EWS/FLI1 suppresses retinoblastoma protein function and senescence in Ewing's sarcoma cells |
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| Authors: | Hsien‐Ming Hu Anna Zielinska‐Kwiatkowska Karen Munro Jason Wilcox Daniel Y. Wu Liu Yang Howard A. Chansky |
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| Affiliation: | 1. Department of Orthopedics and Sports Medicine, School of Medicine, University of Washington, 1660 S. Columbian Way, ORT112, Seattle, Washington 98108;2. Department of Medicine/Oncology, School of Medicine, University of Washington, Seattle, Washington 98195;3. Medical Research Service, VA Puget Sound Health Care System, Seattle, Washington 98108 |
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| 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 p27kip1 and p57kip2, 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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| Keywords: | Ewing's sarcoma EWS/FLI1 retinoblastoma senescence cyclin D1 |
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