Caspase-9 regulation: An update

The complex sequence of events leading to apoptotic cell death is governed by an elaborate regulatory scheme involving the actions of both initiator and executioner proteases. Among the most intensively studied of the initiator caspases is caspase-9, an essential throughput element in the so-called intrinsic or mitochondrially gated pathway of apoptosis. Previous reviews have described the proteolytic processing and activation of this protease in much detail; here we provide an update on caspase-9 regulation. A comprehensive description of the intra- and intermolecular events involved in modulating protein expression and activity are presented. Particular emphasis is placed on the role alternative splicing plays in the expression of functionally divergent protein isoforms, as well as, the participation of specific post-translational events in regulating caspase-9 activity. Such discrete modulation in reported activity characterizes, not only the pivotal role of this protease in the final commitment process itself, but also emphasizes the more general interplay that exists between mutually opposing cytotoxic and cytoprotective influences in maintaining cellular homeostasis.