Abstract
Peptides corresponding to the BH3 domains of Bax (BaxBH3) or Bcl-2 (Bcl2BH3) are potent inducers of apoptosis when fused to the Atennapedia plasma membrane translocation domain (Ant). BaxBH3Ant and Bcl2BH3Ant caused a mitochondrial membrane permeabilization (MMP) and apoptosis, via a mechanism that was not inhibited by overexpressed Bcl-2 or Bcl-XL, yet partially inhibited by cyclosporin A (CsA), an inhibitor of the mitochondrial permeability transition pore. When added to isolated mitochondria, BaxBH3 and Bcl2BH3 induced MMP, which was inhibited by CsA. However, Bcl-2 or Bcl-XL failed to inhibit MMP induced by BaxBH3 and Bc2BH3 in vitro, while they efficiently suppressed the induction of MMP by the Vpr protein (from human immunodeficiency virus-1), a ligand of the adenine nucleotide translocator (ANT). BaxBH3 but not Bcl2BH3 was found to interact with ANT, and only BaxBH3 (not Bcl2BH3) permeabilized ANT proteoliposomes and induced ANT to form non-specific channels in electrophysiological experiments. In contrast, both BaxBH3 and Bcl2BH3 were able to stimulate channel formation by recombinant Bax protein. Thus, BaxBH3 might induce MMP via an action on at least two targets, ANT and Bax-like proteins. In contrast, Bcl2BH3 would elicit MMP in an ANT-independent fashion. In purified mitochondria, two ligands of ANT, bongkrekic acid and the protein vMIA from cytomegalovirus, failed to prevent MMP induced by BaxBH3 or Bcl2BH3. In conclusion, BaxBH3 and Bcl2BH3 induce MMP and apoptosis through a mechanism which overcomes cytoprotection by Bcl-2 and Bcl-XL.
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Abbreviations
- AIF:
-
apoptosis-inducing factor
- ANT:
-
adenine nucleotide translocator
- Atre:
-
etroctyloside
- BA:
-
bongkrekic acid
- COX:
-
cytochrome c oxidase
- CsA:
-
cyclosporin A
- Cyt c:
-
cytochrome c
- DiOC6(3):
-
3,3′dihexyloxacarbocyanine iodide
- δΨm:
-
mitochondral transmembrane potential
- JC-1:
-
5,5′,6,6′-tetrachloro-1,1′, 3,3′-tetraethylbenzinidazolylcarbocyanine iodide
- MMP:
-
mitochondrial membrane permeabilization
- 4-MU:
-
4-methylumbelliferone
- 4-MUP:
-
4-methylumbelliferylphosphate
- PI:
-
propidium iodide
- Rh123:
-
rhodamine 123
- STS:
-
staurosporin
- VDAC:
-
voltage-dependant anion channel
- vMIA:
-
viral mitochondrial inhibitor of apoptosis
- Vpr:
-
virel protien R
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Acknowledgements
We thank Dr John C Reed (the Burnham Institute, La Jolla, CA, USA) for recombinant Bax protein and Didier Métivier for technical assistance. This work has been supported by a special grant from the Ligue Nationale contre le Cancer, as well as grants from ANRS (to G Kroemer), ARC (to C Brenner), FRM (to G Kroemer and C Brenner), French Ministry of Sciences (to C Brenner), and the European Commission (QLG1-CT-1999-00739 to G Kroemer). HLA Vieira receives a fellowship from the Fundação para a Ciência e a Tecnologia PRAXIS XXI, Portugal; P Boya from the European Commission (MCFI-2000-00943), I Cohen and D Haouzi from the Ligue Nationale contre le Cancer, CE Hamel from the Comité Val de Marne de la Ligue contre le Cancer, A-S Belzacq from FRM.
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Vieira, H., Boya, P., Cohen, I. et al. Cell permeable BH3-peptides overcome the cytoprotective effect of Bcl-2 and Bcl-XL. Oncogene 21, 1963–1977 (2002). https://doi.org/10.1038/sj.onc.1205270
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DOI: https://doi.org/10.1038/sj.onc.1205270
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