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.

SUPPLEMENTAL MATERIAL

Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.01517-12.

ACKNOWLEDGMENTS

We are grateful to Imed Gallouzi (McGill University) for providing the anti-G3BP1 and to Edward Khandjian and Jean-Yves Masson (Laval University) for their gift of anti-FXR1 and anti-histone 3 antibodies, respectively. We are thankful to Anne Cammas and Sergio Di Marco (McGill University) for their helpful advice with polysomes. We also thank Yves Labelle and Richard Poulin (CRCHU) for editing the manuscript.

This work was supported by a Canadian Institute Health Research (CIHR) grant (MOP-79334) to R.C.-G. and by both CIHR grant MOP-IC093226-CBT and Canadian Foundation for Innovation grant MOP-GF091050 to R.M. R.M. is a recipient of a CIHR New Investigator Scholarship award.

We declare that no competing interests exist.