Translational control of ERK signaling through miRNA/4EHP-directed silencing
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 g...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
eLife Sciences Publications Ltd
2018-02-01
|
| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/35034 |
| id |
doaj-bfdd543ac6d44c1295839d61e81be1b1 |
|---|---|
| record_format |
Article |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Seyed Mehdi Jafarnejad Clément Chapat Edna Matta-Camacho Idit Anna Gelbart Geoffrey G Hesketh Meztli Arguello Aitor Garzia Sung-Hoon Kim Jan Attig Maayan Shapiro Masahiro Morita Arkady Khoutorsky Tommy Alain Christos, G Gkogkas Noam Stern-Ginossar Thomas Tuschl Anne-Claude Gingras Thomas F Duchaine Nahum Sonenberg |
| spellingShingle |
Seyed Mehdi Jafarnejad Clément Chapat Edna Matta-Camacho Idit Anna Gelbart Geoffrey G Hesketh Meztli Arguello Aitor Garzia Sung-Hoon Kim Jan Attig Maayan Shapiro Masahiro Morita Arkady Khoutorsky Tommy Alain Christos, G Gkogkas Noam Stern-Ginossar Thomas Tuschl Anne-Claude Gingras Thomas F Duchaine Nahum Sonenberg Translational control of ERK signaling through miRNA/4EHP-directed silencing eLife 4EHP miRNA mRNA Translation CCR4-NOT DUSP6 ERK |
| author_facet |
Seyed Mehdi Jafarnejad Clément Chapat Edna Matta-Camacho Idit Anna Gelbart Geoffrey G Hesketh Meztli Arguello Aitor Garzia Sung-Hoon Kim Jan Attig Maayan Shapiro Masahiro Morita Arkady Khoutorsky Tommy Alain Christos, G Gkogkas Noam Stern-Ginossar Thomas Tuschl Anne-Claude Gingras Thomas F Duchaine Nahum Sonenberg |
| author_sort |
Seyed Mehdi Jafarnejad |
| title |
Translational control of ERK signaling through miRNA/4EHP-directed silencing |
| title_short |
Translational control of ERK signaling through miRNA/4EHP-directed silencing |
| title_full |
Translational control of ERK signaling through miRNA/4EHP-directed silencing |
| title_fullStr |
Translational control of ERK signaling through miRNA/4EHP-directed silencing |
| title_full_unstemmed |
Translational control of ERK signaling through miRNA/4EHP-directed silencing |
| title_sort |
translational control of erk signaling through mirna/4ehp-directed silencing |
| publisher |
eLife Sciences Publications Ltd |
| series |
eLife |
| issn |
2050-084X |
| publishDate |
2018-02-01 |
| description |
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. |
| topic |
4EHP miRNA mRNA Translation CCR4-NOT DUSP6 ERK |
| url |
https://elifesciences.org/articles/35034 |
| work_keys_str_mv |
AT seyedmehdijafarnejad translationalcontroloferksignalingthroughmirna4ehpdirectedsilencing AT clementchapat translationalcontroloferksignalingthroughmirna4ehpdirectedsilencing AT ednamattacamacho translationalcontroloferksignalingthroughmirna4ehpdirectedsilencing AT iditannagelbart translationalcontroloferksignalingthroughmirna4ehpdirectedsilencing AT geoffreyghesketh translationalcontroloferksignalingthroughmirna4ehpdirectedsilencing AT meztliarguello translationalcontroloferksignalingthroughmirna4ehpdirectedsilencing AT aitorgarzia translationalcontroloferksignalingthroughmirna4ehpdirectedsilencing AT sunghoonkim translationalcontroloferksignalingthroughmirna4ehpdirectedsilencing AT janattig translationalcontroloferksignalingthroughmirna4ehpdirectedsilencing AT maayanshapiro translationalcontroloferksignalingthroughmirna4ehpdirectedsilencing AT masahiromorita translationalcontroloferksignalingthroughmirna4ehpdirectedsilencing AT arkadykhoutorsky translationalcontroloferksignalingthroughmirna4ehpdirectedsilencing AT tommyalain translationalcontroloferksignalingthroughmirna4ehpdirectedsilencing AT christosggkogkas translationalcontroloferksignalingthroughmirna4ehpdirectedsilencing AT noamsternginossar translationalcontroloferksignalingthroughmirna4ehpdirectedsilencing AT thomastuschl translationalcontroloferksignalingthroughmirna4ehpdirectedsilencing AT anneclaudegingras translationalcontroloferksignalingthroughmirna4ehpdirectedsilencing AT thomasfduchaine translationalcontroloferksignalingthroughmirna4ehpdirectedsilencing AT nahumsonenberg translationalcontroloferksignalingthroughmirna4ehpdirectedsilencing |
| _version_ |
1721459947774935040 |
| spelling |
doaj-bfdd543ac6d44c1295839d61e81be1b12021-05-05T15:35:26ZengeLife Sciences Publications LtdeLife2050-084X2018-02-01710.7554/eLife.35034Translational control of ERK signaling through miRNA/4EHP-directed silencingSeyed Mehdi Jafarnejad0https://orcid.org/0000-0002-5129-7081Clément Chapat1https://orcid.org/0000-0002-5806-7959Edna Matta-Camacho2Idit Anna Gelbart3Geoffrey G Hesketh4Meztli Arguello5Aitor Garzia6Sung-Hoon Kim7Jan Attig8https://orcid.org/0000-0002-2159-2880Maayan Shapiro9Masahiro Morita10Arkady Khoutorsky11Tommy Alain12Christos, G Gkogkas13https://orcid.org/0000-0001-6281-3419Noam Stern-Ginossar14https://orcid.org/0000-0003-3583-5932Thomas Tuschl15Anne-Claude Gingras16Thomas F Duchaine17Nahum Sonenberg18https://orcid.org/0000-0002-4707-8759Goodman Cancer Research Center, McGill University, Montréal, Canada; Department of Biochemistry, McGill University, Montréal, CanadaGoodman Cancer Research Center, McGill University, Montréal, Canada; Department of Biochemistry, McGill University, Montréal, CanadaGoodman Cancer Research Center, McGill University, Montréal, Canada; Department of Biochemistry, McGill University, Montréal, CanadaThe Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, IsraelCentre for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, CanadaGoodman Cancer Research Center, McGill University, Montréal, Canada; Department of Biochemistry, McGill University, Montréal, CanadaLaboratory for RNA Molecular Biology, Howard Hughes Medical Institute, The Rockefeller University, New York, United StatesGoodman Cancer Research Center, McGill University, Montréal, Canada; Department of Biochemistry, McGill University, Montréal, CanadaThe Francis Crick Institute, London, United KingdomGoodman Cancer Research Center, McGill University, Montréal, Canada; Department of Biochemistry, McGill University, Montréal, CanadaGoodman Cancer Research Center, McGill University, Montréal, Canada; Department of Biochemistry, McGill University, Montréal, CanadaDepartment of Anesthesia, McGill University, Montréal, Canada; Alan Edwards Centre for Research on Pain, McGill University, Montréal, CanadaChildren’s Hospital of Eastern Ontario Research Institute, Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, CanadaPatrick Wild Centre, Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, United KingdomThe Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, IsraelLaboratory for RNA Molecular Biology, Howard Hughes Medical Institute, The Rockefeller University, New York, United StatesCentre for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Canada; Department of Molecular Genetics, University of Toronto, Toronto, CanadaGoodman Cancer Research Center, McGill University, Montréal, Canada; Department of Biochemistry, McGill University, Montréal, CanadaGoodman Cancer Research Center, McGill University, Montréal, Canada; Department of Biochemistry, McGill University, Montréal, CanadaMicroRNAs (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.https://elifesciences.org/articles/350344EHPmiRNAmRNA TranslationCCR4-NOTDUSP6ERK |