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Inactivation of the ATMIN/ATM pathway protects against glioblastoma formation.
eLife 5:e08711 (2016)
Glioblastoma multiforme (GBM) is the most aggressive human primary brain cancer. Using a Trp53-deficient mouse model of GBM, we show that genetic inactivation of the Atm cofactor Atmin, which is dispensable for embryonic and adult neural development, strongly suppresses GBM formation. Mechanistically, expression of several GBM-associated genes, including Pdgfra, was normalized by Atmin deletion in the Trp53-null background. Pharmacological ATM inhibition also reduced Pdgfra expression, and reduced the proliferation of Trp53-deficient primary glioma cells from murine and human tumors, while normal neural stem cells were unaffected. Analysis of GBM datasets showed that PDGFRA expression is also significantly increased in human TP53-mutant compared with TP53-wild-type tumors. Moreover, combined treatment with ATM and PDGFRA inhibitors efficiently killed TP53-mutant primary human GBM cells, but not untransformed neural stem cells. These results reveal a new requirement for ATMIN-dependent ATM signaling in TP53-deficient GBM, indicating a pro-tumorigenic role for ATM in the context of these tumors.
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Publikationstyp
Artikel: Journalartikel
Dokumenttyp
Wissenschaftlicher Artikel
Schlagwörter
Dna-damage-response; Neural Stem-cells; Malignant Astrocytic Glioma; Ataxia-telangiectasia; Human Cancer; Kinase Atm; P53; Growth; Inhibitor; Biology
ISSN (print) / ISBN
2050-084X
e-ISSN
2050-084X
Zeitschrift
eLife
Quellenangaben
Band: 5,
Artikelnummer: e08711
Verlag
eLife Sciences Publications
Verlagsort
Cambridge
Nichtpatentliteratur
Publikationen
Begutachtungsstatus
Peer reviewed
Institut(e)
Institute of Stem Cell Research (ISF)