title: Coordinated regulation of cell cycle transcripts by p53-Inducible microRNAs, miR-192 and miR-215.
abstract: Cell cycle arrest in response to DNA damage is an important antitumorigenic mechanism. MicroRNAs (miRNAs) were recently shown to play key regulatory roles in cell cycle progression. For example, miR-34a is induced in response to p53 activation and mediates G(1) arrest by down-regulating multiple cell cycle-related transcripts. Here we show that genotoxic stress promotes the p53-dependent up-regulation of the homologous miRNAs miR-192 and miR-215. Like miR-34a, activation of miR-192/215 induces cell cycle arrest, suggesting that multiple miRNA families operate in the p53 network. Furthermore, we define a downstream gene expression signature for miR-192/215 expression, which includes a number of transcripts that regulate G(1) and G(2) checkpoints. Of these transcripts, 18 transcripts are direct targets of miR-192/215, and the observed cell cycle arrest likely results from a cooperative effect among the modulations of these genes by the miRNAs. Our results showing a role for miR-192/215 in cell proliferation combined with recent observations that these miRNAs are underexpressed in primary cancers support the idea that miR-192 and miR-215 function as tumor suppressors.
authors.affiliation: Rosetta Inpharmatics LLC, Seattle, Washington WA 98109, USA. sara_georges@merck.com
authors.forename: Sara A
authors.initials: SA
authors.lastname: Georges
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Biery
authors.forename: Soo-Yeon
authors.initials: SY
authors.lastname: Kim
authors.forename: Janell M
authors.initials: JM
authors.lastname: Schelter
authors.forename: Jane
authors.initials: J
authors.lastname: Guo
authors.forename: Aaron N
authors.initials: AN
authors.lastname: Chang
authors.forename: Aimee L
authors.initials: AL
authors.lastname: Jackson
authors.forename: Michael O
authors.initials: MO
authors.lastname: Carleton
authors.forename: Peter S
authors.initials: PS
authors.lastname: Linsley
authors.forename: Michele A
authors.initials: MA
authors.lastname: Cleary
authors.forename: B Nelson
authors.initials: BN
authors.lastname: Chau
mesh_terms: D002453:Cell Cycle / Q000235:genetics*; D002455:Cell Division / Q000235:genetics; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D016193:G1 Phase / Q000235:genetics; D016195:G2 Phase / Q000235:genetics; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D016158:Genes, p53; D045325:HCT116 Cells; D006801:Humans; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics*; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics*; D015854:Up-Regulation
chemical_list: D004273:DNA, Neoplasm; D035683:MicroRNAs; D012333:RNA, Messenger; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53