PMID- 17724079 OWN - NLM STAT- MEDLINE DCOM- 20071128 LR - 20211203 IS - 0270-7306 (Print) IS - 1098-5549 (Electronic) IS - 0270-7306 (Linking) VI - 27 IP - 21 DP - 2007 Nov TI - Inhibition of mammalian target of rapamycin induces phosphatidylinositol 3-kinase-dependent and Mnk-mediated eukaryotic translation initiation factor 4E phosphorylation. PG - 7405-13 AB - The initiation factor eukaryotic translation initiation factor 4E (eIF4E) plays a critical role in initiating translation of mRNAs, including those encoding oncogenic proteins. Therefore, eIF4E is considered a survival protein involved in cell cycle progression, cell transformation, and apoptotic resistance. Phosphorylation of eIF4E (usually at Ser209) increases its binding affinity for the cap of mRNA and may also favor its entry into initiation complexes. Mammalian target of rapamycin (mTOR) inhibitors suppress cap-dependent translation through inhibition of the phosphorylation of eIF4E-binding protein 1. Paradoxically, we have shown that inhibition of mTOR signaling increases eIF4E phosphorylation in human cancer cells. In this study, we focused on revealing the mechanism by which mTOR inhibition increases eIF4E phosphorylation. Silencing of either mTOR or raptor could mimic mTOR inhibitors' effects to increase eIF4E phosphorylation. Moreover, knockdown of mTOR, but not rictor or p70S6K, abrogated rapamycin's ability to increase eIF4E phosphorylation. These results indicate that mTOR inhibitor-induced eIF4E phosphorylation is secondary to mTOR/raptor inhibition and independent of p70S6K. Importantly, mTOR inhibitors lost their ability to increase eIF4E phosphorylation only in cells where both Mnk1 and Mnk2 were knocked out, indicating that mTOR inhibitors increase eIF4E phosphorylation through a Mnk-dependent mechanism. Given that mTOR inhibitors failed to increase Mnk and eIF4E phosphorylation in phosphatidylinositol 3-kinase (PI3K)-deficient cells, we conclude that mTOR inhibition increases eIF4E phosphorylation through a PI3K-dependent and Mnk-mediated mechanism. In addition, we also suggest an effective therapeutic strategy for enhancing mTOR-targeted cancer therapy by cotargeting mTOR signaling and Mnk/eIF4E phosphorylation. FAU - Wang, Xuerong AU - Wang X AD - Department of Haematology, Emory University School of Medicine, 1365-C Clifton Road, C3088, Atlanta, GA 30322, USA. FAU - Yue, Ping AU - Yue P FAU - Chan, Chi-Bun AU - Chan CB FAU - Ye, Keqiang AU - Ye K FAU - Ueda, Takeshi AU - Ueda T FAU - Watanabe-Fukunaga, Rie AU - Watanabe-Fukunaga R FAU - Fukunaga, Rikiro AU - Fukunaga R FAU - Fu, Haian AU - Fu H FAU - Khuri, Fadlo R AU - Khuri FR FAU - Sun, Shi-Yong AU - Sun SY LA - eng GR - R01 CA118450/CA/NCI NIH HHS/United States GR - R01 CA118450-01/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20070827 PL - United States TA - Mol Cell Biol JT - Molecular and cellular biology JID - 8109087 RN - 0 (Adaptor Proteins, Signal Transducing) RN - 0 (Eukaryotic Initiation Factor-4E) RN - 0 (IRS1 protein, human) RN - 0 (Insulin Receptor Substrate Proteins) RN - 0 (Intracellular Signaling Peptides and Proteins) RN - 0 (Irs1 protein, mouse) RN - 0 (Phosphoproteins) RN - 0 (Proteins) RN - 0 (RPTOR protein, human) RN - 0 (Regulatory-Associated Protein of mTOR) RN - 67763-96-6 (Insulin-Like Growth Factor I) RN - EC 2.7.- (Protein Kinases) RN - EC 2.7.1.- (MKNK1 protein, human) RN - EC 2.7.1.- (Mknk1 protein, mouse) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.1.1 (mTOR protein, mouse) RN - EC 2.7.10.1 (Receptor, IGF Type 1) RN - EC 2.7.11.1 (Protein Serine-Threonine Kinases) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - W36ZG6FT64 (Sirolimus) SB - IM MH - Adaptor Proteins, Signal Transducing MH - Animals MH - Cell Line, Tumor MH - Enzyme Activation/drug effects MH - Enzyme Induction/drug effects MH - Eukaryotic Initiation Factor-4E/*metabolism MH - Humans MH - Insulin Receptor Substrate Proteins MH - Insulin-Like Growth Factor I/metabolism MH - Intracellular Signaling Peptides and Proteins/*metabolism MH - Mice MH - Models, Biological MH - Neoplasms/enzymology/pathology MH - Phosphatidylinositol 3-Kinases/*biosynthesis MH - Phosphoproteins/metabolism MH - Phosphorylation/drug effects MH - Protein Kinases/*metabolism MH - Protein Serine-Threonine Kinases/*metabolism MH - Proteins/metabolism MH - Proto-Oncogene Proteins c-akt/metabolism MH - Receptor, IGF Type 1/metabolism MH - Regulatory-Associated Protein of mTOR MH - Sirolimus/pharmacology MH - TOR Serine-Threonine Kinases PMC - PMC2169067 EDAT- 2007/08/29 09:00 MHDA- 2007/12/06 09:00 PMCR- 2008/03/01 CRDT- 2007/08/29 09:00 PHST- 2007/08/29 09:00 [pubmed] PHST- 2007/12/06 09:00 [medline] PHST- 2007/08/29 09:00 [entrez] PHST- 2008/03/01 00:00 [pmc-release] AID - MCB.00760-07 [pii] AID - 0760-07 [pii] AID - 10.1128/MCB.00760-07 [doi] PST - ppublish SO - Mol Cell Biol. 2007 Nov;27(21):7405-13. doi: 10.1128/MCB.00760-07. Epub 2007 Aug 27.