1. EWS/ETS fusions activate telomerase in Ewing's tumors.
- Author
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Takahashi A, Higashino F, Aoyagi M, Yoshida K, Itoh M, Kyo S, Ohno T, Taira T, Ariga H, Nakajima K, Hatta M, Kobayashi M, Sano H, Kohgo T, and Shindoh M
- Subjects
- Adenovirus E1A Proteins genetics, Animals, Cell Line, Tumor, DNA-Binding Proteins, Enzyme Activation, HeLa Cells, Humans, Mice, NIH 3T3 Cells, Oncogene Proteins, Fusion genetics, Promoter Regions, Genetic, Proto-Oncogene Protein c-fli-1, Proto-Oncogene Proteins genetics, Proto-Oncogene Proteins c-ets, RNA Interference, RNA, Messenger biosynthesis, RNA, Messenger genetics, RNA-Binding Protein EWS, Sarcoma, Ewing genetics, Telomerase biosynthesis, Telomerase genetics, Transcription Factors genetics, Transcriptional Activation physiology, Adenovirus E1A Proteins physiology, Oncogene Proteins, Fusion physiology, Proto-Oncogene Proteins physiology, Sarcoma, Ewing enzymology, Telomerase metabolism, Transcription Factors physiology
- Abstract
EWS/ETS is a chimeric protein identified in most Ewing's sarcomas. Although EWS/ETS has been shown to activate transcription as a transcription factor, the detailed targets of EWS/ETS in transformed cells have not been clarified. Herein, we demonstrate that telomerase is a new target of EWS/ETS fusions. Both telomerase activity and the expression level of telomerase reverse transcriptase (TERT) mRNA were up-regulated in NIH3T3 cells transformed by EWS/E1AF and EWS/FLI1 as well as in two Ewing's sarcoma cell lines. Luciferase assay using the TERT promoter revealed that EWS/E1AF and EWS/FLI1 function as positive regulators of TERT transcription in an ETS binding site-independent manner. EWS/ETS appeared to be included in the initiation complex of TERT transcription and to cooperate with CREB-binding protein (CBP)/p300. When EWS/FLI1 was knocked down in Ewing's sarcomas cells by RNA interference, the expression level of TERT mRNA and the telomerase activity were significantly decreased. These findings indicate that EWS/ETS fusion proteins activate human telomerase activity in Ewing's tumors through up-regulation of TERT gene expression, probably as a transcriptional coactivator.
- Published
- 2003