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  • Original Paper
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Bcl-2 interferes with the execution phase, but not upstream events, in glucocorticoid-induced leukemia apoptosis

Oncogene volume 18, pages 713–719 (1999)Cite this article

Abstract

Due to their growth arrest- and apoptosis-inducing ability, glucocorticoids (GC) are widely used in the therapy of various lymphoid malignancies. Cell death is associated with activation of members of the interleukin-1β-converting enzyme (ICE) protease/caspase family and, is presumably prevented by the anti-apoptotic protein Bcl-2. To further address the role of Bcl-2 in GC-mediated cytotoxicity, we generated subclones of the GC-sensitive human T-cell acute lymphoblastic leukemia line CCRF-CEM, in which transgenic Bcl-2 expression is regulated by tetracycline. Up to about 48 h, exogenous Bcl-2 almost completely protected these cells from apoptosis, digestion of poly-ADP ribose polymerase (PARP) and generation of Asp-Glu-Val-Asp cleaving (DEVDase) activity. However, when the cells were cultured for another 24 h in the continuous presence of GC, they underwent massive apoptosis that was associated with DEVDase activity and PARP cleavage. Bcl-2 did not markedly affect GC-mediated growth arrest, thereby separating the anti-proliferative from the apoptosis-inducing effect of GC. Moreover, Bcl-2 did not prevent the dramatic reduction in the levels of several mRNAs observed during GC treatment, including the transgenic Bcl-2 mRNA. Thus, Bcl-2 can be placed upstream of effector caspase activation, but downstream of other GC-regulated events, such as growth arrest and the potentially critical repression of steady state levels of multiple mRNA.

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Acknowledgements

The authors thank Drs G Baier, H Bujard, M Eilers, A Helmberg and SJ Korsmeyer for donating vectors, Dr H Wolf for stimulating discussions, I Jaklitsch and S Lobenwein for technical assistance and M Kat Occhipinti for editing the manuscript. Supported by grants from the Austrian Science Fund (SFB-F002 and P11964-Med) and the Austrian National Bank (Project 6156).

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  1. Reinhard Kofler: Author for correspondence

  2. Bernd L Hartmann and Stephan Geley: BL Hartmann and S Geley contributed equally to this work

Authors and Affiliations

  1. Division of Molecular Pathophysiology, Institute for General and Experimental Pathology, University of Innsbruck, Innsbruck, Austria

    Bernd L Hartmann, Stephan Geley, Markus Löffler, Rosa Hattmannstorfer, Elisabeth MC Strasser-Wozak & Reinhard Kofler

  2. Institute for Biochemistry, University of Innsbruck, Innsbruck, Austria

    Bernhard Auer

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Hartmann, B., Geley, S., Löffler, M. et al. Bcl-2 interferes with the execution phase, but not upstream events, in glucocorticoid-induced leukemia apoptosis. Oncogene 18, 713–719 (1999). https://doi.org/10.1038/sj.onc.1202339

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