Plasticity of the Mammalian Integrated Stress Response [atf4]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1114729 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR29130337_1.fastq.gz | Fastqsanger.gz | |||
| SRR29130337_2.fastq.gz | Fastqsanger.gz | |||
| SRR29130338_1.fastq.gz | Fastqsanger.gz | |||
| SRR29130338_2.fastq.gz | Fastqsanger.gz | |||
| SRR29130339_1.fastq.gz | Fastqsanger.gz |
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Similar Datasets
Project description:Decreased nucleotide exchange activity of the eukaryotic translation initiation factor eIF2B coupled with increased phosphorylation of eIF2alpha (eIF2alpha-p) is a hallmark of the “canonical” integrated stress response (c-ISR). In mammals, however, it is unclear whether decreased eIF2B activity in absence of alterations in eIF2alpha-p which occurs in human disease including leukodystrophies, is synonymous to c-ISR. Herein, we describe a previously unknown mechanism of adaptation to decreased eIF2B activity, distinct from c-ISR, which we term “split” ISR (s-ISR). We demonstrate that s-ISR comprises translation reprogramming of only a subset of c-ISR mRNA targets which is accompanied by distinct transcriptomes. In contrast to c-ISR, s-ISR requires eIF4E-dependent translation of the upstream open reading frame 1 and subsequent stabilization of ATF4 mRNA. This is followed by altered expression of a subset of metabolic genes (e.g., PCK2), resulting in metabolic adaptations to maintain cellular bioenergetics under conditions of low eIF2B activity. Overall, these data demonstrate hitherto-unappreciated plasticity of the mammalian ISR, whereby the loss of eIF2B activity in the absence of increased eIF2-p, activates an eIF4E/ATF4/PCK2 axis to maintain energy homeostasis.
2025-01-22 | GSE268127 | GEO
Project description:Plasticity of the Mammalian Integrated Stress Response [eIF2B5_eIF4E]
| PRJNA1114731 | ENA
Project description:Plasticity of the Mammalian Integrated Stress Response [eIF2B5]
| PRJNA1114733 | ENA
Project description:Decreased nucleotide exchange activity of the eukaryotic translation initiation factor eIF2B coupled with increased phosphorylation of eIF2alpha (eIF2alpha-p) is a hallmark of the “canonical” integrated stress response (c-ISR). In mammals, however, it is unclear whether decreased eIF2B activity in absence of alterations in eIF2alpha-p which occurs in human disease including leukodystrophies, is synonymous to c-ISR. Herein, we describe a previously unknown mechanism of adaptation to decreased eIF2B activity, distinct from c-ISR, which we term “split” ISR (s-ISR). We demonstrate that s-ISR comprises translation reprogramming of only a subset of c-ISR mRNA targets which is accompanied by distinct transcriptomes. In contrast to c-ISR, s-ISR requires eIF4E-dependent translation of the upstream open reading frame 1 and subsequent stabilization of ATF4 mRNA. This is followed by altered expression of a subset of metabolic genes (e.g., PCK2), resulting in metabolic adaptations to maintain cellular bioenergetics under conditions of low eIF2B activity. Overall, these data demonstrate hitherto-unappreciated plasticity of the mammalian ISR, whereby the loss of eIF2B activity in the absence of increased eIF2-p, activates an eIF4E/ATF4/PCK2 axis to maintain energy homeostasis.
2025-01-22 | GSE268132 | GEO
Project description:Decreased nucleotide exchange activity of the eukaryotic translation initiation factor eIF2B coupled with increased phosphorylation of eIF2alpha (eIF2alpha-p) is a hallmark of the “canonical” integrated stress response (c-ISR). In mammals, however, it is unclear whether decreased eIF2B activity in absence of alterations in eIF2alpha-p which occurs in human disease including leukodystrophies, is synonymous to c-ISR. Herein, we describe a previously unknown mechanism of adaptation to decreased eIF2B activity, distinct from c-ISR, which we term “split” ISR (s-ISR). We demonstrate that s-ISR comprises translation reprogramming of only a subset of c-ISR mRNA targets which is accompanied by distinct transcriptomes. In contrast to c-ISR, s-ISR requires eIF4E-dependent translation of the upstream open reading frame 1 and subsequent stabilization of ATF4 mRNA. This is followed by altered expression of a subset of metabolic genes (e.g., PCK2), resulting in metabolic adaptations to maintain cellular bioenergetics under conditions of low eIF2B activity. Overall, these data demonstrate hitherto-unappreciated plasticity of the mammalian ISR, whereby the loss of eIF2B activity in the absence of increased eIF2-p, activates an eIF4E/ATF4/PCK2 axis to maintain energy homeostasis.
2025-01-22 | GSE268130 | GEO
Project description:The integrated stress response (ISR) is a central signaling pathway induced by a variety of insults, but how its outputs contribute to downstream physiological effects across diverse cellular contexts remains unclear. Using a synthetic tool, we specifically and tunably activated the ISR and performed multi-omics profiling to define the core modules elicited by this response in the absence of co-activation of parallel pathways commonly induced by pleiotropic stressors. We found that the ISR can elicit time- and dose-dependent gene expression changes that cluster into four modules with ATF4 driving only a small but fast and sensitive module that includes many amino acid metabolic enzymes. We showed that ATF4 was required to reroute carbon utilization towards amino acid synthesis derived both from glucose and reductive carboxylation of glutamine and away from the tricarboxylic acid cycle and fatty acid biogenesis revealing a new role for ATF4 in modulating cellular energetics. We also discovered an ATF4-independent reorganization of cellular lipids that promotes triglycerides synthesis and accumulation of lipid droplets that was essential for cell survival. Together, we demonstrate that a minimal ISR-inducing system is sufficient to trigger formation of two distinct cellular structures, stress granules and lipid droplets, and a previously unappreciated metabolic state.
2024-08-28 | GSE273599 | GEO
Project description:Cancer cells exploit many of the cellular adaptive responses to support their survival needs. One such critical pathway in eukaryotic cells is the integrated stress response (ISR) that is important in normal physiology as well as disease states, including cancer. Since ISR can serve as a lever between survival and death, regulated control of its activity is critical for tumor formation and growth although the underlying mechanisms are poorly understood. Here we show that the main transcriptional effector of ISR, activating transcription factor 4 (ATF4), is essential for prostate cancer (PCa) growth and survival. LNCaP cells were transfected with control siRNA or an ATF4-specific siRNA, and 4 days later treated with 300nM Tg for 5h. Total RNA was isolated and Illumina Human HT-12 expression Bead-Chips (Illumina) were used for global transcriptome analysis according to the manufacturer’s protocol. The experiment was performed in triplicates.
2019-11-01 | GSE125826 | GEO
Project description:Transcriptomics of specific activation of the Integrated Stress Response activation in ATF4 WT and ATF4 KO cells
| PRJNA1142488 | ENA
Project description:Regulation of the Integrated Stress Response through ATF4 and FAM129A in Prostate Cancer
| PRJNA517659 | ENA
Project description:The integrated stress response (ISR) regulates cell fate during conditions of stress by leveraging the cell's capacity to endure sustainable and efficient adaptive stress responses. Protein phosphatase 2A (PP2A) activity modulation has been shown to be successful in achieving both therapeutic efficacy and safety across various cancer models. However, the molecular mechanisms driving its selective antitumor effects remain unclear. Here, we show for the first time that ISR plasticity relies on PP2A activation to regulate drug response and dictate cellular survival under conditions of chronic stress. We demonstrate that genetic and chemical modulation of the PP2A leads to chronic proteolytic stress and triggers an ISR to dictate whether the cell lives or dies. More specifically, we uncovered that the PP2A-TFE3-ATF4 pathway governs ISR cell plasticity during endoplasmic reticular and cellular stress independent of the unfolded protein response. We further show that normal cells reprogram their genetic signatures to undergo ISR-mediated adaptation and homeostatic recovery thereby avoiding toxicity following PP2A-mediated stress. Conversely, oncogenic specific cytotoxicity induced by chemical modulation of PP2A is achieved by activating chronic and irreversible ISR in cancer cells. Our findings propose that a differential response to chemical modulation of PP2A is determined by intrinsic ISR plasticity, providing a novel biological vulnerability to selectively induce cancer cell death and improve targeted therapeutic efficacy.
| S-EPMC11618521 | biostudies-literature