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Truncated PPM1D imp...
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Burocziova, MonikaCzech Acad Sci, Czech Republic
(author)
Truncated PPM1D impairs stem cell response to genotoxic stress and promotes growth of APC-deficient tumors in the mouse colon
- Article/chapterEnglish2019
Publisher, publication year, extent ...
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2019-10-28
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NATURE PUBLISHING GROUP,2019
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electronicrdacarrier
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LIBRIS-ID:oai:DiVA.org:liu-162067
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https://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-162067URI
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https://doi.org/10.1038/s41419-019-2057-4DOI
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Language:English
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Summary in:English
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Subject category:ref swepub-contenttype
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Subject category:art swepub-publicationtype
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Funding Agencies|Czech Science FoundationGrant Agency of the Czech Republic [16-19437S, 18-09709S]; Academy of Sciences of the Czech RepublicCzech Academy of Sciences [RVO 68378050]; EEA Czech-Norwegian Research Programme-Norwegian Financial Mechanism 2009-2014 (PHOSCAN) [7F14061]; Czech Centre for Phenogenomics [LM2015040]; project: Higher quality and capacity for transgenic models [OP RDI CZ.1.05/2.1.0019.0395]; Biotechnology and Biomedicine Centre of the Academy of Sciences [CZ.1.05/1.1.00/02.0109]; Charles University [CZ.1.05/1.1.00/02.0109]; Worldwide Cancer Research foundation [14-1176]; National Sustainability Program I (NPU I) [LO1503]; Swedish Cancer Foundation; Swedish Research CouncilSwedish Research Council; Health Research Council in South-East Sweden; Research Council of NorwayResearch Council of Norway [179571, 250993]; Norwegian Cancer SocietyNorwegian Cancer Society [182759-2016]; South-Eastern Regional Health Authorities
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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.
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Burdova, KamilaCzech Acad Sci, Czech Republic
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Martinikova, Andra S.Czech Acad Sci, Czech Republic
(author)
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Kasparek, PetrCzech Acad Sci, Czech Republic
(author)
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Kleiblova, PetraCharles Univ Prague, Czech Republic
(author)
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Danielsen, Stine A.Oslo Univ Hosp, Norway; Oslo Univ Hosp, Norway
(author)
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Borecka, MariannaCharles Univ Prague, Czech Republic
(author)
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Jenikova, GabrielaCzech Acad Sci, Czech Republic
(author)
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Janeckova, LucieCzech Acad Sci, Czech Republic
(author)
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Pavel, JozefCzech Acad Sci, Czech Republic
(author)
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Zemankova, PetraCharles Univ Prague, Czech Republic
(author)
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Schneiderova, MichaelaCharles Univ Prague, Czech Republic; Gen Fac Hosp Prague, Czech Republic
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Schwarzova, LucieGen Fac Hosp Prague, Czech Republic; Charles Univ Prague, Czech Republic
(author)
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Ticha, IvanaÖstergötlands Läns Landsting,Linköpings universitet,Institutionen för klinisk och experimentell medicin,Medicinska fakulteten,Onkologiska kliniken,Gen Fac Hosp Prague, Czech Republic; Charles Univ Prague, Czech Republic(Swepub:liu)ivati06
(author)
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Sun, Xiao-FengLinköpings universitet,Avdelningen för Kirurgi, Ortopedi och Onkologi,Medicinska fakulteten,Region Östergötland, Onkologiska kliniken US(Swepub:liu)xiasu45
(author)
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Jiraskova, KaterinaASCR, Czech Republic
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Liska, VaclavCharles Univ Prague, Czech Republic
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Vodickova, LudmilaASCR, Czech Republic; Charles Univ Prague, Czech Republic; Charles Univ Prague, Czech Republic
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Vodicka, PavelASCR, Czech Republic; Charles Univ Prague, Czech Republic; Charles Univ Prague, Czech Republic
(author)
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Sedlacek, RadislavCzech Acad Sci, Czech Republic
(author)
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Kleibl, ZdenekCharles Univ Prague, Czech Republic
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Lothe, Ragnhild A.Oslo Univ Hosp, Norway; Oslo Univ Hosp, Norway
(author)
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Korinek, VladimirCzech Acad Sci, Czech Republic
(author)
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Macurek, LiborCzech Acad Sci, Czech Republic
(author)
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Czech Acad Sci, Czech RepublicCharles Univ Prague, Czech Republic
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