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Sökning: onr:"swepub:oai:DiVA.org:liu-162067" > Truncated PPM1D imp...

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

Burocziova, Monika (författare)
Czech Acad Sci, Czech Republic
Burdova, Kamila (författare)
Czech Acad Sci, Czech Republic
Martinikova, Andra S. (författare)
Czech Acad Sci, Czech Republic
visa fler...
Kasparek, Petr (författare)
Czech Acad Sci, Czech Republic
Kleiblova, Petra (författare)
Charles Univ Prague, Czech Republic
Danielsen, Stine A. (författare)
Oslo Univ Hosp, Norway; Oslo Univ Hosp, Norway
Borecka, Marianna (författare)
Charles Univ Prague, Czech Republic
Jenikova, Gabriela (författare)
Czech Acad Sci, Czech Republic
Janeckova, Lucie (författare)
Czech Acad Sci, Czech Republic
Pavel, Jozef (författare)
Czech Acad Sci, Czech Republic
Zemankova, Petra (författare)
Charles Univ Prague, Czech Republic
Schneiderova, Michaela (författare)
Charles Univ Prague, Czech Republic; Gen Fac Hosp Prague, Czech Republic
Schwarzova, Lucie (författare)
Gen Fac Hosp Prague, Czech Republic; Charles Univ Prague, Czech Republic
Ticha, Ivana (författare)
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
Sun, Xiao-Feng (författare)
Linköpings universitet,Avdelningen för Kirurgi, Ortopedi och Onkologi,Medicinska fakulteten,Region Östergötland, Onkologiska kliniken US
Jiraskova, Katerina (författare)
ASCR, Czech Republic
Liska, Vaclav (författare)
Charles Univ Prague, Czech Republic
Vodickova, Ludmila (författare)
ASCR, Czech Republic; Charles Univ Prague, Czech Republic; Charles Univ Prague, Czech Republic
Vodicka, Pavel (författare)
ASCR, Czech Republic; Charles Univ Prague, Czech Republic; Charles Univ Prague, Czech Republic
Sedlacek, Radislav (författare)
Czech Acad Sci, Czech Republic
Kleibl, Zdenek (författare)
Charles Univ Prague, Czech Republic
Lothe, Ragnhild A. (författare)
Oslo Univ Hosp, Norway; Oslo Univ Hosp, Norway
Korinek, Vladimir (författare)
Czech Acad Sci, Czech Republic
Macurek, Libor (författare)
Czech Acad Sci, Czech Republic
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 (creator_code:org_t)
NATURE PUBLISHING GROUP, 2019
2019
Engelska.
Ingår i: Cell Death and Disease. - : NATURE PUBLISHING GROUP. - 2041-4889 .- 2041-4889. ; 10
  • Tidskriftsartikel (refereegranskat)
Abstract Ämnesord
Stäng  
  • 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.

Ämnesord

MEDICAL AND HEALTH SCIENCES  -- Medical Biotechnology -- Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) (hsv//eng)
MEDICIN OCH HÄLSOVETENSKAP  -- Medicinsk bioteknologi -- Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci) (hsv//swe)
MEDICIN OCH HÄLSOVETENSKAP  -- Medicinsk bioteknologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Medical Biotechnology (hsv//eng)

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