CASPASE-2 (NEDD-2) PROCESSING AND DEATH OF TROPHIC FACTOR-DEPRIVED PC12 CELLS AND SYMPATHETIC NEURONS OCCUR INDEPENDENTLY OF CASPASE-3 (CPP32)-LIKE ACTIVITY
L. Stefanis et al., CASPASE-2 (NEDD-2) PROCESSING AND DEATH OF TROPHIC FACTOR-DEPRIVED PC12 CELLS AND SYMPATHETIC NEURONS OCCUR INDEPENDENTLY OF CASPASE-3 (CPP32)-LIKE ACTIVITY, The Journal of neuroscience, 18(22), 1998, pp. 9204-9215
We have previously shown that caspase-2 (Nedd-2) is required for apopt
osis induced by withdrawal of trophic support from PC12 cells and symp
athetic neurons. Here, we examine the relationship of caspase-2 proces
sing 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 proc
essing correlated temporally with induction of caspase-3-like activity
. Agents previously shown to inhibit caspase-3-like activation, such a
s bcI-2 and the Cdk inhibitor flavopiridol, also acted upstream of cas
pase-2 processing. The general caspase inhibitors BAF and zVAD-FMK inh
ibited N-terminal caspase-2 processing. In contrast, the more selectiv
e caspase inhibitor DEVD-FMK inhibited the induction of caspase-3-like
activity but did not affect caspase-2 processing or significantly sup
press death in PC12 cells or sympathetic neurons. This indicates that
caspase3-like activity is not required for either caspase-2 processing
or apoptosis in this paradigm. An antisense oligonucleotide to caspas
e-2 inhibited cell death but did not affect caspase-3-like activity, i
ndicating that caspase-2 is not upstream of this activity and that act
ivation of caspase-3-like caspases is not sufficient for death. Thus,
in our paradigm, caspase-2 processing and caspase3-like activity are i
nduced independently of each other. Moreover, although death requires
caspase-2, caspase-3-like activity is neither necessary nor sufficient
for death.