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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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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
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
Journal
eLife
Quellenangaben
Volume: 5,
Article Number: e08711
Publisher
eLife Sciences Publications
Publishing Place
Cambridge
Non-patent literature
Publications
Reviewing status
Peer reviewed
Institute(s)
Institute of Stem Cell Research (ISF)