Abstract
Apoptosis is accompanied by the activation of a number of apoptotic proteases (caspases) which selectively cleave specific cellular substrates. Caspases themselves are zymogens which are activated by proteolysis. It is widely believed that `initiator' caspases are recruited to and activated within apoptotic signalling complexes, and then cleave and activate downstream `effector' caspases. While activation of the effector caspase, caspase-3, has indeed been observed as distal to activation of several different initiator caspases, evidence for a further downstream proteolytic cascade is limited. In particular, there is little evidence that cellular levels of caspase-3 that are activated via one pathway are sufficient to cleave and activate other initiator caspases. To address this issue, the ability of caspase-3, activated upon addition to cytosolic extracts of cytochrome c, to cause cleavage of caspase-2 was investigated. It was demonstrated that cleavage of caspase-2 follows, and is dependent upon, activation of caspase-3. Moreover, the activation of both caspases was inhibited by Bcl-2. Together, these data indicate that Bcl-2 can protect cells from apoptosis by acting at a point downstream from release of mitochondrial cytochrome c, thereby preventing a caspase-3 dependent proteolytic cascade.
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Acknowledgements
This research is supported by the Medical Research Council (Grants G117/153 and G9533795MA to PGW). We are grateful to B Saulier-Le Drean for the gift of Xenopus PARP cDNA and to Stephen Green (Zeneca) for active caspase-3 and for caspase-2 cDNA.
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Swanton, E., Savory, P., Cosulich, S. et al. Bcl-2 regulates a caspase-3/caspase-2 apoptotic cascade in cytosolic extracts. Oncogene 18, 1781–1787 (1999). https://doi.org/10.1038/sj.onc.1202490
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DOI: https://doi.org/10.1038/sj.onc.1202490
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