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 δ isoform of protein kinase C (PKCδ) 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 PKCδ. This activation is triggered in part by tyrosine phosphorylation of PKCδ by c-Abl tyrosine kinase. PKCδ is further proteolytically activated by caspase-3. The cleaved catalytic fragment of PKCδ translocates to the nucleus and induces apoptosis. Importantly, accumulating data have revealed the nuclear targets for PKCδ in the induction of apoptosis. A pro-apoptotic function of activated PKCδ is mediated by at least several downstream effectors known to be associated with the elicitation of apoptosis. Recent findings also demonstrated that PKCδ is involved in cell cycle-specific activation and induction of apoptotic cell death. Moreover, previous studies have shown that PKCδ 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 PKCδ in the induction of apoptosis with significant impact. This review is focused on the current views regarding the regulation of cell fate by PKCδ signaling in response to DNA damage.