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Downregulation and forced expression of EWS-Fli1 fusion gene results in changes in the expression of G(1)regulatory genes.

Abstract：

:Chromosomal translocation t(11;22)(q24:q12) is detected in approximately 90% of tumours of the Ewing family (ET). This translocation results in EWS-Fli1 gene fusion which produces a EWS-Fli1 fusion protein acting as an aberrant transcriptional activator. We previously reported that the inhibition of EWS-Fli1 expression caused the G(0)/G(1)arrest of ET cells. We, therefore, hypothesized that EWS-Fli1 may affect the expression of G(1)regulatory genes. Downregulation of EWS-Fli1 fusion proteins was observed 48 hours after the treatment with EWS-Fli1 antisense oligonucleotides. The expressions of G(1)cyclins, cyclin D1 and cyclin E, were markedly decreased in parallel with the reduction of EWS-Fli1 fusion protein. On the other hand, the expression of p21 and p27, which are important cyclin-dependent kinase inhibitors (CKIs) for G(1)--S transition, was dramatically increased after the treatment with EWS-Fli1 antisense oligonucleotides. RT-PCR analysis showed that alteration of the expressions of the cyclins and CKIs occurred at the mRNA level. Furthermore, transfection of EWS-Fli1 cDNA to NIH3T3 caused transformation of the cells and induction of the expression of cyclin D1 and E. Clinical samples of ET also showed a high level of expression of cyclin D1 mRNA, whereas mRNAs for p21 and p27 were not detected in the samples. These findings strongly suggest that the G(1)--S regulatory genes may be involved in downstream of EWS-Fli1 transcription factor, and that the unbalanced expression of G(1)--S regulatory factors caused by EWS-Fli1 may lead to the tumorigenesis of ET.

journal_name

Br J Cancer

journal_title

British journal of cancer

authors

Matsumoto Y,Tanaka K,Nakatani F,Matsunobu T,Matsuda S,Iwamoto Y

doi

10.1054/bjoc.2000.1652

subject

Has Abstract

pub_date

2001-03-23 00:00:00

pages

768-75

issue

6

eissn

0007-0920

issn

1532-1827

pii

S0007092000916525

journal_volume

84

pub_type

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