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

Elife. 2018 Feb 7;7:e35034. doi: 10.7554/eLife.35034.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Down-Regulation*
  • Dual Specificity Phosphatase 6 / biosynthesis*
  • Eukaryotic Initiation Factor-4E
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Gene Silencing*
  • Humans
  • MAP Kinase Signaling System*
  • MicroRNAs / metabolism*
  • Protein Biosynthesis
  • RNA Cap-Binding Proteins / metabolism*
  • RNA, Messenger / metabolism


  • EIF4E2 protein, human
  • Eukaryotic Initiation Factor-4E
  • MIRN145 microRNA, human
  • MicroRNAs
  • RNA Cap-Binding Proteins
  • RNA, Messenger
  • Extracellular Signal-Regulated MAP Kinases
  • DUSP6 protein, human
  • Dual Specificity Phosphatase 6