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Translational control of ERK signaling through miRNA/4EHP-directed silencing.

Seyed Mehdi JafarnejadClément ChapatEdna Matta-CamachoIdit Anna GelbartGeoffrey G HeskethMeztli ArguelloAitor GarziaSung-Hoon KimJan AttigMaayan ShapiroMasahiro MoritaArkady KhoutorskyTommy AlainChristos G GkogkasNoam Stern-GinossarThomas TuschlAnne-Claude GingrasThomas F DuchaineNahum Sonenberg
Published in: eLife (2018)
MicroRNAs (miRNAs) exert a broad influence over gene expression by directing effector activities that impinge on translation and stability of mRNAs. We recently discovered that the cap-binding protein 4EHP is a key component of the mammalian miRNA-Induced Silencing Complex (miRISC), which mediates gene silencing. However, little is known about the mRNA repertoire that is controlled by the 4EHP/miRNA mechanism or its biological importance. Here, using ribosome profiling, we identify a subset of mRNAs that are translationally controlled by 4EHP. We show that the Dusp6 mRNA, which encodes an ERK1/2 phosphatase, is translationally repressed by 4EHP and a specific miRNA, miR-145. This promotes ERK1/2 phosphorylation, resulting in augmented cell growth and reduced apoptosis. Our findings thus empirically define the integral role of translational repression in miRNA-induced gene silencing and reveal a critical function for this process in the control of the ERK signaling cascade in mammalian cells.
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