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 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 δ, ε or ζ, we showed a differential regulation of p53-mediated apoptosis by these isoforms. Whereas and ζ had no effect on p53 activity, and ε stimulated a p53-mediated mitochondria-dependent apoptosis. Moreover, using pifithrin-α and -μ, 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 duanyu1531δ and ε. The activation of mitochondrial p53 translocation by duanyu1531δ and ε 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 duanyu1531δ and ε through modulation of p53 transcriptional activity and of its translocation to mitochondria. Finally, it underscores a major role of duanyu1531δ and ε as positive regulators of p53-mediated apoptosis, and therefore as promising therapeutic targets in cancer.

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