Apoptosis initiated by Bcl-2-regulated caspase activation independently of the cytochrome c/Apaf-1/caspase-9 apoptosome
Abstract
Apoptosis is an evolutionarily conserved cell suicide process executed by cysteine proteases (caspases) and regulated by the opposing factions of the Bcl-2 protein family. Mammalian caspase-9 and its activator Apaf-1 were thought to be essential, because mice lacking either of them display neuronal hyperplasia and their lymphocytes and fibroblasts seem resistant to certain apoptotic stimuli. Because Apaf-1 requires cytochrome c to activate caspase-9, and Bcl-2 prevents mitochondrial cytochrome c release, Bcl-2 is widely believed to inhibit apoptosis by safeguarding mitochondrial membrane integrity. Our results suggest a different, broader role, because Bcl-2 overexpression increased lymphocyte numbers in mice and inhibited many apoptotic stimuli, but the absence of Apaf-1 or caspase-9 did not. Caspase activity was still discernible in cells lacking Apaf-1 or caspase-9, and a potent caspase antagonist both inhibited apoptosis and retarded cytochrome c release. We conclude that Bcl-2 regulates a caspase activation programme independently of the cytochrome c/Apaf-1/caspase-9 'apoptosome', which seems to amplify rather than initiate the caspase cascade.
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Blocking post-mitochondrial caspase activation by genetic means or with specific pharmacological inhibitors (Z-VAD-fmk and Q-VD-OPh) generally delays (but does not prevent) intrinsic apoptosis in vitro and in vivo (at least in the mammalian system), as it promotes a switch to other types of RCD.
“Accordingly, blocking post-mitochondrial caspase activation by genetic means or with specific pharmacological inhibitors, such as to N-benzyloxycarbonyl-Val-Ala-Asp(O-Me) fluoromethylketone (Z-VAD-fmk) and (3S)-5-(2,6-difluorophenoxy)-3-[[(2S)-3-methyl-1-oxo-2-[(2-quinolinylcarbonyl)amino]butyl]amino]-4-oxo-pentanoic acid hydrate (Q-VD-OPh), generally delays (but does not prevent) intrinsic apopt”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [225]
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- Authors
- Marsden, V. S., O'Connor, L., O'Reilly, L. A., Silke, J., Metcalf, D., Ekert, P. G., Huang, D. C. S., Cecconi, F., Kuida, K., Tomaselli, K. J., Roy, S., Nicholson, D. W., Vaux, D. L., Bouillet, P., Adams, J. M., & Strasser, A.
- Affiliations
- Walter and Eliza Hall Institute of Medical Research (AU)
- University of Rome Tor Vergata (IT)
- Vertex Pharmaceuticals (United States) (US)
- Merck Canada Inc. (Canada) (CA)
- Corresponding author
- Strasser, Andreas
- ORCID
- Venue
- Nature
- Published
- 2002-09-25
- Volume
- 419
- Issue
- 6907
- Pages
- 634-637
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W1978093163
- Cited by
- 578
- References
- 30
- Citations by year
- 2026: 13 · 2025: 7 · 2024: 17 · 2023: 13 · 2022: 14 · 2021: 22 · 2020: 13 · 2019: 17 · 2018: 18 · 2017: 26 · 2016: 24 · 2015: 18 · 2014: 24 · 2013: 15 · 2012: 20
- FWCI
- 21.90
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Health Sciences › Medicine › Pharmacology › Flavonoids in Medical Research
- Keywords
- apoptosis, Bcl-2, caspase activation, caspase-9, Apaf-1, cytochrome c release, apoptosome, Bcl-2 family proteins, lymphocyte proliferation, mitochondrial membrane integrity
- MeSH terms
- Animals, B-Lymphocytes, Cells, Cultured, Cytochrome c Group, Enzyme Activation, Hematopoiesis, Mice, Inbred C57BL, Proteins, T-Lymphocytes, Apoptosis, Proto-Oncogene Proteins c-bcl-2, Caspases, Mice, Caspase 9, Apoptotic Protease-Activating Factor 1
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