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Truncated PPM1D imp...
Truncated PPM1D impairs stem cell response to genotoxic stress and promotes growth of APC-deficient tumors in the mouse colon
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- Burocziova, Monika (author)
- Czech Acad Sci, Czech Republic
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- Burdova, Kamila (author)
- Czech Acad Sci, Czech Republic
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- Martinikova, Andra S. (author)
- Czech Acad Sci, Czech Republic
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- Kasparek, Petr (author)
- Czech Acad Sci, Czech Republic
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- Kleiblova, Petra (author)
- Charles Univ Prague, Czech Republic
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- Danielsen, Stine A. (author)
- Oslo Univ Hosp, Norway; Oslo Univ Hosp, Norway
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- Borecka, Marianna (author)
- Charles Univ Prague, Czech Republic
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- Jenikova, Gabriela (author)
- Czech Acad Sci, Czech Republic
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- Janeckova, Lucie (author)
- Czech Acad Sci, Czech Republic
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- Pavel, Jozef (author)
- Czech Acad Sci, Czech Republic
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- Zemankova, Petra (author)
- Charles Univ Prague, Czech Republic
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- Schneiderova, Michaela (author)
- Charles Univ Prague, Czech Republic; Gen Fac Hosp Prague, Czech Republic
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- Schwarzova, Lucie (author)
- Gen Fac Hosp Prague, Czech Republic; Charles Univ Prague, Czech Republic
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- Ticha, Ivana (author)
- Östergötlands 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
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- Sun, Xiao-Feng (author)
- Linköpings universitet,Avdelningen för Kirurgi, Ortopedi och Onkologi,Medicinska fakulteten,Region Östergötland, Onkologiska kliniken US
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- Jiraskova, Katerina (author)
- ASCR, Czech Republic
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- Liska, Vaclav (author)
- Charles Univ Prague, Czech Republic
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- Vodickova, Ludmila (author)
- ASCR, Czech Republic; Charles Univ Prague, Czech Republic; Charles Univ Prague, Czech Republic
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- Vodicka, Pavel (author)
- ASCR, Czech Republic; Charles Univ Prague, Czech Republic; Charles Univ Prague, Czech Republic
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- Sedlacek, Radislav (author)
- Czech Acad Sci, Czech Republic
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- Kleibl, Zdenek (author)
- Charles Univ Prague, Czech Republic
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- Lothe, Ragnhild A. (author)
- Oslo Univ Hosp, Norway; Oslo Univ Hosp, Norway
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- Korinek, Vladimir (author)
- Czech Acad Sci, Czech Republic
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- Macurek, Libor (author)
- Czech Acad Sci, Czech Republic
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(creator_code:org_t)
- 2019-10-28
- 2019
- English.
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In: Cell Death and Disease. - : NATURE PUBLISHING GROUP. - 2041-4889. ; 10
- Related links:
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https://liu.diva-por... (primary) (Raw object)
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https://www.nature.c...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Subject headings
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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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinsk bioteknologi -- Medicinsk bioteknologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Medical Biotechnology -- Medical Biotechnology (hsv//eng)
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Burocziova, Moni ...
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Burdova, Kamila
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Martinikova, And ...
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Kasparek, Petr
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Kleiblova, Petra
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Danielsen, Stine ...
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show more...
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Borecka, Mariann ...
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Jenikova, Gabrie ...
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Janeckova, Lucie
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Pavel, Jozef
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Zemankova, Petra
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Schneiderova, Mi ...
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Schwarzova, Luci ...
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Ticha, Ivana
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Sun, Xiao-Feng
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Jiraskova, Kater ...
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Liska, Vaclav
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Vodickova, Ludmi ...
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Vodicka, Pavel
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Sedlacek, Radisl ...
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Kleibl, Zdenek
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Lothe, Ragnhild ...
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Korinek, Vladimi ...
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Macurek, Libor
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Medical Biotechn ...
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and Medical Biotechn ...
- Articles in the publication
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Cell Death and D ...
- By the university
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Linköping University