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Analysis of the expression of cell cycle regulators in Ewing cell lines: EWS-FLI-1 modulates p57KIP2 and c-Myc expression

Oncogene volume 20, pages 3258–3265 (2001)Cite this article

Abstract

Ewing tumour is characterized by specific chromosome translocations which fuse EWS to a subset of genes encoding ETS transcription factors, most frequently FLI-1. We report the analysis of the expression of various cell cycle regulators both in Ewing tumour derived cell lines and in different cellular models with either inducible or constitutive EWS-FLI-1 cDNA expression. In Ewing cell lines, cyclin D1, CDK4, Rb, p27KIP1 and c-Myc were consistently highly expressed whereas p57KIP2, p15INK4B and p14ARF demonstrated undetectable or low expression levels. The amount of p16INK4A, p21CIP1, p18INKAC and CDK6 was variable from one cell line to the other. The inducible expression of EWS-FLI-1 led to a strong upregulation of c-Myc and a considerable downregulation of p57KIP2. Other proteins did not show evident modification. High c-Myc and very low p57KIP2 expression levels were also observed in neuroblastoma NGP cells constitutively expressing EWS-FLI-1 as compared to parental cells. Analysis of the p57KIP2 promoter indicated that EWS-FLI-1 downregulates, possibly through an indirect mechanism, the transcription of this gene. Finally, we show that ectopic expression of p57KIP2 in Ewing cells blocks proliferation through a complete G1 arrest. These results suggest that the modulation of p57KIP2 expression by EWS-FLI-1 is a fundamental step in Ewing tumorigenesis.

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Acknowledgements

We thank Ismail Kola, Christopher Denny and Serge Leibovitch for providing the pMT-CB6+ vector, the EWS-FLI-1 retroviral vector, the GFP-p57KIP2 and the p57KIP2 vectors, respectively. We also thank Danny Rouillard for her help in cell cycle analysis, Catherine Barbarou and Patricia de Cremoux for the analysis of p53. L Dauphinot is a recipient of a fellowship from the Ligue Nationale Contre le Cancer. This work was supported in part by grants from the Association pour la Recherche contre le Cancer, the Ligue Nationale Contre le Cancer and the USPHS, CA63176.

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Authors and Affiliations

  1. INSERM U509, Laboratoire de Pathologie Moléculaire des Cancers, Institut Curie, 26 rue d'Ulm, Paris, Cedex 05, 75248, France

    Luce Dauphinot, Catherine De Oliveira, Thomas Melot, Nicolas Sevenet & Olivier Delattre

  2. Department of Pathology and Laboratory Medicine, 345 Lineberger Cancer Center, CB#7295, University of North Carolina, Chapel Hill, 27599, North Carolina, NC, USA

    Venetia Thomas & Bernard E Weissman

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  1. Luce Dauphinot
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  2. Catherine De Oliveira
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Dauphinot, L., De Oliveira, C., Melot, T. et al. Analysis of the expression of cell cycle regulators in Ewing cell lines: EWS-FLI-1 modulates p57KIP2 and c-Myc expression. Oncogene 20, 3258–3265 (2001). https://doi.org/10.1038/sj.onc.1204437

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