Role of the Akt pathway in mRNA translation of interferon-stimulated genes

Type I interferon (IFN)-dependent activation of Mnk1 and its role in the generation of growth inhibitory responses

“…Work from others has also implicated mTOR in the regulation of IFN-induced apoptosis (10), while in recent studies using cells with targeted deletion of both the Akt1 and Akt2 genes, we established Akt as a critical element of the IFN-signaling pathway required for engagement of mTOR and for mRNA translation of IFN-regulated genes (12,25). Together, the emerging evidence points toward an essential role for mTOR and its effectors in the generation of the biological effects of IFNs.…”

“…One event apparently involves IFN-dependent hierarchical phosphorylation of the translational repressor 4E-BP1 that results in its dissociation from eIF4E (9,11,12); while a second event involves Mnk-dependent phosphorylation of eIF4E on serine 209. Notably, in previous studies we have shown an important regulatory role for the PI 3ЈK/mTOR pathway in the regulation of Isg15 mRNA translation (11,12,26), consistent with the hypothesis that coordinated function of both MAPK pathways regulating eIF4E phosphorylation and mTOR pathways are required for optimal mRNA translation of ISGs. However, it is also possible that additional kinases beyond Mnk regulate IFN-dependent eIF4E phosphorylation in different cell types, and that only a selected group of ISGs is regulated by this pathway.…”

“…However, beyond the classic Jak-Stat pathways, there is evidence that IFNs activate several other signaling cascades, including the mTOR-regulated (8)(9)(10)(11)(12) and mitogen-activated protein kinase (MAPK) signaling cascades (13)(14)(15). Such non-Stat pathways play important roles in the induction of IFN-responses, via their ability to promote optimal IFN-dependent gene transcription (13) or mRNA translation of ISGs (12). Among the different MAPK pathways engaged by IFNs, signals generated by the p38 MAPK have been implicated in the generation of growth inhibitory responses by type I IFNs (14,15).…”

Stat1 stimulates cap-independent mRNA translation to inhibit cell proliferation and promote survival in response to antitumor drugs

“…eIF4F activity is enhanced in tumor cells due to increased eIF4E expression and/or phosphorylation at S209 (24). Cells respond to IFNs by increasing PI3K signaling, leading to increased phosphorylation of 4EBPs and stimulation of capdependent translation of mRNAs transcriptionally induced by Jak-Stat activation (25)(26)(27). Herein, we demonstrate that Stat1 acts independent of IFNs to induce PI3K signaling by facilitating the expression of the p110γ catalytic subunit of PI3K class IB at the transcriptional level.…”

1 Dual regulatory roles of the phosphatidylinositol 3-kinase in interferon signaling

“…Cells were treated with the indicated IFNs for the indicated times, and lysed in phosphorylation lysis buffer (PLB) supplemented with PMSF, aprotinin and orthovanadate, as previously described (25,26,28). Equal protein aliquots were resolved by SDS PAGE and immunoblotting using an enhanced chemiluminescence (ECL) method was performed as in our previous studies (24)(25)(26)28).…”