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Transcriptional modulation of the anti-apoptotic protein BCL-XL by the paired box transcription factors PAX3 and PAX3/FKHR

Oncogene volume 19, pages 2921–2929 (2000)Cite this article

Abstract

The aberrant expression of the transcription factors PAX3 and PAX3/FKHR associated with rhabdomyosarcoma (RMS), solid tumors displaying muscle cell features, suggests that these proteins play an important role in the pathogenesis of RMS. We could previously demonstrate that one of the oncogenic functions of PAX3 and PAX3/FKHR in RMS is protection from apoptosis. BCL-XL is a prominent anti-apoptotic protein present in normal skeletal muscle and RMS cells. In the present study, we establish that BCL-XL is transcriptionally modulated by PAX3 and PAX3/FKHR, since enhanced expression of both PAX proteins stimulates transcription of endogenous BCL-XL mRNA in a cell type specific manner. Further, we present evidence that both PAX3 and PAX3/FKHR can transcriptionally activate the Bcl-x gene promoter in cotransfection assays. Using electrophoretic mobility shift assays, an ATTA binding site for PAX3 and PAX3/FKHR could be localized in the upstream promoter region (position −42 to −39). Finally, ectopic overexpression of either PAX3, PAX3/FKHR or BCL-XL can rescue tumor cells from apoptosis induced by antisense treatment. These results suggest that at least part of the anti-apoptotic effect of PAX3 and PAX3/FKHR is mediated through direct transcriptional modulation of the prominent anti-apoptotic protein BCL-XL.

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Acknowledgements

We thank Dr P Houghton for the generous gift of Rh1 and Rh30 cells, Drs L Boise and A Himmelmann for providing the cDNAs coding for BCL-XL and PAX5, respectively, and Patricia McLoughlin for critical reading of the manuscript. We are especially grateful to Dr U Zangemeister-Wittke for providing the BCL-XL antisense oligonucleotides. Additionally, we thank Omar Murmann for his expert technical assistance with cotranfection studies and electrophoretic mobility shift assays. Prof Dr K Winterhalter and CW Heizmann are acknowledged for their continuous support of this project. The work was supported by grants from the Swiss National Science Foundation (31-46886.96 and 31-56869.99) and the Stiftung für wissenschaftliche Forschung of the University of Zürich.

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  1. Christiane M Margue and Michele Bernasconi: CM Margue and M Bernasconi contributed equally to this work

Authors and Affiliations

  1. Division of Clinical Chemistry and Biochemistry, University of Zurich, Steinwiesstrasse 75, Zurich, 8032, Switzerland

    Michele Bernasconi & Beat W Schäfer

  2. Institute of Biochemistry, ETH Zürich, Switzerland

    Christiane M Margue

  3. Department of Pathology and Laboratory Medicine, School of Medicine, University of Pennsylvania, Philadelphia, 19104, Pennsylvania, PA, USA

    Frederic G Barr

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  1. Christiane M Margue
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  2. Michele Bernasconi
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Margue, C., Bernasconi, M., Barr, F. et al. Transcriptional modulation of the anti-apoptotic protein BCL-XL by the paired box transcription factors PAX3 and PAX3/FKHR. Oncogene 19, 2921–2929 (2000). https://doi.org/10.1038/sj.onc.1203607

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