title: Inactivation of the mTORC1-eukaryotic translation initiation factor 4E pathway alters stress granule formation.
abstract: Stress granules (SG) are cytoplasmic multimeric RNA bodies that form under stress conditions known to inhibit cap-dependent translation. SG contain translation initiation factors, RNA binding proteins, and signaling molecules. SG are known to inhibit apoptotic pathways, thus contributing to chemo- and radioresistance in tumor cells. However, whether stress granule formation involves oncogenic signaling pathways is currently unknown. Here, we report a novel role of the mTORC1-eukaryotic translation initiation factor 4E (eIF4E) pathway, a key regulator of cap-dependent translation initiation of oncogenic factors, in SG formation. mTORC1 specifically drives the eIF4E-mediated formation of SG through the phosphorylation of 4E-BP1, a key factor known to inhibit formation of the mTORC1-dependent eIF4E-eIF4GI interactions. Disrupting formation of SG by inactivation of mTOR with its specific inhibitor pp242 or by depletion of eIF4E or eIF4GI blocks the SG-associated antiapoptotic p21 pathway. Finally, pp242 sensitizes cancer cells to death in vitro and inhibits the growth of chemoresistant tumors in vivo. This work therefore highlights a novel role of the oncogenic mTORC1-eIF4E pathway, namely, the promotion of formation of antiapoptotic SG.
authors.affiliation: Department of Molecular Biology, Laval University, Canada .
authors.forename: Marie-Josée
authors.initials: MJ
authors.lastname: Fournier
authors.forename: Laetitia
authors.initials: L
authors.lastname: Coudert
authors.forename: Samia
authors.initials: S
authors.lastname: Mellaoui
authors.forename: Pauline
authors.initials: P
authors.lastname: Adjibade
authors.forename: Cristina
authors.initials: C
authors.lastname: Gareau
authors.forename: Marie-France
authors.initials: MF
authors.lastname: Côté
authors.forename: Nahum
authors.initials: N
authors.lastname: Sonenberg
authors.forename: René C
authors.initials: RC
authors.lastname: Gaudreault
authors.forename: Rachid
authors.initials: R
authors.lastname: Mazroui
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D018797:Cell Cycle Proteins; D002642:Chick Embryo; D003594:Cytoplasmic Granules / Q000378:metabolism*; D039561:Eukaryotic Initiation Factor-4E / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D011687:Purines / Q000494:pharmacology; D011719:Pyrazines / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D001897:Boronic Acids; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D039561:Eukaryotic Initiation Factor-4E; D007211:Indoles; D046912:Multiprotein Complexes; D010750:Phosphoproteins; D011687:Purines; D011719:Pyrazines; D000069286:Bortezomib; C546842:MTOR protein, human; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; C572919:PP242
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