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Role of protein–protein interactions in the antiapoptotic function of EWS-Fli-1

Oncogene volume 23, pages 7087–7094 (2004)Cite this article

Abstract

In the majority of Ewing’s family tumors, chromosomal translocation t(11;22) leads to aberrant fusion of RNA-binding protein EWS with DNA-binding ETS transcriptional factor Fli-1. EWS-Fli-1 has altered the transcriptional activity and modulating its downstream target genes through this transcriptional activity is thought to be responsible for this tumor. We have previously shown that both EWS-Fli-1 and Fli-1 have antiapoptotic activity against several apoptotic inducers. Here, we show that the transcriptional activity of EWS-Fli-1 and Fli-1 is not essential for its antiapoptotic activity. We also demonstrate that EWS-Fli-1 and Fli-1 interact with CBP through its amino-terminal region and inhibit the CBP-dependent transcriptional activity of RXR. This activity appears to be independent of DNA-binding activity of EWS-Fli-1. Introduction of the dominant-negative form of CBP into Ewing’s sarcoma cells sensitizes these cells against genotoxic or retinoic-acid induced apoptosis. These results suggest that the ability of EWS-Fli-1/Fli-1 to target transcriptional cofactor(s) and modulate apoptotic pathways may be responsible for its antiapoptotic and tumorigenic activities.

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Acknowledgements

We thank R Class for his assistance in the FACS analysis and other colleagues of Reddy and Rao's laboratories for their cooperation throughout this study. We also thank Professor Pierre Chambon for providing us generously mRXR and DR5G-tk CAT plasmids. This work was supported in part by NIH grants RO1 CA 85642, RO1 CA 85343 and US Army medical research grant DAMD 17-99-1-9060 and GCC Distinguished Cancer Scholar award to ESP Reddy and CA 57322 to CA 83591 and GCC Distinguished Cancer Scholar award to VN Rao.

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Authors and Affiliations

  1. Drexel University, Broad and Vine, Philadelphia, 19102, PA, USA

    Ramugounder Ramakrishnan, Yasuo Fujimura, Jian Ping Zou, Fang Liu, Veena N Rao & E Shyam P Reddy

  2. Department of Medicine, Cancer Biology Program, Morehouse School of Medicine, Georgia Cancer Center for Excellence, 80 Jessie Hill Jr Drive, Atlanta, 30303, GA, USA

    Yasuo Fujimura, Veena N Rao & E Shyam P Reddy

  3. SAIC, Frederick, 21702, MD, USA

    Leo Lee

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  1. Ramugounder Ramakrishnan
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Correspondence to E Shyam P Reddy.

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Ramakrishnan, R., Fujimura, Y., Zou, J. et al. Role of protein–protein interactions in the antiapoptotic function of EWS-Fli-1. Oncogene 23, 7087–7094 (2004). https://doi.org/10.1038/sj.onc.1207927

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