
accepted:
09
10
2019
revised:
02
10
2019
entrez:
30
10
2019
pubmed:
30
10
2019
medline:
28
8
2020
Statut:
epublish
Résumé
Protein phosphatase magnesium-dependent 1 delta (PPM1D) terminates cell response to genotoxic stress by negatively regulating the tumor suppressor p53 and other targets at chromatin. Mutations in the exon 6 of the PPM1D result in production of a highly stable, C-terminally truncated PPM1D. These gain-of-function PPM1D mutations are present in various human cancers but their role in tumorigenesis remains unresolved. Here we show that truncated PPM1D impairs activation of the cell cycle checkpoints in human non-transformed RPE cells and allows proliferation in the presence of DNA damage. Next, we developed a mouse model by introducing a truncating mutation in the PPM1D locus and tested contribution of the oncogenic PPM1D
Identifiants
pubmed: 31659152
doi: 10.1038/s41419-019-2057-4
pii: 10.1038/s41419-019-2057-4
pmc: PMC6817818
doi:
Substances chimiques
Adenomatous Polyposis Coli Protein
0
Chromatin
0
Trp53 protein, mouse
0
Tumor Suppressor Protein p53
0
adenomatous polyposis coli protein, mouse
0
PPM1D protein, human
EC 3.1.3.16
Protein Phosphatase 2C
EC 3.1.3.16
Fluorouracil
U3P01618RT
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
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