Transactivation of cyclin E gene by EWS-Fli1 and antitumor effects of cyclin dependent kinase inhibitor on Ewing's family tumor cells.
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.
Li
Xu
X
Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka, Japan.
Tanaka
Kazuhiro
K
Nakatani
Fumihiko
F
Matsunobu
Tomoya
T
Sakimura
Riku
R
Hanada
Masuo
M
Okada
Takamitsu
T
Nakamura
Tomoyuki
T
Iwamoto
Yukihide
Y
D001859:Bone Neoplasms / Q000235:genetics* / Q000473:pathology*; D019927:Cyclin E / Q000096:biosynthesis* / Q000235:genetics*; D006801:Humans; D018242:Neuroectodermal Tumors, Primitive / Q000235:genetics* / Q000473:pathology*; D015514:Oncogene Proteins, Fusion / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D051789:Proto-Oncogene Protein c-fli-1; D034802:RNA-Binding Protein EWS; D012512:Sarcoma, Ewing / Q000235:genetics* / Q000473:pathology*; D014157:Transcription Factors / Q000494:pharmacology*; D015533:Transcriptional Activation; D015854:Up-Regulation
D019927:Cyclin E; C106031:EWS-FLI fusion protein; D015514:Oncogene Proteins, Fusion; D051789:Proto-Oncogene Protein c-fli-1; D034802:RNA-Binding Protein EWS; D014157:Transcription Factors