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ECT2 and AURKB Modulate Formation of Stress Granules Containing Transcripts from Diverse Cellular Pathways in Astrocytoma Cells

ABSTRACT: Stress granules are small RNA-protein granules that modify the translational landscape during cellular stress to promote survival. The RhoGTPase RhoA is implicated in the formation of RNA stress granules. Our data demonstrate that the cytokinetic proteins ECT2 and AurkB are localized to stress granules in human astrocytoma cells. AurkB and its downstream target histone-3 are phosphorylated during arsenite-induced stress. Chemical (AZD1152-HQPA) and siRNA inhibition of AurkB results in fewer and smaller stress granules when analyzed utilizing high throughput fluorescent based cellomics assays. RNA immunoprecipitation with the known stress granule aggregates TIAR and G3BP1 was performed on astrocytoma cells and subsequent analysis revealed that astrocytoma stress granules harbour unique mRNAs for various cellular pathways including cellular migration, metabolism, translation and transcriptional regulation. Human astrocytoma cell stress granules contain mRNA that are known to be involved in glioma signaling and the mTOR pathway. These data provide evidence that RNA stress granules are a novel form of epigenetic regulation in astrocytoma cells, which may be targetable by chemical inhibitors and enhance astrocytoma susceptiblity to conventional therapy such as radiation and chemotherapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE76814 | GEO | 2016/02/29

SECONDARY ACCESSION(S): PRJNA308648

REPOSITORIES: GEO

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ECT2 and AURKB Modulate Formation of Stress Granules Containing Transcripts from Diverse Cellular Pathways in Astrocytoma Cells

Project description:Stress granules are small RNA-protein granules that modify the translational landscape during cellular stress to promote survival. The RhoGTPase RhoA is implicated in the formation of RNA stress granules. Our data demonstrate that the cytokinetic proteins ECT2 and AurkB are localized to stress granules in human astrocytoma cells. AurkB and its downstream target histone-3 are phosphorylated during arsenite-induced stress. Chemical (AZD1152-HQPA) and siRNA inhibition of AurkB results in fewer and smaller stress granules when analyzed utilizing high throughput fluorescent based cellomics assays. RNA immunoprecipitation with the known stress granule aggregates TIAR and G3BP1 was performed on astrocytoma cells and subsequent analysis revealed that astrocytoma stress granules harbour unique mRNAs for various cellular pathways including cellular migration, metabolism, translation and transcriptional regulation. Human astrocytoma cell stress granules contain mRNA that are known to be involved in glioma signaling and the mTOR pathway. These data provide evidence that RNA stress granules are a novel form of epigenetic regulation in astrocytoma cells, which may be targetable by chemical inhibitors and enhance astrocytoma susceptiblity to conventional therapy such as radiation and chemotherapy. Astrocytoma cells were either untreated or treated with arsenite to induce stress granule formation and RNA immunoprecipitates were analyzed by exon array analysis. RNA species that were enriched in TIAR RIPs and G3BP1 RIPS, respectively were compared to compared to TIAR and G3BP1 RIPs from untreated cells and input controls. Ingenuity pathway analysis was performed on the stress granule enriched mRNAs from the TIAR and G3BP1 RIPs to identify significant functional biology networks.

2016-02-29 | E-GEOD-76814 | biostudies-arrayexpress

Homo sapiens

Project description:ECT2 and AURKB Modulate Formation of Stress Granules Containing Transcripts from Diverse Cellular Pathways in Astrocytoma Cells

| PRJNA308648 | ENA

HeberleRazquinNavas2019 - The PI3K and MAPK/p38 pathways control stress granuleassembly in a hierarchical manner model 2

Project description:All cells and organisms exhibit stress-coping mechanisms to ensure survival. Cytoplasmic protein-RNA assemblies termed stress granules are increasingly recognized to promote cellular survival under stress. Thus, they might represent tumor vulnerabilities that are currently poorly explored. The translation-inhibitory eIF2α kinases are established as main drivers of stress granule assembly. Using a systems approach, we identify the translation enhancers PI3K and MAPK/p38 as pro-stress-granule-kinases. They act through the metabolic master regulator mammalian target of rapamycin complex 1 (mTORC1) to promote stress granule assembly. When highly active, PI3K is the main driver of stress granules; however, the impact of p38 becomes apparent as PI3K activity declines. PI3K and p38 thus act in a hierarchical manner to drive mTORC1 activity and stress granule assembly. Of note, this signaling hierarchy is also present in human breast cancer tissue. Importantly, only the recognition of the PI3K-p38 hierarchy under stress enabled the discovery of p38’s role in stress granule formation. In summary, we assign a new pro-survival function to the key oncogenic kinases PI3K and p38, as they hierarchically promote stress granule formation.

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T-cell intracellular antigen (TIA) proteins deficiency in murine embryonic fibroblasts alters cell cycle progression and induces autophagy

Project description:Background: Mice lacking either T-cell intracellular antigen 1 (TIA1) or TIA1-related/like protein (TIAR/TIAL1) show high rates of embryonic lethality, suggesting a relevant role for these proteins during embryonic development. However, intrinsic molecular and cellular consequences of either TIA1 or TIAR deficiency remain poorly defined. Results: By using genome-wide expression profiling approach, we demonstrate that either TIA1 or TIAR inactivation broadly alter normal development-associated signaling pathways in murine embryonic fibroblasts (MEF). Indeed, these analyses highlighted alterations of cytokine-cytokine and ECM-receptor interactions and Wnt, MAPK, TGF-beta dependent signaling pathways. Consistent with these results, TIA1 and TIAR knockout (KO) MEF show reduced rates of cell proliferation, cell cycle progression delay and increased cell size. Furthermore, TIA-proteins deficiency also caused metabolic deficiencies, increased ROS levels and DNA damage, promoting a gentle rise of cell death. Concomitantly, high rates of autophagy were detected in both TIA1 and TIAR KO MEF with induction of the formation of autophagosomes, as evidenced by the up-regulation of the LC3B protein, and autolysosomes, measured by colocalization of LC3B and LAMP1, as a survival mechanism attempt. Conclusions: Taken together, these observations support that TIA proteins orchestrate a transcriptome programme to activate specific developmental decisions. This program is likely to contribute to mouse physiology starting at early stages of the embryonic development. TIA1/TIAR might function as cell sensors to maintain homeostasis and promote adaptation/survival responses to developmental stress. Two independent replicates were performed for each experimental condition and hybridized to Agilent SurePrint G3 Mouse 8x60 microarrays.

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T-cell intracellular antigen (TIA) proteins deficiency in murine embryonic fibroblasts alters cell cycle progression and induces autophagy

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Ribosome profiling on heat shocked wild type and Mettl14 -/- mES cells

Project description:Abstract : "A hallmark of the cellular response to environmental stress is the formation of stress granules. Stress granules are RNA-protein assemblies that provide an adaptive response to stress; however, the basis for their formation and how they contribute to the stress response remains incompletely understood. Here we show that the mRNA modification N6-methyladenosine (m6A) is a mark that targets mRNAs to stress granules. We find that m6A mRNAs are highly enriched in stress granules, and this is mediated by m6A-induced liquid-liquid phase separation of the YTHDF family of m6A-binding proteins. These proteins bind poly-methylated m6A mRNAs, causing them to form liquid droplets that partition into stress granules. Moreover, disrupting either m6A or YTHDF proteins prevents stress granule formation." The goal of this experiment is to understand how recruitment of m6A mRNA to stress granules influences the translational response to heat shock. Result: we found that m6A-containing mRNA are preferentially repressed during stress, and that m6A is required for translational recovery after heat shock

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Project description:The knock down of T-cell intracellular antigen (TIA) proteins enhances the acquisition of aberrant cellular phenotypes promoting uncontrolled cell and tumor growth. Hereby, we report that inducible expression of either TIA1 or TIAR in human embryonic kidney (HEK293) cells represses cell proliferation. Mechanistically, the sustained expression of either TIA1 or TIAR protein abolishes endogenous TIA1/TIAR protein expression via regulating splicing of their own pre-mRNAs. This event is concomitant with cell cycle arrest and cell death by apoptosis. Based on genome-wide analysis of the transcript expression patterns in HuR-, TIA1- or TIAR-expressing HEK293 cells, we found regulatory links among the up-regulation on a select subset of p53 pathway genes involved in G1/S cell-cycle and apoptosis control. Finally, nude mice injected with TIA1- or TIAR-expressing HEK293 cells decrease, and even abolishing, the growth of tumor xenografts relative to control cells. Collectively, these observations show that TIA proteins can function as tumor suppressor genes.

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Recruitment of mRNAs to P granules by gelation with intrinsically-disordered proteins (RNAseq and ribosome profiling)

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