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

eLife

Tommy Alain¹  Thomas Tuschl¹  Clément Chapat¹  Thomas F Duchaine¹  Idit Anna Gelbart¹  Meztli Arguello¹  Maayan Shapiro¹  Sung-Hoon Kim²  Nahum Sonenberg³  Geoffrey G Hesketh⁴  Edna Matta-Camacho⁴  Seyed Mehdi Jafarnejad⁴  Arkady Khoutorsky⁴  Noam Stern-Ginossar⁴  Jan Attig⁴  Anne-Claude Gingras⁴  Masahiro Morita⁵  Aitor Garzia⁶  Christos, G Gkogkas⁷ 

[1] Department of Biochemistry, McGill University, Montréal, Canada;Centre for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Canada;Department of Anesthesia, McGill University, Montréal, Canada;Goodman Cancer Research Center, McGill University, Montréal, Canada;Laboratory for RNA Molecular Biology, Howard Hughes Medical Institute, The Rockefeller University, New York, United States;The Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel;The Francis Crick Institute, London, United Kingdom;

关键词: 4EHP;    miRNA;    mRNA Translation;    CCR4-NOT;    DUSP6;    ERK;   

DOI  :  10.7554/eLife.35034

来源: DOAJ

【 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.

【 授权许可】

Unknown