Publication Date:
2015-05-16
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4456397/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4456397/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bell, Robert J A -- Rube, H Tomas -- Kreig, Alex -- Mancini, Andrew -- Fouse, Shaun D -- Nagarajan, Raman P -- Choi, Serah -- Hong, Chibo -- He, Daniel -- Pekmezci, Melike -- Wiencke, John K -- Wrensch, Margaret R -- Chang, Susan M -- Walsh, Kyle M -- Myong, Sua -- Song, Jun S -- Costello, Joseph F -- DP2 GM105453/GM/NIGMS NIH HHS/ -- P01 CA118816/CA/NCI NIH HHS/ -- P01CA118816-06/CA/NCI NIH HHS/ -- P50CA097257/CA/NCI NIH HHS/ -- R01 CA163336/CA/NCI NIH HHS/ -- R01 CA169316/CA/NCI NIH HHS/ -- R01CA163336/CA/NCI NIH HHS/ -- R01CA169316-01/CA/NCI NIH HHS/ -- R01CA52689/CA/NCI NIH HHS/ -- R25CA112355/CA/NCI NIH HHS/ -- T32 GM008568/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2015 May 29;348(6238):1036-9. doi: 10.1126/science.aab0015. Epub 2015 May 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Neurological Surgery, University of California, San Francisco, CA. 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. ; Institute for Genomic Biology, University of Illinois, Urbana-Champaign, IL. Department of Bioengineering, University of Illinois, Urbana-Champaign, IL. ; Department of Neurological Surgery, University of California, San Francisco, CA. ; Department of Radiation Oncology, University of California San Francisco, San Francisco, CA. ; Department of Anatomic Pathology, University of California San Francisco Medical School, San Francisco, CA 94143, USA. ; 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. ; Division of Neuroepidemiology, Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94158, USA. ; 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. ; Department of Neurological Surgery, University of California, San Francisco, CA. songj@illinois.edu joseph.costello@ucsf.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25977370" target="_blank"〉PubMed〈/a〉
Keywords:
Alleles
;
Cell Line, Tumor
;
GA-Binding Protein Transcription Factor/*metabolism
;
*Gene Expression Regulation, Enzymologic
;
*Gene Expression Regulation, Neoplastic
;
Glioblastoma/*genetics
;
Humans
;
Promoter Regions, Genetic
;
Protein Binding
;
Protein Multimerization
;
Telomerase/*genetics
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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