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, PKCδ 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 PKCδ 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 PKCδ in response to genotoxins. Our studies show that apoptotic signals induce rapid post-translational modification of PKCδ 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 PKCδ and generation of a constitutively activated form of PKCδ [δCF (PKCδ catalytic fragment)]. In contrast with PKCδ, δCF is constitutively present in the nucleus, and this nuclear accumulation of PKCδ is essential for apoptosis. Thus our studies suggest that tight regulation of nuclear import and of PKCδ is critical for cell survival and that caspase cleavage of PKCδ in the nucleus signals an irreversible commitment to apoptosis.

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