miRNPs: versatile regulators of gene expression in vertebrate cells.
TNFalpha (tumour necrosis factor alpha) mRNA bears in its 3'-UTR (untranslated region) a conserved ARE (AU-rich element), a signal that exerts tight post-transcriptional control over the expression of TNFalpha and other cytokines. We found that the TNFalpha ARE increases translational efficiency when cell growth is arrested, a physiologically relevant state occurring during inflammation, angiogenesis and monocyte differentiation. Under these conditions, called quiescence, the miRNP (microribonucleoprotein)-associated proteins FXR1 (Fragile X mental retardation-related protein 1) and AGO2 (Argonaute 2), which are usually considered negative regulators, are transformed into effector molecules that bind the ARE to activate translation. We then identified a specific miRNA (microRNA) that directs the association of AGO2 and FXR1 with the ARE during translational up-regulation. Two other well-characterized miRNAs likewise promote translation activation in quiescent or in contact-inhibited cells; yet, they repress translation in proliferating cells in the late S/G(2)-phase. We conclude that translational regulation by miRNPs oscillates between repression and activation as a function of the cell cycle. The activating role of miRNAs is now being confirmed in the immature Xenopus oocyte, which mimics the quiescent state.
Steitz
Joan A
JA
Department of Molecular Biophysics and Biochemistry, Howard Hughes Medical Institute, Yale University School of Medicine, BCMM, New Haven, CT 06536, USA. joan.steitz@yale.edu
Vasudevan
Shobha
S
D020413:3' Untranslated Regions; D000818:Animals; D060565:Argonaute Proteins; D002453:Cell Cycle / Q000502:physiology; D002478:Cells, Cultured; D015852:Eukaryotic Initiation Factor-2 / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D012261:Ribonucleoproteins / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D020413:3' Untranslated Regions; C466422:AGO2 protein, human; D060565:Argonaute Proteins; D015852:Eukaryotic Initiation Factor-2; C096916:FXR1 protein, human; D035683:MicroRNAs; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D012261:Ribonucleoproteins; D014409:Tumor Necrosis Factor-alpha