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Transactivation of cyclin E gene by EWS‐Fli1 and antitumor effects of cyclin dependent kinase inhibitor on Ewing's family tumor cells
Author(s) -
Li Xu,
Tanaka Kazuhiro,
Nakatani Fumihiko,
Matsunobu Tomoya,
Sakimura Riku,
Hanada Masuo,
Okada Takamitsu,
Nakamura Tomoyuki,
Iwamoto Yukihide
Publication year - 2005
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.21010
Subject(s) - transactivation , cyclin dependent kinase , cyclin d1 , cyclin a2 , cancer research , cyclin d , biology , cyclin , cyclin e , microbiology and biotechnology , cyclin dependent kinase complex , cyclin a , cyclin dependent kinase 2 , cell cycle , kinase , transcription factor , protein kinase a , gene , genetics
Chromosomal translocation t(11; 22)(q24; q12) is detected in approximately 90% of Ewing's family tumors (EFTs) including Ewing's sarcoma and primitive neuroectodermal tumor. This results in the formation of the EWS‐Fli1 fusion gene, which produces EWS‐Fli1 fusion protein. This chimerical gene product acts as an aberrant transcriptional activator, which may be responsible for the tumorigenesis of EFTs. We have previously reported that cyclin E expression was upregulated in EFT cells and in EWS‐Fli1 transformed fibroblastic cells. However, the mechanism of the overexpression of cyclin E by EWS‐Fli1 is still unknown. In our study, we investigated the mechanism of transactivation of the cyclin E gene in EFT cells. We found that EWS‐Fli1 enhanced the activity of the cyclin E gene promoter partially through E2F binding sites in the promoter. In addition, the basic transcriptional factor, Sp1, might also be involved in the transactivation of the cyclin E gene by EWS‐Fli1. To study the biological significance of cyclin E overexpression in EFT cells, we used flavopiridol, a pan‐cyclin‐dependent kinase (CDK) inhibitor and found that flavopiridol efficiently suppressed the growth of EFT cells in vitro and in vivo by the inhibition of cyclinE/CDK2 kinase activity and the induction of apoptosis. These results suggest that targeting of the cyclin/CDK complex may provide new insight into treatment of EFTs. © 2005 Wiley‐Liss, Inc.