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Molecular effects of ISRIB during asparagine deprivation

ABSTRACT: Molecular effects of ISRIB during asparagine deprivation

PROVIDER: PRJNA521363 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR8545490.fastq.gz	Fastqsanger.gz
	SRR8545500.fastq.gz	Fastqsanger.gz
	SRR8545491.fastq.gz	Fastqsanger.gz
	SRR8545501.fastq.gz	Fastqsanger.gz
	SRR8545492.fastq.gz	Fastqsanger.gz

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Molecular effects of ISRIB during asparagine deprivation

Project description:The integrated stress response (ISR) is a conserved pathway which is activated by cells that are exposed to stress. In lung adenocarcinoma (LUAD), activation of the ATF4 branch of the ISR by particular oncogenic mutations has been linked to the regulation of amino acid metabolism. In the present study, we provide evidence for ATF4 activation across multiple stages and molecular subtypes of human LUAD. In response to extracellular amino acid limitation, LUAD cells with diverse genotypes broadly induce ATF4 in an eIF2α dependent manner, which can be blocked pharmacologically using the integrated stress response inhibitor (ISRIB). Although suppressing eIF2α or ATF4 can trigger different biological consequences, adaptive cell cycle progression and cell migration are particularly sensitive to inhibition of the ISR. These phenotypes specifically require the ATF4 target gene asparagine synthetase (ASNS), which maintains protein translation independently of the mTOR/PI3K pathway. Moreover, NRF2 protein levels and oxidative stress can be modulated by the ISR downstream of ASNS. Finally, we demonstrate that the ISR via ASNS controls the biosynthesis of select proteins, including the cell cycle regulator cyclin B1, which are associated with poor LUAD patient prognosis. Our findings uncover new regulatory layers of the ISR pathway and its control of proteostasis in lung cancer cells as they adapt to metabolic barriers during tumor progression.

2019-10-23 | GSE126232 | GEO

Identification of critical therapeutic nodes to overcome Asparagine deprivation resistance in melanoma

Project description:Asparagine deprivation by L-Asparaginase is a successful therapeutic strategy in Acute Lymphoblastic Leukemia, with resistance occurring due to upregulation of ASNS. L-Asparaginase efficacy in solid tumors is hampered by dose-related toxicities. Large scale loss of function genetic screens identified ASNS, the only human enzyme synthetizing asparagine, as a cancer dependency in several solid malignancies, including melanoma. We here evaluate the therapeutic potential of targeting ASNS in melanoma cells in-vitro and in-vivo. Using ex-vivo quantitative proteome and transcriptome profiling, we observed that concomitant ASNS deletion and asparagine deprivation elicit a compensatory mechanism allowing tumor growth. Genome wide CRISPR screens upon manipulation of aminoacid levels identifies MAPK and GCN2 as critical nodes mediating the observed resistance mechanism. Importantly MEK and GCN2 inhibitor synergize with L-Asparaginase suggesting novel potential therapeutic strategy in melanoma.

2022-02-15 | PXD015152 | Pride

The Small Molecule ISRIB Reverses the Effects of eIF2α Phosphorylation on Translation and Stress Granule Assembly

Project description:We recently identified ISRIB as a potent inhibitor of the integrated stress response (ISR). ISRIB renders cells resistant to the effects of eIF2α phosphorylation and enhances long-term memory in rodents (10.7554/eLife.00498). Here we show by genome-wide in vivo ribosome profiling that translation of a restricted subset of mRNAs is induced upon ISR activation. ISRIB substantially reversed the translational effects elicited by phosphorylation of eIF2α and induced no major changes in translation or mRNA levels in unstressed cells. eIF2α phosphorylation-induced stress granule (SG) formation was blocked by ISRIB. Strikingly, ISRIB addition to stressed cells with pre-formed SGs induced their rapid disassembly, liberating mRNAs into the actively translating pool. Restoration of mRNA translation and modulation of SG dynamics may be an effective treatment of neurodegenerative diseases characterized by eIF2α phosphorylation, SG formation and cognitive loss. Ribosome profiling with paired RNA-seq

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Asparagine availability controlsgerminal centre B cell homeostasis

Project description:Germinal centre (GC) B cells proliferate at some of the highest rates of any mammalian cell. Yet the metabolic processes which enable this are poorly understood. We performed integrated metabolomic and transcriptomic profiling of GC B cells, and found that asparagine metabolism is highly upregulated. Asparagine is conditionally essential to B cells, and its synthetic enzyme, asparagine synthetase (ASNS) is markedly upregulated following their activation, through the integrated stress response sensor general control non-derepressible 2 (GCN2). When Asns is deleted, B cell survival in low asparagine conditions is severely impaired. Using stable isotope tracing, we found that metabolic adaptation to the absence of asparagine requires ASNS, and that the synthesis of nucleotides is particularly sensitive to asparagine deprivation. Conditional deletion of Asns in B cells selectively impairs GC formation, associated with a reduction in RNA synthesis rates. Finally, removal of environmental asparagine by asparaginase was found to also severely compromise the GC reaction.

2024-04-03 | GSE228845 | GEO

The Small Molecule ISRIB Reverses the Effects of eIF2α Phosphorylation on Translation and Stress Granule Assembly

2015-02-27 | GSE65778 | GEO

ISRIB can temporarily maintain the cell fate of human trophoblast stem cell without activating WNT and inhibiting TGFβ

Project description:To investigate the role of ISRIB in human trophoblast stem cell(hTSC) maintenance without activation of WNT & TGFβ. We performed gene expression profiling analysis using data obtained from RNA-seq of hTSCs cultured in the medium contained 0.5 µM ISRIB and 10 µM Y27652, after removing CHIR99021, A83-01, SB431542.

2023-12-31 | GSE221409 | GEO

Resetting proteostasis in aged animals with ISRIB prevents recruitment of profibrotic monocyte-derived alveolar macrophages during pulmonary fibrosis

Project description:Aging is among the most important risk factors for the development of pulmonary fibrosis. Inappropriate or prolonged activation of the integrated stress response has been implicated in the pathobiology of both aging and pulmonary fibrosis. We found that a small molecule that relieves translational inhibition induced by activation of the integrated stress response (ISRIB) attenuated the severity pulmonary fibrosis in young and old mice. We demonstrate that severe fibrosis in old mice was associated with increased number of pathogenic monocyte-derived alveolar macrophages. Using transcriptomic profiling we found that ISRIB modulates stress response signaling in alveolar epithelial cells resulting in decreased recruitment of pathogenic monocyte-derived alveolar macrophages. Thus our data suggest that inhibition of the integrated stress response in the lung epithelium can ameliorate pulmonary fibrosis by preventing the recruitment of monocyte-derived alveolar macrophages.

2021-04-16 | GSE145295 | GEO

Resetting proteostasis in aged animals with ISRIB prevents recruitment of profibrotic monocyte-derived alveolar macrophages during pulmonary fibrosis [AT2]

2021-04-16 | GSE145771 | GEO

Molecular mechanism of mice embryonic diapause induction by nutrient deprivation

Project description:Molecular mechanism of mice embryonic diapause induction by nutrient deprivation

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Gene expression profiling of leukemia cells following asparagine depletion

Project description:We will report the gene expression changes following asparagine depletion in human ALL cell line, RS4;11

2019-08-06 | GSE135420 | GEO