Truncated PPM1D impairs stem cell response to genotoxic stress and promotes growth of APC-deficient tumors in the mouse colon

0520680 - ÚMG 2020 RIV GB eng J - Journal Article
Burocziová, Monika - Burdová, Kamila - Martiníková, Andra Stefania - Kašpárek, Petr - Kleiblová, P. - Danielsen, S.A. - Borecka, M. - Jeníková, Gabriela - Janečková, Lucie - Pavel, Jozef - Zemankova, P. - Schneiderová, M. - Schwarzová, L. - Tichá, I. - Sun, X.-F. - Jirásková, Kateřina - Liška, V. - Vodičková, Ludmila - Vodička, Pavel - Sedláček, Radislav - Kleibl, Z. - Lothe, R. A. - Kořínek, Vladimír - Macůrek, Libor
Truncated PPM1D impairs stem cell response to genotoxic stress and promotes growth of APC-deficient tumors in the mouse colon.
Cell Death & Disease. Roč. 10, č. 11 (2019), č. článku 818. ISSN 2041-4889. E-ISSN 2041-4889
R&D Projects: GA ČR GA16-19437S; GA ČR(CZ) GA18-09709S; GA MŠMT 7F14061; GA MŠMT(CZ) LM2015040; GA MŠMT(CZ) ED1.1.00/02.0109; GA MŠMT ED2.1.00/19.0395
Institutional support: RVO:68378050 ; RVO:68378041
Keywords : dna-damage response * multiple intestinal neoplasia * consensus molecular subtypes * wip1 phosphatase * wip1-dependent regulation * cancer cells * mutations * gene * breast * tumorigenesis
OECD category: Cell biology; Cell biology (UEM-P)
Impact factor: 6.304, year: 2019
Method of publishing: Open access
https://www.nature.com/articles/s41419-019-2057-4

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(T) allele to colon tumorigenesis. We found that p53 pathway was suppressed in colon stem cells harboring PPM1D(T) resulting in proliferation advantage under genotoxic stress condition. In addition, truncated PPM1D promoted tumor growth in the colon in Apc(min) mice and diminished survival. Moreover, tumor organoids derived from colon of the Apc(min)Ppm1d(T/+) mice were less sensitive to 5-fluorouracil when compared to Apc(min)Ppm1d(+/+)and the sensitivity to 5-fluorouracil was restored by inhibition of PPM1D. Finally, we screened colorectal cancer patients and identified recurrent somatic PPM1D mutations in a fraction of colon adenocarcinomas that are p53 proficient and show defects in mismatch DNA repair. In summary, we provide the first in vivo evidence that truncated PPM1D can promote tumor growth and modulate sensitivity to chemotherapy.
Permanent Link: http://hdl.handle.net/11104/0305939