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Dissecting eIF4E action in tumorigenesis
Open accessAbstract
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.
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Efficient translation of MCL-1 mRNA requires cap-dependent translation in some cancers.
“Previous studies had demonstrated that efficient translation of MCL-1 mRNA requires cap-dependent translation in some cancers (36–38).”
From mTOR Inhibition Specifically Sensitizes Colorectal Cancers with KRAS or BRAF Mutations to BCL-2/BCL-XL Inhibition by Suppressing MCL-1 (2014) · cites this paper as [36]
The Results and Discussion report that eIF4E and MNK1 increase Mcl-1 translation in the authors’ model and that phosphorylated eIF4E correlates with MCL-1 in human lymphomas. The paper connects eIF4E phosphorylation with cap-dependent translation, but it does not establish that efficient MCL-1 translation requires cap-dependent translation in those cancers. (LLM, conf=0.84)
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Research works printed but not linked: 1
- Mamane, Y., Petroulakis, E., Martineau, Y., Sato, T.A., Larsson, O., Ra- jasekhar, V.K., and Sonenberg, N. 2007. Epigenetic activation of a subset of mRNAs by eIF4E explains its effects on cell proliferation. PLoS ONE 2: e242. doi: 10.1371/journal.pone.0000242. · DOI
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Metadata
- Authors
- Wendel, H.-G., Silva, R. L. A., Malina, A., Mills, J. R., Zhu, H., Ueda, T., Watanabe-Fukunaga, R., Fukunaga, R., Teruya-Feldstein, J., Pelletier, J., & Lowe, S. W.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- The University of Osaka (JP)
- Howard Hughes Medical Institute (US)
- ORCID
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2007-11-30
- Volume
- 21
- Issue
- 24
- Pages
- 000.2-000
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC2113024
- OpenAlex
- W2132519593
- Cited by
- 487
- References
- 0
- Citations by year
- 2026: 12 · 2025: 10 · 2024: 17 · 2023: 21 · 2022: 19 · 2021: 22 · 2020: 22 · 2019: 23 · 2018: 31 · 2017: 26 · 2016: 31 · 2015: 36 · 2014: 44 · 2013: 31 · 2012: 26
- Type
- posted content
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- other-oa
- Locations
- Genes & Development (publishedVersion, other-oa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- Leukemia and Lymphoma Society
- Cold Spring Harbor Laboratory
- National Cancer Institute (P01CA087497, P01CA013106, P30CA008748)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- eIF4E, carcinogenesis, MNK1, translation initiation, oncogenic translation, mouse lymphoma model, apoptosis inhibition, Mcl-1, translational regulation, cancer therapy targets
- MeSH terms
- Animals, Base Sequence, Cell Transformation, Neoplastic, Cells, Cultured, Flow Cytometry, Mice, Transgenic, Neoplasm Proteins, Phosphorylation, Blotting, Western, Protein Serine-Threonine Kinases, DNA Primers, Proto-Oncogene Proteins c-bcl-2, Eukaryotic Initiation Factor-4E, Mice, Myeloid Cell Leukemia Sequence 1 Protein
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