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The Journal of Neuroscience, November 15, 1998, 18(22):9204-9215
Caspase-2 (Nedd-2) Processing and Death of Trophic Factor-Deprived PC12 Cells and Sympathetic Neurons Occur Independently of Caspase-3 (CPP32)-Like Activity
Leonidas Stefanis1, 2, Carol M. Troy1, Haiqing Qi1, Michael L. Shelanski1, and Lloyd A. Greene1 Departments of 1 Pathology and 2 Neurology, Taub Center for Alzheimer's Disease Research and Center for Neurobiology and Behavior, Columbia University College of Physicians and Surgeons, New York, New York 10032
We have previously shown that caspase-2 (Nedd-2) is required for apoptosis induced by withdrawal of trophic support from PC12 cells and sympathetic neurons. Here, we examine the relationship of caspase-2 processing and cell death to induction of caspase-3 (CPP32)-like activity in PC12 cells. Caspase-2 processing, at a site tentatively identified as D333, led to the formation of an N-terminal 37 kDa product. This processing correlated temporally with induction of caspase-3-like activity. Agents previously shown to inhibit caspase-3-like activation, such as bcl-2 and the Cdk inhibitor flavopiridol, also acted upstream of caspase-2 processing. The general caspase inhibitors BAF and zVAD-FMK inhibited N-terminal caspase-2 processing. In contrast, the more selective caspase inhibitor DEVD-FMK inhibited the induction of caspase-3-like activity but did not affect caspase-2 processing or significantly suppress death in PC12 cells or sympathetic neurons. This indicates that caspase-3-like activity is not required for either caspase-2 processing or apoptosis in this paradigm. An antisense oligonucleotide to caspase-2 inhibited cell death but did not affect caspase-3-like activity, indicating that caspase-2 is not upstream of this activity and that activation of caspase-3-like caspases is not sufficient for death. Thus, in our paradigm, caspase-2 processing and caspase-3-like activity are induced independently of each other. Moreover, although death requires caspase-2, caspase-3-like activity is neither necessary nor sufficient for death.
Key words: caspase; apoptosis; cell death; PC12; cell cycle; processing
Copyright © 1998 Society for Neuroscience 0270-6474/98/18229204-12$05.00/0
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