title: 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.
abstract: 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 PKCα, δ, ε or ζ, we showed a differential regulation of p53-mediated apoptosis by these PKC isoforms. Whereas PKCα and ζ had no effect on p53 activity, PKCδ 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 PKCδ and ε. The activation of mitochondrial p53 translocation by PKCδ 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 PKCδ and ε through modulation of p53 transcriptional activity and of its translocation to mitochondria. Finally, it underscores a major role of PKCδ and ε as positive regulators of p53-mediated apoptosis, and therefore as promising therapeutic targets in cancer.
authors.affiliation: Departamento de Ciências Biológicas, Universidade do Porto, Rua Aníbal Cunha, Portugal.
authors.forename: Isabel
authors.initials: I
authors.lastname: Coutinho
authors.forename: Clara
authors.initials: C
authors.lastname: Pereira
authors.forename: Gil
authors.initials: G
authors.lastname: Pereira
authors.forename: Jorge
authors.initials: J
authors.lastname: Gonçalves
authors.forename: Manuela
authors.initials: M
authors.lastname: Côrte-Real
authors.forename: Lucília
authors.initials: L
authors.lastname: Saraiva
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D052160:Benzothiazoles / Q000378:metabolism; D002417:Cattle; D015966:Gene Expression Regulation, Fungal; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D016877:Oxidants / Q000494:pharmacology; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D051571:Protein Kinase C-alpha / Q000235:genetics / Q000378:metabolism*; D051745:Protein Kinase C-delta / Q000235:genetics / Q000378:metabolism*; D051744:Protein Kinase C-epsilon / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D014050:Toluene / Q000031:analogs & derivatives / Q000378:metabolism; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D000099221:Protein Kinase C zeta
chemical_list: D052160:Benzothiazoles; D006861:Hydrogen Peroxide; D016877:Oxidants; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha; D051745:Protein Kinase C-delta; D051744:Protein Kinase C-epsilon; D017382:Reactive Oxygen Species; D014050:Toluene; D016159:Tumor Suppressor Protein p53; D000099221:Protein Kinase C zeta; C121565:pifithrin