ATF4-dependent fructolysis fuels brain tumorigenesis (WGS)
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ABSTRACT:
PROVIDER: PRJNA836872 | ENA |
REPOSITORIES: ENA
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Project description:ATF4-dependent fructolysis fuels brain tumorigenesis
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Project description:Engineered extrachromosomal circular DNAs promote tumorigenesis (WGS)
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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:Tumors often undergo stress and need to reprogram their metabolism to survive and grow under nutrient challenging conditions. The stroma could play a critical role in this process by providing nutrients or signals to support the epithelial compartment of the tumor. Autophagy has been shown to play key roles both in the stroma and in the epithelium. However, how autophagy adaptors, such as p62, participate in the mechanisms whereby the stroma supports tumor progression is not yet fully understood. Here we show that p62 deficiency in stromal fibroblasts promotes resistance to glutamine deprivation through a metabolic reprogramming orchestrated by the direct control of ATF4 stability by p62-mediated polyubiquitination. This, in turn, activates the flux of glucose carbons through a pyruvate carboxylase-asparagine synthase cascade that results in asparagine-mediated stromal cell growth and tumor epithelial proliferation, independent of autophagy. This supports a new model in which p62 directly targets nuclear transcription factors to control metabolic reprograming in the microenvironment to repress tumorigenesis, and emerges as global tumor suppressor.
2018-02-14 | GSE94343 | GEO
Project description:Dysregulation of the proto-oncogene c-Myc (MYC henceforward) drives malignant progression, but also induces robust anabolic and proliferative programs leading to intrinsic stress. The mechanisms enabling adaptation to MYC-induced stress are not fully understood. We have uncovered an essential role for the transcription factor ATF4 in cell survival following MYC activation. MYC- upregulates ATF4 by activating GCN2 kinase through uncharged tRNAs. Subsequently, ATF4 co-occupies promoter regions of over 30 MYC target genes, including those regulating amino acid biosynthesis/transport and protein synthesis. ATF4 is essential for MYC-induced upregulation of the negative translational regulator and mTOR target 4E-BP1 and genetic or pharmacological inhibition of mTOR signaling rescues ATF4 deficient cells from MYC-induced stress. Acute deletion of ATF4 significantly delays MYC-driven tumor progression and increases survival in mouse models. Our results establish ATF4 as a cellular rheostat of MYC-activity, ensuring enhanced translation rates are compatible with survival and tumor progression.
2018-07-18 | GSE117240 | GEO
Project description:To determine gene expression changes induced by ATF4 overexpression, RNA was isolated from BEAS2B cells after overexpression of ATF4 or negative control. mRNA expression was profiled using Affymetrix Human Gene 1.0 ST Arrays. RNA isolated from BEAS2B cells after overexpression of ATF4 or empty vector was processed and hybridized to Affymetrix Human Gene 1.0 ST Arrays. Experiments were performed in triplicate. Data from the 6 microarrays were used for RMA normalization. RMA normalization was performed in the R statsitical environment using the affy package. A t-test was used to determine the association of gene expression with ATF4 overexpression.
2013-05-01 | E-GEOD-45949 | biostudies-arrayexpress
Project description:Tumors often undergo stress and need to reprogram their metabolism to survive and grow under nutrient challenging conditions. The stroma could play a critical role in this process by providing nutrients or signals to support the epithelial compartment of the tumor. Autophagy has been shown to play key roles both in the stroma and in the epithelium. However, how autophagy adaptors, such as p62, participate in the mechanisms whereby the stroma supports tumor progression is not yet fully understood. Here we show that p62 deficiency in stromal fibroblasts promotes resistance to glutamine deprivation through a metabolic reprogramming orchestrated by the direct control of ATF4 stability by p62-mediated polyubiquitination. This, in turn, activates the flux of glucose carbons through a pyruvate carboxylase-asparagine synthase cascade that results in asparagine-mediated stromal cell growth and tumor epithelial proliferation, independent of autophagy. This supports a new model in which p62 directly targets nuclear transcription factors to control metabolic reprograming in the microenvironment to repress tumorigenesis, and emerges as global tumor suppressor.
2018-02-14 | GSE94367 | GEO
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