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EIF4E/mTOR-independent mRNA translation plasticity conferred by DAP5/eIF3d is required for breast cancer cell mesenchymal transition and metastasis

ABSTRACT: eIF4E/mTOR-independent mRNA translation plasticity conferred by DAP5/eIF3d is required for breast cancer cell mesenchymal transition and metastasis

PROVIDER: PRJNA780006 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR16936726.fastq.gz	Fastqsanger.gz
	SRR16936727.fastq.gz	Fastqsanger.gz
	SRR16936728.fastq.gz	Fastqsanger.gz
	SRR16936729.fastq.gz	Fastqsanger.gz
	SRR16936730.fastq.gz	Fastqsanger.gz

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eIF4E/mTOR-independent mRNA translation plasticity conferred by DAP5/eIF3d is required for breast cancer cell mesenchymal transition and metastasis

Project description:We report the application of polysome profiling sequencing technology for high-throughput transcriptomics and translatomics in 4T1 cells. We compare reduction of Dap5 to control in a BALB/c mouse breast cancer cell line in transcription and polysome enriched translation using RNA sequencing. Genome-wide transcriptomic and translatomic analyses indicate that DAP5 is required for translation of many transcription factors and their mRNA targets involved in EMT, angiogenesis, DNA repair and translation initiation, among other mRNAs. Metastatic potential of cells is significanlty decreased upon Dap5 silencing as confirmed by different in vivo models.

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eIF4E-independent translation is largely eIF3d-dependent

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eIF4E-independent translation is largely eIF3d-dependent

Project description:eIF4E-independent translation is largely eIF3d-dependent

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Project description:Shutoff of global protein synthesis is a conserved response to cellular stresses. This general phenomenon is accompanied by induction of distinct gene programs tailored to each stress condition. Although the mechanisms that lead to general repression of protein synthesis are well characterized, how cells reprogram the translation machinery for selective gene expression remains poorly understood. Here we show that the noncanonical 5′ cap-binding protein eIF3d is specifically activated in response to metabolic stress, due to loss of CK2-mediated phosphorylation near the eIF3d cap-binding pocket. Activated eIF3d controls a gene program enriched in factors important for glucose homeostasis, including members of the mTOR pathway, and eIF3d-mediated translation adaptation is essential for cell survival during chronic glucose deprivation. Our findings reveal a new mechanism of translation reprogramming engaged in response to metabolic stress.

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Transcriptome and translatome of human regulatory T cells differentiated with TGFbeta and mTOR inhibitor everolimus

Project description:Regulatory T cells (Tregs) inhibit effector T cells and maintain immune system homeostasis. Treg maturation in peripheral sites (pTregs) is poorly understood but is known to require inhibition of protein kinase mTORC1 (e.g.RAD001) and exposure to TGFb. Paradoxically, Treg maturation requires protein synthesis yet mTORC1 inhibition downregulates it, leaving unanswered how Tregs carry-out essential mRNA translation for development and immune suppression activity. Using human CD4+ T cells differentiated in culture (iTregs) and genome-wide transcription and translation profiling, we show that TGFb transcriptionally reprograms naïve T cells to express iTreg differentiation and immune suppression mRNAs, while mTORC1 inhibition impairs translation of T cell mRNAs but not those induced by TGFb. TGFb-induced Treg mRNAs were found to utilize an alternate mechanism for cap-dependent mRNA translation directed by the DAP5/eIF3d complex rather than canonical mTORC1/eIF4E during Treg development, which is directed by their 5’-untranslated regions. iTreg differentiation is therefore mediated by combined TGFb transcriptional and translational reprogramming and a privileged mechanism of mRNA translation

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Project description:All cells respond to intrinsic and extrinsic stresses by reducing global protein synthesis and activating select gene programs necessary for survival. Here, we show the fundamental integrated stress response (ISR) is driven by the non-canonical cap-binding protein eIF3d which acts as a master effector to control core stress response orchestrators, the translation factor eIF2ɑ and the transcription factor ATF4. We find that during persistent stress, eIF3d activates translation of the protein kinase GCN2, inducing eIF2ɑ phosphorylation and inhibiting global protein synthesis. In parallel, eIF3d upregulates the m6A demethylase enzyme ALKBH5 to drive 5′ UTR-specific demethylation of stress response genes, including ATF4. Ultimately, this cascade converges on ATF4 expression by increasing mRNA engagement of translation machinery and enhancing ribosome bypass of upstream open reading frames. Our results reveal that eIF3d acts as a critical life-or-death decision point during adaptation to chronic stress and uncover a synergistic signaling mechanism in which translational cascades dynamically complement transcriptional amplification to control essential cellular processes.

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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.

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

Project description:mTOR regulates mRNA translation. Whereas ribosome-profiling suggested that mTOR exclusively stimulates translation of TOP (containing a 5â-terminal oligopyrimidine [5âTOP] motif) and TOP-like mRNAs, polysome-profiling implied that mTOR also modulates translation of non-TOP mRNAs. We show that ribosome-, but not polysome-profiling, is biased towards identification of TOP mRNAs as differentially translated while obscuring detection of changes in non-TOP mRNA translation. Transcription start site profiling by Nano-Cap Analysis of Gene Expression (nanoCAGE) revealed that many mTOR-sensitive mRNAs do not have 5âTOP motifs. Moreover, nanoCAGE showed that 5â UTR features distinguish two functionally and translationally distinct subsets of mTOR-sensitive mRNAs: i) those with short 5â UTRs enriched for mitochondrial functions such as respiration, that are translated in an eIF4E, but not eIF4A1-dependent manner and ii) mRNAs encoding proliferation- and survival-promoting proteins, that harbor long 5â UTRs, and require both eIF4E and eIF4A1 for their efficient translation. Selective inhibition of translation of mRNAs harboring long 5â UTRs via suppression of eIF4A leads to uncoupling of expression of proteins involved in respiration (e.g. ATP5O) from those protecting mitochondrial integrity (e.g. BCL-2) ultimately resulting in apoptosis. Conversely, simultaneous translational downregulation of both long and short 5â UTR mRNAs by mTOR inhibitors results in suppression of mitochondrial respiration and predominantly cytostatic effects. Therefore, 5â UTR features define differential modes of translation of functionally distinct mTOR-sensitive mRNAs, which explains discrepancies between the effects of mTOR and eIF4A inhibitors on neoplastic cells. Determination of 5'UTR lengths using nanoCAGE in MCF7 cells

2016-03-14 | E-GEOD-77033 | biostudies-arrayexpress

Project description:Eukaryotic translation initiation factor 4E (eIF4E)–binding protein 1 (4E-BP1) inhibits cap-dependent translation in eukaryotes by competing with eIF4G for an interaction with eIF4E. Phos-phorylation at Ser-83 of 4E-BP1 occurs during mitosis through the activity of cyclin-dependent kinase 1 (CDK1)/cyclin B rather than through canonical mTOR kinase activity. Here, we investi-gated the interaction of eIF4E with 4E-BP1 or eIF4G during interphase and mitosis. We observed that 4E-BP1 and eIF4G bind eIF4E at similar levels during interphase and mitosis. The most highly phosphorylated mitotic 4E-BP1 isoform (δ) did not interact with eIF4E, whereas a distinct 4E-BP1 phospho-isoform, EB-γ—phosphorylated at Thr-70, Ser-83, and Ser-101—bound to eIF4E during mitosis. Two-dimensional gel electropho-retic analysis corroborated the identity of the phosphorylation marks on the eIF4E-bound 4E-BP1 isoforms and uncovered a population of phosphorylated 4E-BP1 molecules lacking Thr-37/Thr-46–priming phosphorylation. Moreover, proximity ligation assays for phospho–4E-BP1 and eIF4E revealed different in situ interactions during interphase and mitosis. The eIF4E:eIF4G interaction was not inhibited, but rather increased in mitotic cells, consistent with active translation initiation during mitosis. Phospho-defective substitution of 4E-BP1 at Ser-83 did not change global translation or individual mRNA translation profiles as measured by single-cell nascent protein synthesis and eIF4G RNA-immunoprecipitation sequencing. Mitotic 5’-terminal oligopyrimidine RNA translation was active and, unlike interphase translation, resistant to mTOR inhibition. Our findings reveal the phosphorylation profiles of 4E-BP1 isoforms and their interactions with eIF4E throughout the cell cycle and indicate that 4E-BP1 does not specifically inhibit translation initiation during mitosis.

2019-06-14 | GSE131668 | GEO

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