Translational control of ERK signalling pathway by the mRNA cap-binding protein 4EHP
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA421497 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6359211.fastq.gz | Fastqsanger.gz | |||
| SRR6359212.fastq.gz | Fastqsanger.gz | |||
| SRR6359213.fastq.gz | Fastqsanger.gz | |||
| SRR6359214.fastq.gz | Fastqsanger.gz | |||
| SRR6359215.fastq.gz | Fastqsanger.gz |
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Project description:microRNA (miRNA)-mediated gene silencing is commonly deregulated in a wide variety of diseases. Therefore, a better understanding of how miRNAs govern the translation and stability of mRNAs is of paramount importance. We recently demonstrated that the cap-binding protein 4EHP is recruited by the miRNA machinery to effect translational repression. However, the impact of 4EHP on regulation of endogenous mRNAs and its role in cell biology is debated. Herein, using the ribosome profiling assay, we identify a subset of endogenous mRNAs that are sensitive to translational repression by 4EHP. We show that expression of DUSP6, a phosphatase that reverses ERK1/2 phosphorylation, is regulated by 4EHP. This regulation, which occurs exclusively at the level of mRNA translation, without affecting the stability of Dusp6 mRNA, is engendered through 4EHP- and miRNA-dependent elements in Dusp6 3´UTR. Consequently, 4EHP protein controls ERK1/2 phosphorylation, promotes cell growth and inhibits apoptosis. Our data reveal a crucial role for translational control mechanisms in the regulation of the ERK pathway.
2018-02-20 | GSE107826 | GEO
Project description:About 50% of human malignancies exhibit unregulated signalling through the Ras-ERK1/2 (ERK) pathway, as a consequence of activating mutations in members of Ras and Raf families. However, the quest for alternative Ras-ERK pathway-directed therapies is desirable. Upon phosphorylation ERK dimerize. We had previously demonstrated that dimerization is essential for ERK extranuclear but not nuclear signaling. Furthermore, by molecular biology approaches, we showed that specifically inhibiting ERK extranuclear component, by impeding ERK dimerization, is sufficient for curtailing tumor progression. Here, we have identified a small molecule inhibitor for ERK dimerization in vitro and in vivo that, without affecting ERK phosphorylation, prevents tumorigenesis driven by Ras-ERK pathway oncogenes, both in cellular and animal models. Importantly, this compound is unaffected by resistance-acquisition processes that hamper “classical” Ras-ERK pathway inhibitors. Thus, ERK dimerization inhibitors provide the proof of principle for two novel concepts in cancer therapy: 1) The blockade of sublocalization-specific sub-signals, rather than total signals, as a means of effectively counteracting oncogenic Ras-ERK signaling. 2) Targeting regulatory protein-protein interactions such as dimerization, rather than catalytic activities, within a signaling route, as an approach for producing effective anti-tumoral agents. Strategies aimed at preventing aberrant flux through this route remain an attractive option for therapeutic intervention in cancer. In this respect, drugs inhibiting the kinase activities of BRaf and MEK have yielded promising results. A375p cells treated with10 μM of either DEL22379, SCH772984 or DMSO as a control for two hours. mRNA from A375p cells was extrated using RNeasy mini kit (Qiagen, Germany) according to the manufacturer's instructions. Cells were previously treated with10 μM of either DEL22379, SCH772984 or DMSO as a control for two hours.
2015-04-24 | E-GEOD-68230 | biostudies-arrayexpress
Project description:This randomized phase I/II clinical trial is studying the side effects and best dose of gamma-secretase/notch signalling pathway inhibitor RO4929097 when given together with vismodegib and to see how well they work in treating patients with advanced or metastatic sarcoma. Vismodegib may slow the growth of tumor cells. Gamma-secretase/notch signalling pathway inhibitor RO4929097 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving vismodegib together with gamma-secretase/notch signalling pathway inhibitor RO4929097 may be an effective treatment for sarcoma.
| 2091475 | ecrin-mdr-crc
Project description:About 50% of human malignancies exhibit unregulated signalling through the Ras-ERK1/2 (ERK) pathway, as a consequence of activating mutations in members of Ras and Raf families. However, the quest for alternative Ras-ERK pathway-directed therapies is desirable. Upon phosphorylation ERK dimerize. We had previously demonstrated that dimerization is essential for ERK extranuclear but not nuclear signaling. Furthermore, by molecular biology approaches, we showed that specifically inhibiting ERK extranuclear component, by impeding ERK dimerization, is sufficient for curtailing tumor progression. Here, we have identified a small molecule inhibitor for ERK dimerization in vitro and in vivo that, without affecting ERK phosphorylation, prevents tumorigenesis driven by Ras-ERK pathway oncogenes, both in cellular and animal models. Importantly, this compound is unaffected by resistance-acquisition processes that hamper “classical” Ras-ERK pathway inhibitors. Thus, ERK dimerization inhibitors provide the proof of principle for two novel concepts in cancer therapy: 1) The blockade of sublocalization-specific sub-signals, rather than total signals, as a means of effectively counteracting oncogenic Ras-ERK signaling. 2) Targeting regulatory protein-protein interactions such as dimerization, rather than catalytic activities, within a signaling route, as an approach for producing effective anti-tumoral agents. Strategies aimed at preventing aberrant flux through this route remain an attractive option for therapeutic intervention in cancer. In this respect, drugs inhibiting the kinase activities of BRaf and MEK have yielded promising results.
2015-04-24 | GSE68230 | GEO
Project description:The EGFR/Ras/ERK signalling pathway is a primary driver of cancer cell proliferation and metastasis in tumours that exhibit high cell-to-cell heterogeneity. While the signalling activity of this pathway is frequently amplified in tumours, it is not understood how the kinetic aspects of its activation in tumours differ from normal cellular signalling. We explored these single-cell kinetic differences using live-cell reporters of ERK signalling in the breast cancer progression series HMT-3522 and found that ERK activity in invasive cells is similar in amplitude to non-malignant cells but is highly dynamic and more disordered, leading to more heterogeneous expression of ERK target genes. We traced this variability to a high degree of amphiregulin-mediated autocrine signalling by invasive cells. Dynamic ERK activity could be transferred from invasive to pre-malignant cells through paracrine signalling in co-culture, and could drive temporal variation in the expression of genes including Fra-1, c-Myc, and Egr1 at the single-cell level. Our findings establish a mechanism for the generation of tumour cell plasticity, in which paracrine signalling in the microenvironment is translated into continually shifting diversity in gene expression profiles, helping drive the phenotypic heterogeneity of tumour cells.
2020-08-01 | GSE118312 | GEO
Project description:Fibroblast Growth Factor (FGF) signalling via ERK exerts diverse roles in development and disease. In mammalian preimplantation embryos and naïve pluripotent stem cells ERK promotes differentiation, whereas in primed pluripotent states closer to somatic differentiation ERK sustains self-renewal. How can the same pathway produce different outcomes in two related cell types? To explore context-dependent ERK signalling in embryonic development and differentiation we generated cell and mouse lines that allow for tissue- and time-specific cell intrinsic ERK activation. Using these tools, we find variations in response to ERK are mostly mediated by repression of transcriptional targets that occur in tandem with reductions in chromatin accessibility at regulatory regions. Furthermore, immediate early ERK responses are largely shared by different cell types but become refined producing cell-specific programs as increasing durations of signalling interface with cell specific gene regulatory networks. Induction in naïve pluripotency is accompanied by chromatin changes, whereas in later stages it is not, suggesting that chromatin context doesn’t shape signalling response. Altogether, our data suggest that cell-type specific responses to ERK signalling exploit the same immediate early response, but then sculpt it to specific lineages via repression of distinct cellular programs and downstream indirect stimulation of available enhancer networks.
2024-03-05 | GSE259236 | GEO
Project description:Fibroblast Growth Factor (FGF) signalling via ERK exerts diverse roles in development and disease. In mammalian preimplantation embryos and naïve pluripotent stem cells ERK promotes differentiation, whereas in primed pluripotent states closer to somatic differentiation ERK sustains self-renewal. How can the same pathway produce different outcomes in two related cell types? To explore context-dependent ERK signalling in embryonic development and differentiation we generated cell and mouse lines that allow for tissue- and time-specific cell intrinsic ERK activation. Using these tools, we find variations in response to ERK are mostly mediated by repression of transcriptional targets that occur in tandem with reductions in chromatin accessibility at regulatory regions. Furthermore, immediate early ERK responses are largely shared by different cell types but become refined producing cell-specific programs as increasing durations of signalling interface with cell specific gene regulatory networks. Induction in naïve pluripotency is accompanied by chromatin changes, whereas in later stages it is not, suggesting that chromatin context doesn’t shape signalling response. Altogether, our data suggest that cell-type specific responses to ERK signalling exploit the same immediate early response, but then sculpt it to specific lineages via repression of distinct cellular programs and downstream indirect stimulation of available enhancer networks.
2024-03-05 | GSE259235 | GEO
Project description:Fibroblast Growth Factor (FGF) signalling via ERK exerts diverse roles in development and disease. In mammalian preimplantation embryos and naïve pluripotent stem cells ERK promotes differentiation, whereas in primed pluripotent states closer to somatic differentiation ERK sustains self-renewal. How can the same pathway produce different outcomes in two related cell types? To explore context-dependent ERK signalling in embryonic development and differentiation we generated cell and mouse lines that allow for tissue- and time-specific cell intrinsic ERK activation. Using these tools, we find variations in response to ERK are mostly mediated by repression of transcriptional targets that occur in tandem with reductions in chromatin accessibility at regulatory regions. Furthermore, immediate early ERK responses are largely shared by different cell types but become refined producing cell-specific programs as increasing durations of signalling interface with cell specific gene regulatory networks. Induction in naïve pluripotency is accompanied by chromatin changes, whereas in later stages it is not, suggesting that chromatin context doesn’t shape signalling response. Altogether, our data suggest that cell-type specific responses to ERK signalling exploit the same immediate early response, but then sculpt it to specific lineages via repression of distinct cellular programs and downstream indirect stimulation of available enhancer networks.
2024-03-05 | GSE259234 | GEO
Project description:Fibroblast Growth Factor (FGF) signalling via ERK exerts diverse roles in development and disease. In mammalian preimplantation embryos and naïve pluripotent stem cells ERK promotes differentiation, whereas in primed pluripotent states closer to somatic differentiation ERK sustains self-renewal. How can the same pathway produce different outcomes in two related cell types? To explore context-dependent ERK signalling in embryonic development and differentiation we generated cell and mouse lines that allow for tissue- and time-specific cell intrinsic ERK activation. Using these tools, we find variations in response to ERK are mostly mediated by repression of transcriptional targets that occur in tandem with reductions in chromatin accessibility at regulatory regions. Furthermore, immediate early ERK responses are largely shared by different cell types but become refined producing cell-specific programs as increasing durations of signalling interface with cell specific gene regulatory networks. Induction in naïve pluripotency is accompanied by chromatin changes, whereas in later stages it is not, suggesting that chromatin context doesn’t shape signalling response. Altogether, our data suggest that cell-type specific responses to ERK signalling exploit the same immediate early response, but then sculpt it to specific lineages via repression of distinct cellular programs and downstream indirect stimulation of available enhancer networks.
2024-03-05 | GSE259233 | GEO
Project description:Fibroblast Growth Factor (FGF) signalling via ERK exerts diverse roles in development and disease. In mammalian preimplantation embryos and naïve pluripotent stem cells ERK promotes differentiation, whereas in primed pluripotent states closer to somatic differentiation ERK sustains self-renewal. How can the same pathway produce different outcomes in two related cell types? To explore context-dependent ERK signalling in embryonic development and differentiation we generated cell and mouse lines that allow for tissue- and time-specific cell intrinsic ERK activation. Using these tools, we find variations in response to ERK are mostly mediated by repression of transcriptional targets that occur in tandem with reductions in chromatin accessibility at regulatory regions. Furthermore, immediate early ERK responses are largely shared by different cell types but become refined producing cell-specific programs as increasing durations of signalling interface with cell specific gene regulatory networks. Induction in naïve pluripotency is accompanied by chromatin changes, whereas in later stages it is not, suggesting that chromatin context doesn’t shape signalling response. Altogether, our data suggest that cell-type specific responses to ERK signalling exploit the same immediate early response, but then sculpt it to specific lineages via repression of distinct cellular programs and downstream indirect stimulation of available enhancer networks.
2024-03-05 | GSE259232 | GEO