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Truncated PPM1D impairs stem cell response to genotoxic stress and promotes growth of APC-deficient tumors in the mouse colon
Czech Acad Sci, Czech Republic.
Czech Acad Sci, Czech Republic.
Czech Acad Sci, Czech Republic.
Czech Acad Sci, Czech Republic.
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2019 (English)In: Cell Death and Disease, ISSN 2041-4889, E-ISSN 2041-4889, Vol. 10, article id 818Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP , 2019. Vol. 10, article id 818
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
URN: urn:nbn:se:liu:diva-162067DOI: 10.1038/s41419-019-2057-4ISI: 000493385500003PubMedID: 31659152OAI: oai:DiVA.org:liu-162067DiVA, id: diva2:1371337
Note

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

Available from: 2019-11-19 Created: 2019-11-19 Last updated: 2020-01-13

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