Transactivation of cyclin E gene by EWS-Fli1 and antitumor effects of cyclin dependent kinase inhibitor on Ewing's family tumor cells

Xu Li, Kazuhiro Tanaka, Fumihiko Nakatani, Tomoya Matsunobu, Riku Sakimura, Masuo Hanada, Takamitsu Okada, Tomoyuki Nakamura, Yukihide Iwamoto

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20 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)385-394
Number of pages10
JournalInternational Journal of Cancer
Volume116
Issue number3
DOIs
Publication statusPublished - Sep 1 2005

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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