Dissecting eIF4E action in tumorigenesis
Hans-Guido Wendel,Ricardo L.A. Silva,Abba Malina,John R. Mills,Hong Zhu,Takeshi Ueda,Rie Watanabe-Fukunaga,Rikiro Fukunaga,Julie Teruya-Feldstein,Jerry Pelletier,Scott W. Lowe +10 more
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TLDR
Insight is provided into how eIF4E contributes to tumorigenesis and a level of translational control that may be suitable for therapeutic intervention is pinpointed.Abstract:
Genetically engineered mouse models are powerful tools for studying cancer genes and validating targets for cancer therapy. We previously used a mouse lymphoma model to demonstrate that the translation initiation factor eIF4E is a potent oncogene in vivo. Using the same model, we now show that the oncogenic activity of eIF4E correlates with its ability to activate translation and become phosphorylated on Ser 209. Furthermore, constitutively activated MNK1, an eIF4E Ser 209 kinase, promotes tumorigenesis in a manner similar to eIF4E, and a dominant-negative MNK mutant inhibits the in vivo proliferation of tumor cells driven by mutations that deregulate translation. Phosphorylated eIF4E promotes tumorigenesis primarily by suppressing apoptosis and, accordingly, the anti-apoptotic protein Mcl-1 is one target of both phospho-eIF4E and MNK1 that contributes to tumor formation. Our results provide insight into how eIF4E contributes to tumorigenesis and pinpoint a level of translational control that may be suitable for therapeutic intervention.read more
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Hans-Guido Wendel,Elisa de Stanchina,Jordan S. Fridman,Jordan S. Fridman,Abba Malina,Sagarika Ray,Scott C. Kogan,Carlos Cordon-Cardo,Jerry Pelletier,Scott W. Lowe +9 more
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Malignant transformation by a eukaryotic initiation factor subunit that binds to mRNA 5' cap
TL;DR: It is reported here that overexpression of eIF-4E in NIH 3T3 and Rat 2 fibroblasts causes their tumorigenic transformation as determined by three criteria: formation of transformed foci on a monolayer of cells; anchorage-independent growth; and tumour formation in nude mice.
Journal ArticleDOI
Mitogen-activated protein kinases activate the serine/threonine kinases Mnk1 and Mnk2
Andrew J. Waskiewicz,Andrea Flynn,Christopher G. Proud,Jonathan A. Cooper,Jonathan A. Cooper +4 more
TL;DR: Mnk1 may define a convergence point between the growth factor‐activated and one of the stress‐activated protein kinase cascades and is a candidate to phosphorylate eIF‐4E in cells.