ArticlePloS one2011
Sensitivity of global translation to mTOR inhibition in REN cells depends on the equilibrium between eIF4E and 4E-BP1.
Article in PloS one, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 24 citations in OpenAlex.
- Exploiting Translation Machinery for Cancer Therapy: Translation Factors as Promising Targets.International journal of molecular sciences · 2024Review
- Article
- The pathogenesis of mesothelioma is driven by a dysregulated translatome.Nature communications · 2021Article
- Driver mutations of the adenoma-carcinoma sequence govern the intestinal epithelial global translational capacity.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Consideration of Binding Kinetics in the Design of Stapled Peptide Mimics of the Disordered Proteins Eukaryotic Translation Initiation Factor 4E-Binding Protein 1 and Eukaryotic Translation Initiation Factor 4G.Journal of medicinal chemistry · 2019Article
- The Translational Machinery of Human CD4Cell metabolism · 2018Article
- A Polysome-Based microRNA Screen Identifies miR-24-3p as a Novel Promigratory miRNA in Mesothelioma.Cancer research · 2018Article
- High-Throughput Chemical Probing of Full-Length Protein-Protein Interactions.ACS combinatorial science · 2017Article
- The role of eukaryotic translation initiation factor 6 in tumors.Oncology letters · 2017Article
- Article
- Icariside II, a natural mTOR inhibitor, disrupts aberrant energy homeostasis via suppressing mTORC1-4E-BP1 axis in sarcoma cells.Oncotarget · 2016Article
- Expression and activity of eIF6 trigger malignant pleural mesothelioma growth in vivo.Oncotarget · 2015Article
- Global mRNA selection mechanisms for translation initiation.Genome biology · 2015Article
- Review
- Aldose reductase inhibition suppresses colon cancer cell viability by modulating microRNA-21 mediated programmed cell death 4 (PDCD4) expression.European journal of cancer (Oxford, England : 1990) · 2013Article
- Inactivation of the mTORC1-eukaryotic translation initiation factor 4E pathway alters stress granule formation.Molecular and cellular biology · 2013Article
- Cap dependent translation contributes to resistance of myeloma cells to bortezomib.Translation (Austin, Tex.) · 2013Article
- Article
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Authors and funding
6 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Initiation is the rate-limiting phase of protein synthesis, controlled by signaling pathways regulating the phosphorylation of translation factors. Initiation has three steps, 43S, 48S and 80S formation. 43S formation is repressed by eIF2α phosphorylation. The subsequent steps, 48S and 80S formation are enabled by growth factors. 48S relies on eIF4E-mediated assembly of eIF4F complex; 4E-BPs competitively displace eIF4E from eIF4F. Two pathways control eIF4F: 1) mTORc1 phosphorylates and inactivates 4E-BPs, leading to eIF4F formation; 2) the Ras-Mnk cascade phosphorylates eIF4E. We show that REN and NCI-H28 mesothelioma cells have constitutive activation of both pathways and maximal translation rate, in the absence of exogenous growth factors. Translation is rapidly abrogated by phosphorylation of eIF2α. Surprisingly, pharmacological inhibition of mTORc1 leads to the complete dephosphorylation of downstream targets, without changes in methionine incorporation. In addition, the combined administration of mTORc1 and MAPK/Mnk inhibitors has no additive effect. The inhibition of both mTORc1 and mTORc2 does not affect the metabolic rate. In spite of this, mTORc1 inhibition reduces eIF4F complex formation, and depresses translocation of TOP mRNAs on polysomes. Downregulation of eIF4E and overexpression of 4E-BP1 induce rapamycin sensitivity, suggesting that disruption of eIF4F complex, due to eIF4E modulation, competes with its recycling to ribosomes. These data suggest the existence of a dynamic equilibrium in which eIF4F is not essential for all mRNAs and is not displaced from translated mRNAs, before recycling to the next.
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