title: The mechanism of micro-RNA-mediated translation repression is determined by the promoter of the target gene.
abstract: MicroRNAs (miRNAs) are noncoding RNAs that base pair imperfectly to homologous regions in target mRNAs and negatively influence the synthesis of the corresponding proteins. Repression is mediated by a number of mechanisms, one of which is the direct inhibition of protein synthesis. Surprisingly, previous studies have suggested that two mutually exclusive mechanisms exist, one acting at the initiation phase of protein synthesis and the other at a postinitiation event. Here, we resolve this apparent dichotomy by demonstrating that the promoter used to transcribe the mRNA influences the type of miRNA-mediated translational repression. Transcripts derived from the SV40 promoter that contain let-7 target sites in their 3' UTRs are repressed at the initiation stage of translation, whereas essentially identical mRNAs derived from the TK promoter are repressed at a postinitiation step. We also show that there is a miR-34 target site within the 3' UTR of c-myc mRNA and that promoter dependency is also true for this endogenous 3' UTR. Overall, these data establish a link between the nuclear history of an mRNA and the mechanism of miRNA-mediated translational regulation in the cytoplasm.
authors.affiliation: School of Pharmacy, Centre for Biomolecular Sciences, University of Nottingham, University Park, Nottingham NG7 2RD, United Kingdom.
authors.forename: Yi Wen
authors.initials: YW
authors.lastname: Kong
authors.forename: Ian G
authors.initials: IG
authors.lastname: Cannell
authors.forename: Cornelia H
authors.initials: CH
authors.lastname: de Moor
authors.forename: Kirsti
authors.initials: K
authors.lastname: Hill
authors.forename: Paul G
authors.initials: PG
authors.lastname: Garside
authors.forename: Tiffany L
authors.initials: TL
authors.lastname: Hamilton
authors.forename: Hedda A
authors.initials: HA
authors.lastname: Meijer
authors.forename: Helen C
authors.initials: HC
authors.lastname: Dobbyn
authors.forename: Mark
authors.initials: M
authors.lastname: Stoneley
authors.forename: Keith A
authors.initials: KA
authors.lastname: Spriggs
authors.forename: Anne E
authors.initials: AE
authors.lastname: Willis
authors.forename: Martin
authors.initials: M
authors.lastname: Bushell
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D001483:Base Sequence; D003513:Cycloheximide / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D008969:Molecular Sequence Data; D010442:Peptide Chain Initiation, Translational / Q000187:drug effects; D011132:Polyribosomes / Q000187:drug effects / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics*; D014176:Protein Biosynthesis / Q000187:drug effects; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; D035683:MicroRNAs; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; C487931:mirnlet7 microRNA, human; D003513:Cycloheximide