Distinct regulation of p53-mediated apoptosis by protein kinase Cα, δ, ε and ζ: Evidence in yeast for transcription-dependent and -independent p53 apoptotic mechanisms

The role of individual protein kinase C (PKC) isoforms in the regulation of p53-mediated apoptosis is still uncertain. Using yeast cells co-expressing the human wild-type p53 and a single mammalian PKC alpha, delta, epsilon or zeta, we showed a differential regulation of p53-mediated apoptosis by these PKC isoforms. Whereas PKC alpha and zeta had no effect on p53 activity. PKC delta and epsilon stimulated a p53-mediated mitochondria-dependent apoptosis. Moreover, using pifithrin-alpha and -mu, selective inhibitors of p53 transcriptional activity and mitochondrial p53 translocation, respectively, we showed the activation of a transcription-dependent and -independent p53-mediated apoptosis by PKC delta and epsilon. The activation of mitochondrial p53 translocation by PKC delta and epsilon was further confirmed by immunofluorescence and Western blot analysis. Together, this work reveals the conservation in yeast of functional transcription-dependent and -independent p53 apoptotic mechanisms. Furthermore, it gives mechanistic insights about the regulation of p53-mediated apoptosis by PKC delta and epsilon through modulation of p53 transcriptional activity and of its translocation to mitochondria. Finally, it underscores a major role of PKC delta and epsilon as positive regulators of p53-mediated apoptosis, and therefore as promising therapeutic targets in cancer. (C) 2011 Elsevier Inc. All rights reserved.