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Eukaryotic Initiation Factor 4E-BP Protien Family: Sentinels at a Translational Checkpoint in Lung Tumor Defense

ABSTRACT: The usurping of translational control by sustained activation of translation initiation factors is oncogenic. Here we show that the primary negative regulators of these oncogenic initiation factors - the 4E-BP protein family - operate as guardians of a translational control checkpoint in tumor defense. When challenged with the tobacco carcinogen NNK, 4ebp1-/-/4ebp2-/- mice showed increased sensitivity to tumorigenesis compared to their wild type counterparts. The 4E-BP deficient state per se creates pro-oncogenic, genome-wide skewing of the molecular landscape - with translational activation of genes governing angiogenesis, growth and proliferation; and translational activation of the precise cytochrome p450 enzyme isoform (CYP2A5) that bioactivates NNK into mutagenic metabolites. Our study provides in vivo proof for a translational control checkpoint in tumor defense.

ORGANISM(S): Mus musculus

PROVIDER: GSE17406 | GEO | 2010/06/01

SECONDARY ACCESSION(S): PRJNA118857

REPOSITORIES: GEO

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Mus musculus

Project description:Eukaryotic Initiation Factor 4E-BP Protien Family: Sentinels at a Translational Checkpoint in Lung Tumor Defense

| PRJNA118857 | ENA

TRIBE editing reveals specific mRNA targets of eIF4E-BP in Drosophila and in mammals

Project description:4E-BP (eIF4E-BP) represses translation initiation by binding to the 5’cap-binding protein eIF4E and inhibiting its activity. Although 4E-BP has been shown to be important in growth control, stress response, cancer, neuronal activity and mammalian circadian rhythms, it is not understood how it preferentially represses a subset of mRNAs. We successfully used hyperTRIBE (Targets of RNA-binding proteins identified by editing) to identify in vivo 4E-BP mRNA targets in both Drosophila and mammals under conditions known to activate 4E-BP. The protein associates with specific mRNAs, and ribosome profiling data show that mTOR inhibition changes the translational efficiency of 4E-BP TRIBE targets compared to non-targets. In both systems, these targets have specific motifs and are enriched in translation-related pathways, which correlate well with the known activity of 4E-BP and suggest that it modulates the binding specificity of eIF4E and contributes to mTOR translational specificity.

2020-08-20 | GSE153346 | GEO

4E-BP1-dependent translation in microglia controls mechanical hypersensitivity

Project description:Spinal microglia play a pivotal role in the development of neuropathic pain. Peripheral nerve injury induces changes in the transcriptional profile of microglia, including increased expression of components of translational machinery. Whether microglial protein synthesis is stimulated following nerve injury and has a functional role in mediating pain hypersensitivity is unknown. Here, we show that nascent protein synthesis is upregulated in spinal microglia following peripheral nerve injury. Stimulating mRNA translation in microglia, via selective ablation of the translational repressor, eukaryotic initiation factor 4E-binding protein 1 (4E-BP1), promoted the transition of microglia to a reactive state and induced mechanical hypersensitivity. Conversely, inhibiting microglial translation by expressing mutant 4E-BP1 in microglia attenuated their peripheral nerve injury-induced activation and alleviated neuropathic pain. Thus, the stimulation of 4E-BP1-dependent translation promotes microglia reactivity and mechanical hypersensitivity, whereas its inhibition alleviates neuropathic pain.

2024-01-31 | GSE254472 | GEO

Refinement of synapses without postsynaptic activity: Role for a 4E-BP dependent mechanism

Project description:Refinement of synaptic connections during development requires both the elimination of some inputs and the strengthening of others. It is well accepted that this competitive process takes place throughout the nervous system and relies on synaptic activity. However, the mechanisms that link activity to refinement remain largely unresolved. Here we demonstrate that refinement of preganglionic axons in sympathetic ganglia, a process that depends unequivocally on synaptic activity, involves eukaryotic initiation factor 4E binding protein (4E-BP), a protein that regulates cap-dependent translation. In mice lacking the 3 nicotinic receptor subunit, silent synapses between preganglionic axons and postsynaptic nicotinic neurons do not refine unless synaptic activity is restored, or surprisingly, when 4E-BP is absent. Our findings demonstrate that synapses can refine in the absence of synaptic activity during development and identify 4E-BP as a critical player in this process.

2017-07-26 | MSV000081386 | MassIVE

4E-BP1-dependent translation in nociceptors controls mechanical hypersensitivity via TRIM32/type I interferon signaling

Project description:Activation of the mechanistic target of rapamycin complex 1 (mTORC1) contributes to the development of chronic pain. However, the specific mechanisms by which mTORC1 causes hypersensitivity remain elusive. The eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) is a key mTORC1 downstream effector that represses translation initiation. Here we show that nociceptor-specific deletion of 4E-BP1, mimicking activation of mTORC1-dependent translation, is sufficient to cause mechanical hypersensitivity.

2023-03-27 | GSE227978 | GEO

Identification of protein-protein interactions involving the eIF4E binding proteins Caf20p and Eap1p on yeast via affinity purification and LC-MSMS.

Project description:There are multiple translational control pathways. These include pathways involving eIF4E binding proteins (4E-BPs), which inhibit translation by binding and sequestering the 5’ cap binding protein eIF4E away from its partner eIF4G. Saccharomyces cerevisiae has two 4E-BPs: Caf20p and Eap1p. Previous analyses had shown that each 4E-BP regulates different subsets of mRNAs. In order to assess whether binding different proteins caused their different regulatory role, we used tandem affinity purification followed by label-free mass spectrometry to compare the proteomes pulled-down with the TAP-tagged 4E-BPs, and the global proteome. These analyses point out that Caf20p and Eap1p share most interaction partners, including ribosomes, and that both bind several other RNA-binding proteins.

2016-06-29 | PXD001407 | Pride

Transcriptional and translational effect of the lack of translation initiation factor eIF(iso)4E

Project description:One of the most regulated steps of translation initiation is the recruitment of an mRNA by the translation machinery. In eukaryotes, this step is mediated by the 5M-BM-4end cap-binding factor eIF4E bound to the bridge protein eIF4G and forming the eIF4F complex. In plants, different isoforms of eIF4E and eIF4G form the antigenically distinct eIF4F and eIF(iso)4F complexes proposed to mediate selective translation. Using a microarray analysis of polyribosome- and non-polyribosome-purified mRNAs from 15 day-old Arabidopsis thaliana wild type [WT] and eIF(iso)4E knockout mutant [AteIF(iso)4E-1] seedlings we found 79 transcripts shifted from polyribosomes toward non-polyribosomes, and 47 mRNAs with the opposite behavior in the mutant. The translationally decreased mRNAs were overrepresented in root-preferentially expressed genes and proteins from the endomembrane system, including several transporters such as the phosphate transporter PHOSPHATE1 (PHO1), Sucrose transporter 3 (SUC3), the ABC transporter-like with ATPase activity (MRP11) and five electron transporters, as well as signal transduction-, protein modification- and transcription-related proteins. For transcriptional analysis used total RNA of AteIF(iso)4E-1 seedlings of 15 days old to known the changes on transcripts leves by the eIF(iso)4E absence, using as control Wt seedlings. The experiments were performed in duplicate, and swap analysis were done. For translational analysis, used non-polysomal and polysomal RNA of AteIF(iso)4E-1 seedlings of 15 days old in order to known the transcripts that are modified in their translational levels by the eIF(iso)4E absence, using as control non polysomal and polysomal RNA of Wt seddlings.

2013-07-26 | E-GEOD-29386 | biostudies-arrayexpress

Analysis of the role of yeast eIF4E-binding protein Caf20p in translation control

Project description:Caf20p is one of two Saccharomyces cerevisiae eIF4E binding proteins (4E-BPs) involved in translational control. Both 4E-BPs inhibit translation of a different subset of mRNAs, indicating that 4E-BPs bind specific targets. We used normal and mutated Caf20p to perform RIP-Seq analyses in order to explore the ability of Caf20p for binding mRNAs in 4E-dependent and 4E-independent manners.

2015-09-30 | E-MTAB-2892 | biostudies-arrayexpress

Distinct translational control in CD4+ T-cell subsets

Project description:Regulatory T cells expressing the transcription factor Foxp3 play indispensable roles for the induction and maintenance of immunological self-tolerance and immune homeostasis. Genome-wide mRNA expression-studies have defined canonical signatures of T-cell subsets. Changes in steady-state mRNA levels do, however, often not reflect those of corresponding proteins due to post-transcriptional mechanisms including mRNA translation. Here, we unveil a unique translational signature, contrasting CD4+Foxp3+ regulatory T (TFoxp3+) and CD4+Foxp3- non-regulatory T (TFoxp3-) cells, which imprints subset-specific protein expression. We further show that translation of eukaryotic translation initiation factor 4E (eIF4E) is induced during T-cell activation and, in turn, regulates translation of cell cycle related mRNAs and proliferation in both TFoxp3- and TFoxp3+ cells. Unexpectedly, eIF4E also affects Foxp3 expression and thereby lineage identity. Thus, mRNA-specific translational control directs both common and distinct cellular processes in CD4+ T-cell subset. CD4+/Foxp3+ and CD4+Foxp3- cells were studied ex vivo or activated in vitro for 36h. Both polysome-associated and cytoplasmic RNA was isolated to enables studies of translational control

2013-06-01 | E-GEOD-45401 | biostudies-arrayexpress

Arabidopsis thaliana

Project description:Transcriptional and translational effect of the lack of translation initiation factor eIF(iso)4E

| PRJNA140031 | ENA