Switching from repression to activation: microRNAs can up-regulate translation.
AU-rich elements (AREs) and microRNA target sites are conserved sequences in messenger RNA (mRNA) 3' untranslated regions (3'UTRs) that control gene expression posttranscriptionally. Upon cell cycle arrest, the ARE in tumor necrosis factor-alpha (TNFalpha) mRNA is transformed into a translation activation signal, recruiting Argonaute (AGO) and fragile X mental retardation-related protein 1 (FXR1), factors associated with micro-ribonucleoproteins (microRNPs). We show that human microRNA miR369-3 directs association of these proteins with the AREs to activate translation. Furthermore, we document that two well-studied microRNAs-Let-7 and the synthetic microRNA miRcxcr4-likewise induce translation up-regulation of target mRNAs on cell cycle arrest, yet they repress translation in proliferating cells. Thus, activation is a common function of microRNPs on cell cycle arrest. We propose that translation regulation by microRNPs oscillates between repression and activation during the cell cycle.
Vasudevan
Shobha
S
Department of Molecular Biophysics and Biochemistry, Howard Hughes Medical Institute, Yale University School of Medicine, Boyer Center for Molecular Medicine, 295 Congress Avenue, New Haven, CT 06536, USA.
Tong
Yingchun
Y
Steitz
Joan A
JA
D020413:3' Untranslated Regions; D060565:Argonaute Proteins; D020029:Base Pairing; D002453:Cell Cycle; D002460:Cell Line; D049109:Cell Proliferation; D019295:Computational Biology; D015852:Eukaryotic Initiation Factor-2 / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D025743:HMGA2 Protein / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D007399:Interphase; D035683:MicroRNAs / Q000378:metabolism*; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D012261:Ribonucleoproteins / Q000378:metabolism; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics*; D015854:Up-Regulation
D020413:3' Untranslated Regions; C466422:AGO2 protein, human; D060565:Argonaute Proteins; D015852:Eukaryotic Initiation Factor-2; C096916:FXR1 protein, human; D025743:HMGA2 Protein; D035683:MicroRNAs; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D012261:Ribonucleoproteins; D014409:Tumor Necrosis Factor-alpha; C487931:mirnlet7 microRNA, human