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J. Exp. Med.,
Volume 187, Number 4, February 16, 1998 587-600
By
From the * Department of Hematology and Oncology, Clinical Sciences for Pathological Organs,
Graduate School of Medicine, Kyoto University, Kyoto 606, Japan; the Two novel synthetic tetrapeptides, VEID-CHO and DMQD-CHO, could selectively inhibit
caspase-6 and caspase-3, respectively. We used these inhibitors to dissect the pathway of caspase
activation in Fas-stimulated Jurkat cells and identify the roles of each active caspase in apoptotic
processes. Affinity labeling techniques revealed a branched protease cascade in which caspase-8
activates caspase-3 and -7, and caspase-3, in turn, activates caspase-6. Both caspase-6 and -3 have major roles in nuclear apoptosis. Caspase-6 cleaves nuclear mitotic apparatus protein
(NuMA) and mediates the shrinkage and fragmentation of nuclei. Caspase-3 cleaves NuMA at
sites distinct from caspase-6, and mediates DNA fragmentation and chromatin condensation. It
is also involved in extranuclear apoptotic events: cleavage of PAK2, formation of apoptotic
bodies, and exposure of phosphatidylserine on the cell surface. In contrast, a caspase(s) distinct
from caspase-3 or -6 mediates the disruption of mitochondrial membrane potential (permeability transition) and the shrinkage of cytoplasm. These findings demonstrate that caspases are organized in a protease cascade, and that each activated caspase plays a distinct role(s) in the execution of Fas-induced cell death.
Department of Viral
Oncology, Institute for Virus Research, Kyoto University, Kyoto 606, Japan; and the § College of
Medical Technology, Kyoto University, Kyoto 606, Japan
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