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

Elife. 2018 Feb 07;7
Seyed Mehdi Jafarnejad 1 , Clément Chapat 1 , Edna Matta-Camacho 1 , Idit Anna Gelbart 2 , Geoffrey G Hesketh 3 , Meztli Arguello 1 , Aitor Garzia 4 , Sung-Hoon Kim 1 , Jan Attig 5 , Maayan Shapiro 1 , Masahiro Morita 1 , Arkady Khoutorsky 6 , Tommy Alain 7 , Christos G Gkogkas 8 , Noam Stern-Ginossar 2 , Thomas Tuschl 4 , Anne-Claude Gingras 9 , Thomas F Duchaine 1 , Nahum Sonenberg 1
Seyed Mehdi Jafarnejad 1 , Clément Chapat 1 , Edna Matta-Camacho 1 , Idit Anna Gelbart 2 , Geoffrey G Hesketh 3 , Meztli Arguello 1 , Aitor Garzia 4 , Sung-Hoon Kim 1 , Jan Attig 5 , Maayan Shapiro 1 , Masahiro Morita 1 , Arkady Khoutorsky 6 , Tommy Alain 7 , Christos G Gkogkas 8 , Noam Stern-Ginossar 2 , Thomas Tuschl 4 , Anne-Claude Gingras 9 , Thomas F Duchaine 1 , Nahum Sonenberg 1
+ et al

[No authors listed]

Author information
  • 1 Department of Biochemistry, McGill University, Montréal, Canada.
  • 2 The Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
  • 3 Centre for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Canada.
  • 4 Laboratory for RNA Molecular Biology, Howard Hughes Medical Institute, The Rockefeller University, New York, United States.
  • 5 The Francis Crick Institute, London, United Kingdom.
  • 6 Alan Edwards Centre for Research on Pain, McGill University, Montréal, Canada.
  • 7 Children's Hospital of Eastern Ontario Research Institute, Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Canada.
  • 8 Patrick Wild Centre, Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom.
  • 9 Department of Molecular Genetics, University of Toronto, Toronto, Canada.

摘要

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.

KEYWORDS: 4EHP, CCR4-NOT, DUSP6, ERK, biochemistry, cell biology, chemical biology, human, mRNA Translation, miRNA, mouse

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