Expression data from arsenite treated wildtype and ATF4-deficient mouse cortical neurons
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE336776 | GEO | 2026/07/01
REPOSITORIES: GEO
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Project description:Expression data from arsenite treated wildtype and ATF4-deficient mouse cortical neurons
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Project description:Oxidative stress is pathogenic in neurological diseases including stroke. The identity of oxidative stress-inducible transcription factors and their role(s) in propagating the death cascade are poorly understood. Microarray analysis of neurons undergoing oxidative stress showed significant induction of prodeath genes. These genes have been shown to be regulated by the bZip transcription factor, ATF4. ATF4 protein localized to the promoter of a putative death gene in neurons in vitro and in vivo. Germline deletion of ATF4 in neurons resulted in a reduction in oxidative stress-induced gene expression and resistance to oxidative death. ATF4 knockout mice experienced significantly smaller infarcts and improved behavioral recovery as compared to wild-type mice subjected to the same reductions in blood flow in a rodent model of stroke. ATF4 modulates an early, upstream event in the death pathway, as resistance to oxidative death by ATF4 deletion was associated with decreased consumption of the antioxidant glutathione. Restoration of ATF4 protein in knockout neurons was sufficient to restore sensitivity to oxidative death and to reaccelerate loss of glutathione. Together, these findings establish ATF4 as a redox-regulated, pro-death transcriptional activator in the nervous system that propagates death responses to oxidative stress in vitro and to stroke in vivo. Keywords: ATF4, oxidative stress, gene expression, neuroprotection, stroke WT and ATF4 KO embryonic neurons were studied. Untreated neurons (no=8 per genotype) and neurons challenged with oxidative stress with the glutamate homolog homocysteate (HCA, no=4 per genotype) were studied, for a total of 24 samples.
2010-06-25 | E-GEOD-10470 | biostudies-arrayexpress
Project description:The molecular mechanisms linking the stress of unfolded proteins in the endoplasmic reticulum (ER stress) to glucose intolerance in obese animals are poorly understood. In this study enforced expression of a translation initiation 2α (eIF2α)-specific phosphatase, GADD34, was used to selectively compromise signaling in the eIF2(αP)-dependent arm of the ER unfolded protein response in liver of transgenic mice. The transgene resulted in lower liver glycogen levels and susceptibility to fasting hypoglycemia in lean mice and glucose tolerance and diminished hepato-steatosis in animals fed a high fat diet. Attenuated eIF2(αP) correlated with lower expression of the adipogenic nuclear receptor PPARγ and its upstream regulators, the transcription factors C/EBPα and C/EBPβ, in transgenic mouse liver, whereas eIF2α phosphorylation promoted C/EBP translation in cultured cells and primary hepatocytes. These observations suggest that eIF2(αP)-mediated translation of key hepatic transcriptional regulators of intermediary metabolism contributes to the detrimental consequences of nutrient excess. Keywords: genotype comparison The low expressing Ttr::Fv2E-Perk transgene (#58) was bred into the Atf4 knockout strain and the derivative compound heterozygous mice (in the mixed FvB/n; Swiss Webster background) were backcrossed to the Atf4+/- parental stock and Ttr::Fv2E-PERK positive siblings with Atf4+/+ and Atf4-/- genetypes were analyzed.
2011-12-23 | E-GEOD-11116 | biostudies-arrayexpress
Project description:ATF4 is a stress-responsive gene which is critical for cell survival under stress conditions. ATF4 expression is upregulated under mitochondrial stress. Global ATF4-bound targets were mapped using chromatin Immunoprecipitation followed by high-throughput sequencing on differentiated neurons after lentiviral shOpa1-knockdown or shScrambled control. ATF4 antibody is from Cell Signaling (#11815S).
2026-06-10 | GSE242440 | GEO
Project description:Metabotropic glutamate receptor (mGluR)-dependent long-term depression (LTD) is an essential mechanism of synaptic plasticity across various brain regions and is closely linked to numerous learning processes. Previous studies have demonstrated the interplay between mGluR-LTD and the phosphorylation of eukaryotic translation initiation factor 2α (p-eIF2α), a key component of the integrated stress response (ISR) pathway. However, the role of activating transcription factor 4 (ATF4)—the primary downstream effector of the integrated stress response (ISR)—in the mechanisms underlying mGluR-LTD has not been thoroughly investigated. In this study, we examine the role of ATF4 in mGluR-LTD and identify several targets that show differential expression when the gene encoding ATF4 is deleted in excitatory neurons.
2026-02-05 | PXD066551 | Pride
Project description:For additional details see Ebert et al, Identification and Small Molecule Inhibition of an ATF4-dependent Pathway to Age-related Skeletal Muscle Weakness and Atrophy. Quadriceps femoris muscles were harvested from 22-month-old muscle-specfic ATF4 knockout (ATF4 mKO) mice and littermate controls. mRNA levels in ATF4 mKO muscles were normalized to levels in littermate control muscles.
2015-09-03 | E-GEOD-72658 | biostudies-arrayexpress
Project description:Activating Transcription Factor 4 (ATF4) is a transcription factor induced by the integrated stress response (ISR). This experiment is a genome-wide profiling of ATF4-dependent RNA expression in human HAP-1 cells. HAP-1 is a near-haploid human cell line that was derived from KBM-7 cells isolated from a patient with Chronic Myelogenous Leukemia. We analyzed WT and ATF4 KO cells. We induced ATF4 expression by mimicking amino acid starvation with the drug histidinol. RNA expression profiles were generated for WT and ATF4 KO HAP1 cells. ATF4 genes were mutated using Cas9 genome editing technology. Amino acid starvation was mimicked by treating WT and ATF4 KO cells with 2 mM histidinol for 24 hours, which increases ATF4 expression.
2015-08-28 | E-GEOD-69308 | biostudies-arrayexpress
Project description:Lysosomes are central platforms for not only the degradation of macromolecules but also the integration of multiple signaling pathways. However, whether and how lysosomes mediate the mitochondrial stress response (MSR) remain largely unknown. Here, we demonstrate that lysosomal acidification via the vacuolar H+-ATPase (v-ATPase) is essential for the transcriptional activation of the mitochondrial unfolded protein response (UPRmt). Mitochondrial stress stimulates v-ATPase-mediated lysosomal activation of the mechanistic target of rapamycin complex 1 (mTORC1), which then directly phosphorylates the MSR transcription factor, activating transcription factor 4 (ATF4). Disruption of mTORC1-dependent ATF4 phosphorylation blocks the UPRmt, but not other similar stress responses, such as the UPRER. Finally, ATF4 phosphorylation downstream of the v-ATPase/mTORC1 signaling is indispensable for sustaining mitochondrial redox homeostasis and protecting cells from reactive oxygen species (ROS)-associated cell death upon mitochondrial stress. Thus, v-ATPase/mTORC1-mediated ATF4 phosphorylation via lysosomes links mitochondrial stress to UPRmt activation and mitochondrial function resilience.
2023-06-19 | GSE179510 | GEO
Project description:Oxidative stress is pathogenic in neurological diseases including stroke. The identity of oxidative stress-inducible transcription factors and their role(s) in propagating the death cascade are poorly understood. Microarray analysis of neurons undergoing oxidative stress showed significant induction of prodeath genes. These genes have been shown to be regulated by the bZip transcription factor, ATF4. ATF4 protein localized to the promoter of a putative death gene in neurons in vitro and in vivo. Germline deletion of ATF4 in neurons resulted in a reduction in oxidative stress-induced gene expression and resistance to oxidative death. ATF4 knockout mice experienced significantly smaller infarcts and improved behavioral recovery as compared to wild-type mice subjected to the same reductions in blood flow in a rodent model of stroke. ATF4 modulates an early, upstream event in the death pathway, as resistance to oxidative death by ATF4 deletion was associated with decreased consumption of the antioxidant glutathione. Restoration of ATF4 protein in knockout neurons was sufficient to restore sensitivity to oxidative death and to reaccelerate loss of glutathione. Together, these findings establish ATF4 as a redox-regulated, pro-death transcriptional activator in the nervous system that propagates death responses to oxidative stress in vitro and to stroke in vivo. Keywords: ATF4, oxidative stress, gene expression, neuroprotection, stroke
2008-03-01 | GSE10470 | GEO