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From the * Palo Alto Institute of Molecular Medicine, Mountain View, California 94043;
and The 24-kD apoptotic protease (AP24) is a serine protease that is activated during apoptosis and
has the capacity to activate internucleosomal DNA fragmentation in isolated nuclei. This study examined the following: (a) the functional relationship between AP24 and the CPP32-like
proteases of the caspase family; and (b) whether activation of CPP32-like proteases is sufficient
to commit irreversibly a cell to apoptotic death. In three different leukemia cell lines, we
showed that agents that directly (carbobenzoxy-Ala-Ala-borophe (DK120) or indirectly inhibit
activation of AP24 (protein kinase inhibitors, basic fibroblast growth factor, tosylphenylalaninechloromethylketone, and caspase inhibitors) protected cells from apoptosis induced by TNF or
UV light. Only the caspase inhibitors, however, prevented activation of CPP32-like activity as
revealed by cleavage of the synthetic substrate, DEVD-pNa, by cell cytosols, and also by in vivo cleavage of poly (ADP-ribosyl) polymerase, a known substrate of CPP32. Activation of
DEVD-pNa cleaving activity without apoptosis was also demonstrated in two variants derived
from the U937 monocytic leukemia in the absence of exogenous inhibitors. Cell-permeable peptide inhibitors selective for CPP32-like proteases suppressed AP24 activation and apoptotic
death. These findings indicate that CPP32-like activity is one of several upstream signals required for AP24 activation. Furthermore, activation of CPP32-like proteases alone is not sufficient to commit irreversibly a cell to apoptotic death under conditions where activation of
AP24 is inhibited.
College of Pharmacy, Ohio Northern University, Ada, Ohio 45810
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