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BH3-only protein BIK induces caspase-independent cell death with autophagic features in Bcl-2 null cells

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Abstract

The BH3-only protein BIK normally induces apoptotic cell death. Here, we have investigated the role of BCL-2 in BIK-induced cell death using Bcl-2+/+ and Bcl-2−/− mouse embryo fibroblasts. Ectopic expression of BIK in Bcl-2−/− cells resulted in enhanced cell death compared to Bcl-2+/+ cells. In these cells, while caspase-8 was activated, there was no significant activation of caspase-9 and 3. There was no detectable mitochondrial to cytosolic release of cytochrome-c. However, there was significant redistribution of AIF from mitochondria to the nucleus. The extent of BIK-induced cell death was augmented by treatment with the pancaspase inhibitor, zVAD-fmk. The Bcl-2 null cells expressing BIK exhibited autophagic features such as cytosolic vacuoles, punctate distribution of LC3 and enhanced expression of Beclin-1. The survival of BIK-expressing Bcl-2−/− cells was enhanced in the presence of PI3 kinase inhibitors 3-methyladenine and Wortmannin and also by depletion of Atg5 and Beclin-1. Death of BIK-expressing Bcl-2−/− cells treated with zVAD-fmk was increased under caspase-8 depletion. Our results suggest enhanced expression of BIK in the Bcl-2 deficient cells leads to cell death with autophagic features and the extent of such cell death could be increased by inhibition of caspases.

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Acknowledgements

This work was supported by research grants CA-73803, CA-116262 and CA-33616 from the National Cancer Institute. The MEF cells were kindly provided by late Stanley Korsmeyer.

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  1. R Rashmi and S G Pillai: These authors have contributed equally to this work.

Authors and Affiliations

  1. Institute for Molecular Virology, Saint Louis University Health Sciences Center, St Louis, MO, USA

    R Rashmi, S G Pillai, S Vijayalingam & G Chinnadurai

  2. Department of Pathology, Saint Louis University Health Sciences Center, St Louis, MO, USA

    J Ryerse

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  1. R Rashmi
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  2. S G Pillai
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  3. S Vijayalingam
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  4. J Ryerse
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  5. G Chinnadurai
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Correspondence to G Chinnadurai.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Rashmi, R., Pillai, S., Vijayalingam, S. et al. BH3-only protein BIK induces caspase-independent cell death with autophagic features in Bcl-2 null cells. Oncogene 27, 1366–1375 (2008). https://doi.org/10.1038/sj.onc.1210783

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  • DOI: https://doi.org/10.1038/sj.onc.1210783

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