Differential Requirements for eIF4E Dose in Normal Development and Cancer

Truitt, Morgan; Conn, Crystal S.; Shi, Zhen; Pang, Xiaming; Tokuyasu, Taku A.; Coady, Alison; Seo, Youngho; Barna, Maria; Ruggero, Davide

doi:10.1016/j.cell.2015.05.049

Cited by 300 publications

(350 citation statements)

References 46 publications

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“…Cold Spring Harbor Laboratory Press on April 27, 2019 -Published by genome.cshlp.org Downloaded from EIF4E predominantly affects translation of non-TOP mRNAs implicated in ROS clearance using polysome-profiling (Truitt et al 2015).…”

Section: Discussionmentioning

confidence: 99%

nanoCAGE reveals 5′ UTR features that define specific modes of translation of functionally related MTOR-sensitive mRNAs

et al. 2016

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The diversity of MTOR-regulated mRNA translation remains unresolved. Whereas ribosome-profiling suggested that MTOR almost exclusively stimulates translation of the TOP (terminal oligopyrimidine motif) and TOP-like mRNAs, polysome-profiling indicated that MTOR also modulates translation of mRNAs without the 5′ TOP motif (non-TOP mRNAs). We demonstrate that in ribosome-profiling studies, detection of MTOR-dependent changes in non-TOP mRNA translation was obscured by low sensitivity and methodology biases. Transcription start site profiling using nano-cap analysis of gene expression (nanoCAGE) revealed that not only do many MTOR-sensitive mRNAs lack the 5′ TOP motif but that 5′ UTR features distinguish two functionally and translationally distinct subsets of MTOR-sensitive mRNAs: (1) mRNAs with short 5′ UTRs enriched for mitochondrial functions, which require EIF4E but are less EIF4A1-sensitive; and (2) long 5′ UTR mRNAs encoding proliferation- and survival-promoting proteins, which are both EIF4E- and EIF4A1-sensitive. Selective inhibition of translation of mRNAs harboring long 5′ UTRs via EIF4A1 suppression leads to sustained expression of proteins involved in respiration but concomitant loss of those protecting mitochondrial structural integrity, resulting in apoptosis. Conversely, simultaneous suppression of translation of both long and short 5′ UTR mRNAs by MTOR inhibitors results in metabolic dormancy and a predominantly cytostatic effect. Thus, 5′ UTR features define different modes of MTOR-sensitive translation of functionally distinct subsets of mRNAs, which may explain the diverse impact of MTOR and EIF4A inhibitors on neoplastic cells.

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Section: Discussionmentioning

confidence: 99%

nanoCAGE reveals 5′ UTR features that define specific modes of translation of functionally related MTOR-sensitive mRNAs

et al. 2016

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“…Malignant cells exhibit altered translational programming that is characterized by augmented activity of many components of the translation machinery, leading to increased overall protein synthesis and modulation of specific oncogenic networks [46]. This was shown, for example, in mice engineered to carry only a single copy of the translation initiation factor eIF4E gene [47]. These mice develop normally and show a functional translation machinery at basal.…”

Section: Discussionmentioning

confidence: 99%

“…These mice develop normally and show a functional translation machinery at basal. However, oncogenic transformation and tumorigenesis were affected by decreased eIF4E levels, indicating that tumors rely on maximal translation capacity [47]. Therefore, therapeutic agents that target components of the translation machinery to decrease translation rates hold promise as broad activity anticancer drugs that could overcome intra-tumor heterogeneity [48].…”

Section: Discussionmentioning

confidence: 99%

Pharmacological eEF 2K activation promotes cell death and inhibits cancer progression

et al. 2016

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Activation of the elongation factor 2 kinase (eEF2K) leads to the phosphorylation and inhibition of the elongation factor eEF2, reducing mRNA translation rates. Emerging evidence indicates that the regulation of factors involved in protein synthesis may be critical for controlling diverse biological processes including cancer progression. Here we show that inhibitors of the HIV aspartyl protease (HIV-PIs), nelfinavir in particular, trigger a robust activation of eEF2K leading to the phosphorylation of eEF2. Beyond its anti-viral effects, nelfinavir has antitumoral activity and promotes cell death. We show that nelfinavir-resistant cells specifically evade eEF2 inhibition. Decreased cell viability induced by nelfinavir is impaired in cells lacking eEF2K. Moreover, nelfinavir-mediated anti-tumoral activity is severely compromised in eEF2K-deficient engrafted tumors in vivo. Our findings imply that exacerbated activation of eEF2K is detrimental for tumor survival and describe a mechanism explaining the anti-tumoral properties of HIV-PIs.

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“…Its overexpression upregulates the translation of mRNAs for cell cycle, growth and reactive oxygen species (ROS) regulatory proteins (De Benedetti and Graff, 2004;De Benedetti and Rhoads, 1990;Rosenwald, 2004;Rosenwald et al, 1993), leading to the cancer phenotype. However, eIF4E-1 depletion by just 50% prevents lung cancer growth in mice (Truitt et al, 2015). eIF4E is essential for cap-dependent protein synthesis in order to recruit mRNAs to the ribosome for translation.…”

Section: Introductionmentioning

confidence: 99%

Spatial and temporal translational control of germ cell mRNAs mediated by the eIF4E isoform IFE-1

Friday

Henderson

Morrison

et al. 2015

Journal of Cell Science

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Regulated mRNA translation is vital for germ cells to produce new proteins in the spatial and temporal patterns that drive gamete development. Translational control involves the de-repression of stored mRNAs and their recruitment by eukaryotic initiation factors (eIFs) to ribosomes. C. elegans expresses five eIF4Es (IFE-1-IFE-5); several have been shown to selectively recruit unique pools of mRNA. Individual IFE knockouts yield unique phenotypes due to inefficient translation of certain mRNAs. Here, we identified mRNAs preferentially translated through the germline-specific eIF4E isoform IFE-1. Differential polysome microarray analysis identified 77 mRNAs recruited by IFE-1. Among the IFE-1-dependent mRNAs are several required for late germ cell differentiation and maturation. Polysome association of gld-1, vab-1, vpr-1, rab-7 and rnp-3 mRNAs relies on IFE-1. Live animal imaging showed IFE-1-dependent selectivity in spatial and temporal translation of germline mRNAs. Altered MAPK activation in oocytes suggests dual roles for IFE-1, both promoting and suppressing oocyte maturation at different stages. This single eIF4E isoform exerts positive, selective translational control during germ cell differentiation.

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Differential Requirements for eIF4E Dose in Normal Development and Cancer

Cited by 300 publications

References 46 publications

nanoCAGE reveals 5′ UTR features that define specific modes of translation of functionally related MTOR-sensitive mRNAs

nanoCAGE reveals 5′ UTR features that define specific modes of translation of functionally related MTOR-sensitive mRNAs

Pharmacological eEF 2K activation promotes cell death and inhibits cancer progression

Spatial and temporal translational control of germ cell mRNAs mediated by the eIF4E isoform IFE-1

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