title: Cancer. The transcription factor GABP selectively binds and activates the mutant TERT promoter in cancer.
abstract: Reactivation of telomerase reverse transcriptase (TERT) expression enables cells to overcome replicative senescence and escape apoptosis, which are fundamental steps in the initiation of human cancer. Multiple cancer types, including up to 83% of glioblastomas (GBMs), harbor highly recurrent TERT promoter mutations of unknown function but specific to two nucleotide positions. We identified the functional consequence of these mutations in GBMs to be recruitment of the multimeric GA-binding protein (GABP) transcription factor specifically to the mutant promoter. Allelic recruitment of GABP is consistently observed across four cancer types, highlighting a shared mechanism underlying TERT reactivation. Tandem flanking native E26 transformation-specific motifs critically cooperate with these mutations to activate TERT, probably by facilitating GABP heterotetramer binding. GABP thus directly links TERT promoter mutations to aberrant expression in multiple cancers.
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, CA. Department of Biostatistics and Epidemiology, University of California, San Francisco, CA.
authors.forename: Robert J A
authors.initials: RJ
authors.lastname: Bell
authors.affiliation: Department of Physics, University of Illinois, Urbana-Champaign, IL. Institute for Genomic Biology, University of Illinois, Urbana-Champaign, IL.
authors.forename: H Tomas
authors.initials: HT
authors.lastname: Rube
authors.affiliation: Institute for Genomic Biology, University of Illinois, Urbana-Champaign, IL. Department of Bioengineering, University of Illinois, Urbana-Champaign, IL.
authors.forename: Alex
authors.initials: A
authors.lastname: Kreig
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, CA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Mancini
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, CA.
authors.forename: Shaun D
authors.initials: SD
authors.lastname: Fouse
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, CA.
authors.forename: Raman P
authors.initials: RP
authors.lastname: Nagarajan
authors.affiliation: Department of Radiation Oncology, University of California San Francisco, San Francisco, CA.
authors.forename: Serah
authors.initials: S
authors.lastname: Choi
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, CA.
authors.forename: Chibo
authors.initials: C
authors.lastname: Hong
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, CA.
authors.forename: Daniel
authors.initials: D
authors.lastname: He
authors.affiliation: Department of Anatomic Pathology, University of California San Francisco Medical School, San Francisco, CA 94143, USA.
authors.forename: Melike
authors.initials: M
authors.lastname: Pekmezci
authors.affiliation: Division of Neuroepidemiology, Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94158, USA. Institute for Human Genetics, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: John K
authors.initials: JK
authors.lastname: Wiencke
authors.affiliation: Division of Neuroepidemiology, Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94158, USA. Institute for Human Genetics, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Margaret R
authors.initials: MR
authors.lastname: Wrensch
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, CA.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Chang
authors.affiliation: Division of Neuroepidemiology, Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Kyle M
authors.initials: KM
authors.lastname: Walsh
authors.affiliation: Institute for Genomic Biology, University of Illinois, Urbana-Champaign, IL. Department of Bioengineering, University of Illinois, Urbana-Champaign, IL.
authors.forename: Sua
authors.initials: S
authors.lastname: Myong
authors.affiliation: Department of Biostatistics and Epidemiology, University of California, San Francisco, CA. Department of Physics, University of Illinois, Urbana-Champaign, IL. Institute for Genomic Biology, University of Illinois, Urbana-Champaign, IL. Department of Bioengineering, University of Illinois, Urbana-Champaign, IL. songj@illinois.edu joseph.costello@ucsf.edu.
authors.forename: Jun S
authors.initials: JS
authors.lastname: Song
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, CA. songj@illinois.edu joseph.costello@ucsf.edu.
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Costello
mesh_terms: D000483:Alleles; D045744:Cell Line, Tumor; D051268:GA-Binding Protein Transcription Factor / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000235:genetics*; D006801:Humans; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D055503:Protein Multimerization; D019098:Telomerase / Q000235:genetics*
chemical_list: D051268:GA-Binding Protein Transcription Factor; C495661:GABPA protein, human; C509186:TERT protein, human; D019098:Telomerase