PKCδ signaling:: Mechanisms of DNA damage response and apoptosis

The cellular response to genotoxic stress that damages DNA includes cell cycle arrest, activation of DNA repair, and in the event of irreparable damage, induction of apoptosis. However, the signals that determine cell fate, that is, survival or apoptosis, are largely unknown. The delta isoform of protein kinase C (PKC delta) has been implicated in many important cellular processes, including regulation of apoptotic cell death. The available information supports a model in which certain sensors of DNA lesions activate PKC delta. This activation is triggered in part by tyrosine phosphorylation of PKC delta by c-Abl tyrosine kinase. PKC delta is further proteolytically activated by caspase-3. The cleaved catalytic fragment of PKC delta translocates to the nucleus and induces apoptosis. Importantly, accumulating data have revealed the nuclear targets for PKC delta in the induction of apoptosis. A pro-apoptotic function of activated PKC delta is mediated by at least several downstream effectors known to be associated with the elicitation of apoptosis. Recent findings also demonstrated that PKC delta is involved in cell cycle-specific activation and induction of apoptotic cell death. Moreover, previous studies have shown that PKC delta regulates transcription by phosphorylating various transcription factors, including the p53 tumor suppressor that is critical for cell cycle arrest and apoptosis in response to DNA damage. These findings collectively support a pivotal role for PKC delta in the induction of apoptosis with significant impact. This review is focused on the current views regarding the regulation of cell fate by PKC delta signaling in response to DNA damage. (c) 2007 Elsevier Inc. All rights reserved.