EWS/ETS fusions activate telomerase in Ewing's tumors.
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.
Takahashi
Akiko
A
Department of Oral Pathobiological Science, Hokkaido University Graduate School of Dental Medicine, Sapporo, Japan.
Higashino
Fumihiro
F
Aoyagi
Mariko
M
Yoshida
Koichi
K
Itoh
Miyuki
M
Kyo
Satoru
S
Ohno
Takatoshi
T
Taira
Takahiro
T
Ariga
Hiroyoshi
H
Nakajima
Kohichi
K
Hatta
Mitsutoki
M
Kobayashi
Masanobu
M
Sano
Hidehiko
H
Kohgo
Takao
T
Shindoh
Masanobu
M
D017500:Adenovirus E1A Proteins / Q000235:genetics / Q000502:physiology*; D000818:Animals; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins; D004789:Enzyme Activation; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000502:physiology*; D011401:Promoter Regions, Genetic; D051789:Proto-Oncogene Protein c-fli-1; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D050783:Proto-Oncogene Proteins c-ets; D034622:RNA Interference; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D034802:RNA-Binding Protein EWS; D012512:Sarcoma, Ewing / Q000201:enzymology* / Q000235:genetics; D019098:Telomerase / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D015533:Transcriptional Activation / Q000502:physiology
D017500:Adenovirus E1A Proteins; D004268:DNA-Binding Proteins; C079853:ETV4 protein, human; C106031:EWS-FLI fusion protein; D015514:Oncogene Proteins, Fusion; D051789:Proto-Oncogene Protein c-fli-1; D011518:Proto-Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; D012333:RNA, Messenger; D034802:RNA-Binding Protein EWS; D014157:Transcription Factors; C509186:TERT protein, human; D019098:Telomerase; C509187:Tert protein, mouse