Apoptosis is a genetically programmed, morphologically distinct form of cel
l death that can be triggered by a variety of physiological and pathologica
l stimuli. Studies performed over the past 10 years have demonstrated that
proteases play critical roles in initiation and execution of this process.
The caspases, a family of cysteine-dependent aspartate-directed proteases,
are prominent among the death proteases. Caspases are synthesized as relati
vely inactive zymogens that become activated by scaffold-mediated transacti
vation or by cleavage via upstream proteases in an intracellular cascade. R
egulation of caspase activation and activity occurs at several different le
vels: (a) Zymogen gene transcription is regulated; (b) antiapoptotic member
s of the Bcl-2 family and other cellular polypeptides block proximity-induc
ed activation of certain procaspases; and (c) certain cellular inhibitor of
apoptosis proteins (cIAPs) can bind to and inhibit active caspases. Once a
ctivated, caspases cleave a variety of intracellular polypeptides, includin
g major structural elements of the cytoplasm and nucleus, components of the
DNA repair machinery, and a number of protein kinases. Collectively, these
scissions disrupt survival pathways and disassemble important architectura
l components of the cell, contributing to the stereotypic morphological and
biochemical changes that characterize apoptotic cell death.