Caspase Pro-Domains and the Regulation of Apoptosis.

摘要

Apoptosis is a program of cellular suicide in which individual cells are removed from the midst of a living tissue without damaging overall tissue architecture. In recent years it has been recognized that tumor formation results not only from an increase in cellular proliferation, but also from a failure of cells to die by apoptosis. Moreover, many ohemotherapeutic agents are now believed to act through induction of apoptosis. Hence, an understanding of basic mechanisms of apoptosis should aid in the treatment of a variety of tumors. The work funded by this proposal utilized a novel cell-free assay derived from Xenopus eggs to study the biochemical mechanisms underlying apoptotic progression. Using this system we have uncovered a number of novel apoptotic regulators, as well as demonstrating that apoptosis can be inhibited at several points after initiation of a death signal. In particular, we have found that several different kinase signaling pathways can prevent induction of cell death very late in the process, after a number of important apoptotic regulators have already transited from the mitochondria to the cytoplasm. Specifically, MAP kinase pathways and the Bcr/Abl tyrosine kinase can both act to prevent processing and activation of death proteases (the caspases) even after a caspase co-activator, cytochrome c, has exited the mitochondria.