liu.seSearch for publications in DiVA
Endre søk
RefereraExporteraLink to record
Permanent link

Direct link
Referera
Referensformat
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • Annet format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annet språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf
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.
Vise andre og tillknytning
2019 (engelsk)Inngår i: Cell Death and Disease, ISSN 2041-4889, E-ISSN 2041-4889, Vol. 10, artikkel-id 818Artikkel i tidsskrift (Fagfellevurdert) 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.

sted, utgiver, år, opplag, sider
NATURE PUBLISHING GROUP , 2019. Vol. 10, artikkel-id 818
HSV kategori
Identifikatorer
URN: urn:nbn:se:liu:diva-162067DOI: 10.1038/s41419-019-2057-4ISI: 000493385500003PubMedID: 31659152OAI: oai:DiVA.org:liu-162067DiVA, id: diva2:1371337
Merknad

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

Tilgjengelig fra: 2019-11-19 Laget: 2019-11-19 Sist oppdatert: 2020-05-03

Open Access i DiVA

fulltext(4212 kB)30 nedlastinger
Filinformasjon
Fil FULLTEXT01.pdfFilstørrelse 4212 kBChecksum SHA-512
89db6d6fc89968a4de2c5155effbc4fddad894f6749d70d769f55817e2466313781749ec1f38b427c989eed26600a24402db5fb1a7e23b9e4a80a55b24931bf3
Type fulltextMimetype application/pdf

Andre lenker

Forlagets fulltekstPubMed

Søk i DiVA

Av forfatter/redaktør
Ticha, IvanaSun, Xiao-Feng
Av organisasjonen
I samme tidsskrift
Cell Death and Disease

Søk utenfor DiVA

GoogleGoogle Scholar
Totalt: 30 nedlastinger
Antall nedlastinger er summen av alle nedlastinger av alle fulltekster. Det kan for eksempel være tidligere versjoner som er ikke lenger tilgjengelige

doi
pubmed
urn-nbn

Altmetric

doi
pubmed
urn-nbn
Totalt: 42 treff
RefereraExporteraLink to record
Permanent link

Direct link
Referera
Referensformat
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • Annet format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annet språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf