title: Tumor suppressor miR-22 determines p53-dependent cellular fate through post-transcriptional regulation of p21.
abstract: Selective activation of p53 target genes in response to various cellular stresses is a critical step in determining the ability to induce cell-cycle arrest or apoptosis. Here we report the identification of the microRNA miR-22 as a p53 target gene that selectively determines the induction of p53-dependent apoptosis by repressing p21. Combinatorial analyses of the AGO2 immunocomplex and gene expression profiles identified p21 as a direct target of miR-22. Induction of p21 was inhibited by miR-22 after exposure to the genotoxic agent Adriamycin (doxorubicin; Bedford Laboratories), sensitizing cells to p53-dependent apoptosis. Interestingly, the activation of miR-22 depended on the intensity of the stresses that induced cells to undergo apoptosis in the presence of p21 suppression. Our findings define an intrinsic molecular switch that determines p53-dependent cellular fate through post-transcriptional regulation of p21.
authors.affiliation: Division of Cancer Development System and Cancer Differentiation, National Cancer Center Research Institute, Tsukiji, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Tsuchiya
authors.forename: Masashi
authors.initials: M
authors.lastname: Izumiya
authors.forename: Hiroko
authors.initials: H
authors.lastname: Ogata-Kawata
authors.forename: Koji
authors.initials: K
authors.lastname: Okamoto
authors.forename: Yuko
authors.initials: Y
authors.lastname: Fujiwara
authors.forename: Makiko
authors.initials: M
authors.lastname: Nakai
authors.forename: Atsushi
authors.initials: A
authors.lastname: Okabe
authors.forename: Aaron J
authors.initials: AJ
authors.lastname: Schetter
authors.forename: Elise D
authors.initials: ED
authors.lastname: Bowman
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Midorikawa
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Sugiyama
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Aburatani
authors.forename: Curtis C
authors.initials: CC
authors.lastname: Harris
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Nakagama
mesh_terms: D017209:Apoptosis / Q000235:genetics; D001483:Base Sequence; D003110:Colonic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis / Q000235:genetics*; D016147:Genes, Tumor Suppressor; D023281:Genomics / Q000379:methods; D045325:HCT116 Cells; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D008969:Molecular Sequence Data; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C548375:MIRN22 microRNA, human; D035683:MicroRNAs; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53