Abstract
Bcl-xS, a proapoptotic member of the Bcl-2 protein family, is localized in the mitochondria and induces apoptosis in a caspase- and BH3-dependent manner by a mechanism involving cytochrome c release. The way in which Bcl-xS induces caspase activation and cytochrome c release, as well as the relationship between Bcl-xS and other proapoptotic members of the Bcl-2 family, is not known. Here we used embryonic fibroblasts derived from mice deficient in the multidomain proapoptotic members of the Bcl-2 family (Bax and Bak) and the apoptotic components of the apoptosome (Apaf-1 and caspase-9) to unravel the cascade of events by which Bcl-xS promotes apoptosis. Our results show that Bak but not Bax is essential for Bcl-xS-induced apoptosis. Bcl-xS induced activation of Bak, which in turn promoted apoptosis by apoptosome-dependent and -independent pathways. These findings provide the first evidence that a proapoptotic Bcl-2 family protein induces apoptosis exclusively via Bak.
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Abbreviations
- BH:
-
Bcl-2 homology
- DKO:
-
Bax−/− Bak−/− double knockout
- DMEM:
-
Dulbecco's modified Eagle's medium
- ER:
-
endoplasmic reticulum
- GFP:
-
green fluorescent protein
- OMM:
-
outer mitochondrial membrane
- MEF:
-
mouse embryonic fibroblast
- NT:
-
N terminus
- PBS:
-
phosphate-buffered saline
- SEAP:
-
secreted alkaline phosphatase
- WT:
-
wild type
- TBS:
-
Tris-buffered saline
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Acknowledgements
We are grateful to Ms. Shirley Smith for excellent editorial assistance. We thank Drs. S Korsmeyer, A Strasser, and T Mak for providing us with the different MEFs. This work was supported by the German–Israeli Foundation (to RS and CB) and Deutsche Forschungsgemeinschaft (BO-1933) (to CB).
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Lindenboim, L., Kringel, S., Braun, T. et al. Bak but not Bax is essential for Bcl-xS-induced apoptosis. Cell Death Differ 12, 713–723 (2005). https://doi.org/10.1038/sj.cdd.4401638
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DOI: https://doi.org/10.1038/sj.cdd.4401638
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