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EWS/FLI1 suppresses retinoblastoma protein function and senescence in Ewing's sarcoma cells

✍ Scribed by Hsien-Ming Hu; Anna Zielinska-Kwiatkowska; Karen Munro; Jason Wilcox; Daniel Y. Wu; Liu Yang; Howard A. Chansky

Publisher: Elsevier Science
Year: 2008
Tongue: English
Weight: 251 KB
Volume: 26
Category: Article
ISSN: 0736-0266
DOI: 10.1002/jor.20597

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✦ Synopsis

Abstract

Ewing's Family Tumors (EFTs) most commonly harbor a specific t(11;22) translocation that generates the EWS/FLI1 fusion protein responsible for malignant transformation. Many potential downstream targets of EWS/FLI1 have been identified but a detailed mechanism by which the fusion protein brings about transformation remains unknown. In this report, we show that depletion of EWS/FLI1 in Ewing's cell lines results in a senescence phenotype, a marked increase in expression of the G1/S regulatory proteins p27^kip1^ and p57^kip2^, and a significant decrease in cyclin D1 and CDK2. We also demonstrate for the first time, to our knowledge, that knockdown of EWS/FLI1 leads to hypophosphorylation and functional activation of the retinoblastoma (pRb) family of proteins. Consistent with activation of the pRb proteins, E2F‐responsive genes such as cyclin A are repressed in EWS/FLI1‐depleted cells. Together, these results support the role of EWS/LI1 as an inhibitor of cellular senescence and implicate the retinoblastoma family of proteins as key mediators of this inhibition. © 2008 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 26:886–893, 2008

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