title: Transcriptional induction of protein kinase C delta by p53 tumor suppressor in the apoptotic response to DNA damage.
abstract: Genetic alterations and aberrant gene expression trigger malignant tumors. Tumor suppressor p53 is the most altered gene in human cancers. p53 induces apoptosis by promoting pro-apoptotic genes in response to DNA damage. Protein kinase C delta (PKCδ) also induces apoptosis via various mechanisms including modification of p53. The PKCδ-dependent apoptotic mechanism has been extensively studied; however, the transcriptional regulation of PKCδ remains obscure. The current study demonstrates the transcriptional regulation of PKCδ by p53 upon genotoxic stress. The p53-binding site in the promoter region of PKCδ was detected by the ChIP-sequencing assay. Notably, the expression of PKCδ was increased upon DNA damage, which is required for the stabilization of p53. More importantly, targeting single guide RNA-driven dead Cas9 to the p53-binding site of PKCδ disturbed p53-promoted PKCδ expression and suppressed apoptosis following DNA damage. Thus, our findings suggest that the transcriptional regulation of PKCδ is controlled by p53 in a positive feedback mechanism to induce apoptosis in response to DNA damage.
authors.affiliation: Dept. of Biochemistry, Jikei University School of Medicine, 3-25-8, Nishi-Shinbashi, Minato-ku, Tokyo, 105-8461, Japan.
authors.forename: Nurmaa
authors.initials: N
authors.lastname: Dashzeveg
authors.affiliation: Dept. of Biochemistry, Jikei University School of Medicine, 3-25-8, Nishi-Shinbashi, Minato-ku, Tokyo, 105-8461, Japan.
authors.forename: Satomi
authors.initials: S
authors.lastname: Yogosawa
authors.affiliation: Dept. of Biochemistry, Jikei University School of Medicine, 3-25-8, Nishi-Shinbashi, Minato-ku, Tokyo, 105-8461, Japan. Electronic address: kyoshida@jikei.ac.jp.
authors.forename: Kiyotsugu
authors.initials: K
authors.lastname: Yoshida
mesh_terms: D017209:Apoptosis / Q000235:genetics; D001483:Base Sequence; D001665:Binding Sites; D045744:Cell Line, Tumor; D004249:DNA Damage; D004790:Enzyme Induction; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D057809:HEK293 Cells; D006801:Humans; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051745:Protein Kinase C-delta / Q000096:biosynthesis* / Q000235:genetics*; D015533:Transcriptional Activation; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D051745:Protein Kinase C-delta
keywords: Apoptosis; CRISPRi; DNA damage; PKCδ; Tumor suppressor; p53