Protein kinase Cδ and apoptosis

The PKC (protein kinase C) family regulates diverse cellular functions and specific isciforms have been shown to be critical regulators of cell proliferation and survival. in particular, PKC delta 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 PKC delta 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 PKC delta in response to genotoxins. Our studies show that apoptotic signals induce rapid post-translational modification of PKC delta 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 PKC delta and generation of a constitutively activated form of PKC delta [delta CF (PKC delta catalytic fragment)]. in contrast with PUS, delta CF is constitutively present in the nucleus, and this nuclear accumulation of PKC delta is essential for apoptosis. Thus our studies suggest that tight regulation of nuclear import and of PKC delta is critical for cell survival and that caspase cleavage of PKC delta in the nucleus signals an irreversible commitment to apoptosis.