The Francis Crick Institute, London, United Kingdom
Maayan Shapiro
Goodman Cancer Research Center, McGill University, Montréal, Canada; Department of Biochemistry, McGill University, Montréal, Canada
Masahiro Morita
Goodman Cancer Research Center, McGill University, Montréal, Canada; Department of Biochemistry, McGill University, Montréal, Canada
Arkady Khoutorsky
Department of Anesthesia, McGill University, Montréal, Canada; Alan Edwards Centre for Research on Pain, McGill University, Montréal, Canada
Tommy Alain
Children’s Hospital of Eastern Ontario Research Institute, Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Canada
The Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel
Thomas Tuschl
Laboratory for RNA Molecular Biology, Howard Hughes Medical Institute, The Rockefeller University, New York, United States
Anne-Claude Gingras
Centre for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Canada; Department of Molecular Genetics, University of Toronto, Toronto, Canada
Thomas F Duchaine
Goodman Cancer Research Center, McGill University, Montréal, Canada; Department of Biochemistry, McGill University, Montréal, Canada
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.
