Apoptosis is a type of cell death carried out by intrinsic cellular machinery. This machinery is often circumvented in cancer cells, which prevents cancer cells from killing themselves and causes cancer-cell resistance to anti-cancer drugs. The biochemical mechanisms of apoptosis have just begun to be discovered. To dissect these mechanisms, we developed a cell-free system that reproduces apoptosis in vitro. This system has provided biochemical evidence that caspases, a family of highly specific and closely related cysteine proteases, plays a central role in cell execution, the terminal stage of apoptosis. The identity, function, and regulation of those caspases directly involved in apoptosis are largely unknown. Using the cell-free system, we will biochemically identify caspases directly involved in apoptosis. The regulation of these caspases will be revealed (I) by identifying the mechanisms by which they are proteolytically processed and thus activated; (ii) by identifying how their function is inhibited by viral and cellular inhibitors of their function; and (iii) by identifying changes in their subcellular localization upon activation. The function of caspases in apoptosis will be investigated by identifying and characterizing their substrates. These studies will advance our understanding of the mechanisms a cell uses to kill itself and will help determine how these mechanisms can be manipulated to selectively induce cell death.
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