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Truncated PPM1D impairs stem cell response to genotoxic stress and promotes growth of APC-deficient tumors in the mouse colon
M. Burocziova, K. Burdova, AS. Martinikova, P. Kasparek, P. Kleiblova, SA. Danielsen, M. Borecka, G. Jenikova, L. Janečková, J. Pavel, P. Zemankova, M. Schneiderova, L. Schwarzova, I. Ticha, XF. Sun, K. Jiraskova, V. Liska, L. Vodickova, P....
Jazyk angličtina Země Velká Británie
Typ dokumentu časopisecké články, práce podpořená grantem
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Directory of Open Access Journals
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- MeSH
- chromatin účinky léků MeSH
- exony genetika MeSH
- fluoruracil farmakologie MeSH
- karcinogeneze účinky léků MeSH
- kontrolní body buněčného cyklu genetika MeSH
- lidé MeSH
- mutace genetika MeSH
- myši MeSH
- nádorový supresorový protein p53 genetika MeSH
- nádory tračníku farmakoterapie genetika patologie MeSH
- oprava DNA účinky léků MeSH
- poškození DNA účinky léků MeSH
- proliferace buněk účinky léků MeSH
- protein familiární adenomatózní polypózy genetika MeSH
- proteinfosfatasa 2C genetika MeSH
- regulace genové exprese u nádorů účinky léků MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
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 PPM1DT allele to colon tumorigenesis. We found that p53 pathway was suppressed in colon stem cells harboring PPM1DT resulting in proliferation advantage under genotoxic stress condition. In addition, truncated PPM1D promoted tumor growth in the colon in Apcmin mice and diminished survival. Moreover, tumor organoids derived from colon of the ApcminPpm1dT/+ mice were less sensitive to 5-fluorouracil when compared to ApcminPpm1d+/+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.
Biomedical Centre Faculty of Medicine in Pilsen Charles University Prague Czech Republic
Molecular Biology of Cancer Institute of Experimental Medicine ASCR Prague Czech Republic
Citace poskytuje Crossref.org
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- $a 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 PPM1DT allele to colon tumorigenesis. We found that p53 pathway was suppressed in colon stem cells harboring PPM1DT resulting in proliferation advantage under genotoxic stress condition. In addition, truncated PPM1D promoted tumor growth in the colon in Apcmin mice and diminished survival. Moreover, tumor organoids derived from colon of the ApcminPpm1dT/+ mice were less sensitive to 5-fluorouracil when compared to ApcminPpm1d+/+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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