Protein kinase Cdelta and apoptosis

The PKC (protein kinase C) family regulates diverse cellular functions and specific isoforms have been shown to be critical regulators of cell proliferation and survival. In particular, PKCdelta is known to be a critical pro-apoptotic signal in many cell types. Work in our laboratory has focused on understanding the molecular mechanisms through which PKCdelta regulates apoptosis and on how the pro-apoptotic activity of this ubiquitous kinase is regulated such that cells only activate the apoptotic cascade when appropriate. We have identified multiple regulatory steps that activate the pro-apoptotic function of PKCdelta in response to genotoxins. Our studies show that apoptotic signals induce rapid post-translational modification of PKCdelta in the regulatory domain, which facilitates translocation of the kinase from the cytoplasm to the nucleus. Active caspase 3 also accumulates in the nucleus under these conditions, resulting in caspase cleavage of PKCdelta and generation of a constitutively activated form of PKCdelta [deltaCF (PKCdelta catalytic fragment)]. In contrast with PKCdelta, deltaCF is constitutively present in the nucleus, and this nuclear accumulation of PKCdelta is essential for apoptosis. Thus our studies suggest that tight regulation of nuclear import and of PKCdelta is critical for cell survival and that caspase cleavage of PKCdelta in the nucleus signals an irreversible commitment to apoptosis.