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Mancini, Andrew; Xavier-Magalhães, Ana; Woods, Wendy S.; Nguyen, Kien-Thiet; Amen, Alexandra M.; Hayes, Josie L.; Fellmann, Christof; Gapinske, Michael; McKinney, Andrew M.; Hong, Chibo; Jones, Lindsey E.; Walsh, Kyle M.; Bell, Robert J.A.; Doudna, Jennifer A.; Costa, Bruno M.; Song, Jun S.; Perez-Pinera, Pablo; Costello, Joseph F.
Cancer cell, 09/2018, Letnik: 34, Številka: 3Journal Article
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. •The β1L tetramer-forming isoform of GABP activates the mutant TERT promoter•β1L disruption induces telomere loss and death only in TERT promoter mutant cells•Disruption of β1L reduces tumor growth and prolongs survival in xenografted mice•GABPβ1L is a potential therapeutic target for TERT promoter mutant glioblastoma TERT promoter mutations generate a binding site for GABP and reactivate TERT expression. Mancini et al. show that GABPβ1L, among GABP subunits, is specifically required for the function of TERT promoter mutants, and disrupting GABPβ1L causes telomere loss and cell death exclusively in TERT promoter mutant cells.
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in: SICRIS
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