| Literature DB >> 30205050 |
Andrew Mancini1, Ana Xavier-Magalhães2, Wendy S Woods3, Kien-Thiet Nguyen1, Alexandra M Amen4, Josie L Hayes1, Christof Fellmann5, Michael Gapinske3, Andrew M McKinney1, Chibo Hong1, Lindsey E Jones1, Kyle M Walsh6, Robert J A Bell1, Jennifer A Doudna7, Bruno M Costa8, Jun S Song9, Pablo Perez-Pinera10, Joseph F Costello11.
Abstract
TERT promoter mutations reactivate telomerase, allowing for indefinite telomere maintenance and enabling cellular immortalization. These mutations specifically recruit the multimeric ETS factor GABP, which can form two functionally independent transcription factor species: a dimer or a tetramer. We show that genetic disruption of GABPβ1L (β1L), a tetramer-forming isoform of GABP that is dispensable for normal development, results in TERT silencing in a TERT promoter mutation-dependent manner. Reducing TERT expression by disrupting β1L culminates in telomere loss and cell death exclusively in TERT promoter mutant cells. Orthotopic xenografting of β1L-reduced, TERT promoter mutant glioblastoma cells rendered lower tumor burden and longer overall survival in mice. These results highlight the critical role of GABPβ1L in enabling immortality in TERT promoter mutant glioblastoma.Entities:
Keywords: GABP; TERT promoter mutation; cancer immortality; glioblastoma; telomerase; telomeres
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Year: 2018 PMID： 30205050 PMCID： PMC6135086 DOI： 10.1016/j.ccell.2018.08.003
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743