Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA214596 | ENA |
REPOSITORIES: ENA
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Project description:Roles for ATF6-regulated miRNAs in the ER stress response
| PRJNA148817 | ENA
Project description:Activating transcription factor 6 alpha (ATF6⍺) is one of the three endoplasmic reticulum (ER) transmembrane stress sensors that mediate the unfolded protein response (UPR). Despite its significant involvement in long-term ER stress adaption, regulation of ATF6⍺ signalling is still poorly understood, possibly because its activation involves Golgi and nucleus trafficking. Here, we have generated a dual CHO-K1 ATF6⍺/IRE1⍺ reporter cell line to perform an unbiased genome-wide CRISPR/Cas9 mutagenesis screen, in the presence and absence of ER stress, to systematically profile genetic factors that specifically contribute to ATF6⍺ signalling. Anticipated and new candidate genes that regulate ATF6⍺ activation were discovered. Among these, calreticulin (CRT), a key ER luminal chaperone, emerged as a selective repressor molecule of ATF6⍺ signalling. Cells lacking CRT constitutively activated a BiP::sfGFP ATF6⍺-dependent reporter, had higher BiP levels and an increased rate of trafficking and processing of ATF6⍺. Purified CRT interacts with the luminal domain of ATF6⍺ in vitro and the two proteins co-immunoprecipitated from cell lysates. CRT depletion exposed a negative feedback loop implicating ATF6⍺ in repressing IRE1⍺ activity basally and overexpression of CRT reversed phenotype. Our data indicate that CRT, in addition to its known role as a chaperone, also serves as an ER repressor of ATF6⍺ to maintain selective regulation of the UPR.
2024-07-26 | GSE254745 | GEO
Project description:We recently found that the endoplasmic reticulum (ER) stress response (ERSR) is activated in surviving cardiac myocytes in a mouse model of in vivo myocardial infarction. ATF6 is an ER stress-activated transcription factor that induces ERSR genes, some of which encode proteins that may protect against ischemic damage. However, few ERSR genes have been identified in the heart, and there have been no gene expression profiling studies of ATF6-inducible genes, in vivo. We previously generated transgenic (TG) mice that express tamoxifen-activated ATF6, ATF6-MER, in the heart; ATF6-MER conferred tamoxifen-dependent ATF6 activation and protection from ischemic damage. To understand of the mechanism of ATF6-mediated cardioprotection, gene expression profiling of ATF6-MER TG mouse hearts was performed. Activated ATF6 changed expression levels of 1,162 genes in the heart; of the 775 ATF6-inducible genes, only 23 are known ERSR genes. One of the genes not expected to be induced by ATF6 is modulatory calcinuerin-interacting protein-1 (MCIP1). MCIP1 is induced in a calcineurin/NFAT-dependent manner during myocardial hypertrophy and it can feedback inhibit cardiomyocyte growth. We found that MCIP1 expression in cultured cardiomyocytes was increased by the prototypical ER stresser, tunicamycin (TM), or by simulated ischemia. Moreover, infecting cardiomyocytes with adenovirus encoding activated ATF6 induced MCIP1 expression and inhibited myocyte growth in response to the ï¡-adrenergic agonist, phenylephrine. These results suggest that MCIP1 can be induced in the heart by ER stresses, such as ischemia. Moreover, b integrating hypertrophy and ER stress, MCIP-modulated myocyte growth may help rejuvenate nascent ER protein folding, which could contribute to protection from ischemic damage. Experiment Overall Design: 12 mice were analyzed in this study. Four treatment groups were included in this study: transgenic ATF6-MER mice treated with tamoxifen, transgenic ATF6-MER mice treated with vehicle, nontransgenic littermates treated with tamoxifen, and nontransgenic littermates treated with vehicle. Each treatment group included 3 separate biological replicate samples. Each mouse sampled was male, C57/BL6, ~30 weeks old. Each mouse was treated, then the mouse was sacrificed, the heart was extracted, and left ventricle was isolated. Total RNA was isolated from the left ventricle, and used for hybridization onto an Affymetrix mus 430 2.0 full-genome chip. Each heart was hybridized onto its own chip.
2008-04-06 | E-GEOD-8322 | biostudies-arrayexpress
Project description:We recently found that the endoplasmic reticulum (ER) stress response (ERSR) is activated in surviving cardiac myocytes in a mouse model of in vivo myocardial infarction. ATF6 is an ER stress-activated transcription factor that induces ERSR genes, some of which encode proteins that may protect against ischemic damage. However, few ERSR genes have been identified in the heart, and there have been no gene expression profiling studies of ATF6-inducible genes, in vivo. We previously generated transgenic (TG) mice that express tamoxifen-activated ATF6, ATF6-MER, in the heart; ATF6-MER conferred tamoxifen-dependent ATF6 activation and protection from ischemic damage. To understand of the mechanism of ATF6-mediated cardioprotection, gene expression profiling of ATF6-MER TG mouse hearts was performed. Activated ATF6 changed expression levels of 1,162 genes in the heart; of the 775 ATF6-inducible genes, only 23 are known ERSR genes. One of the genes not expected to be induced by ATF6 is modulatory calcinuerin-interacting protein-1 (MCIP1). MCIP1 is induced in a calcineurin/NFAT-dependent manner during myocardial hypertrophy and it can feedback inhibit cardiomyocyte growth. We found that MCIP1 expression in cultured cardiomyocytes was increased by the prototypical ER stresser, tunicamycin (TM), or by simulated ischemia. Moreover, infecting cardiomyocytes with adenovirus encoding activated ATF6 induced MCIP1 expression and inhibited myocyte growth in response to the alpha 1-adrenergic agonist, phenylephrine. These results suggest that MCIP1 can be induced in the heart by ER stresses, such as ischemia. Moreover, b integrating hypertrophy and ER stress, MCIP-modulated myocyte growth may help rejuvenate nascent ER protein folding, which could contribute to protection from ischemic damage. Keywords: Gene expression analysis of the effect of activating ATF6 in the hearts of transgenic mice upon treatment with tamoxifen.
2008-03-06 | GSE8322 | GEO
Project description:Hepatocellular carcinoma (HCC) is the fastest growing cause of cancer-related mortality with limited therapies. While endoplasmic reticulum (ER)-stress and the unfolded protein response (UPR) are implicated in HCC, the involvement of the UPR-transducer activating transcription factor 6 alpha (ATF6α) remains unclear. We generated hepatocyte specific n-ATF6 overexpression transgenic mice via Cre-mediated recombination.
2024-12-28 | GSE285262 | GEO
Project description:The unfolded protein response (UPR) maintains endoplasmic reticulum (ER) homeostasis by sensing protein-folding stress and orchestrating cellular adaptation via the ER-transmembrane proteins IRE1, PERK and ATF6. Malignant cells can co-opt UPR signaling by IRE1 and PERK to sustain tumor growth; however, the importance of ATF6 in cancer remains poorly deciphered. We observed elevated ATF6 transcriptional activity in several cancers including colorectal carcinoma (CRC). Genetic silencing or small molecule inhibition of ATF6 blocked cell cycle progression and reduced viability of several human CRC cell lines in vitro and disrupted tumor progression in vivo. Unexpectedly, ATF6 interference also disabled Myc and Wnt signaling and reduced stemness. ATF6 inhibition attenuated growth of organoids derived from malignant but not normal human intestinal tissue, reducing Wnt-pathway activity and driving cellular differentiation. Wnt-surrogate agonism rescued the growth inhibitory phenotype of ATF6 interference. Our findings identify ATF6 as an unexpected facilitator of oncogenic Wnt signaling in CRC.
2024-08-12 | MSV000095581 | MassIVE
Project description:The unfolded protein response maintains endoplasmic reticulum (ER) homeostasis by sensing protein-folding stress and orchestrating cellular adaptation via the ER-transmembrane proteins IRE1, PERK and ATF6. Malignant cells can co-opt IRE1 and PERK to sustain growth; however, the importance of ATF6 in cancer remains poorly deciphered. We observed elevated ATF6 transcriptional activity in several cancers including colorectal carcinoma (CRC). Genetic silencing or small molecule inhibition of ATF6 blocked cell cycle progression and reduced viability of several human CRC cell lines in vitro and disrupted tumor progression in vivo. Unexpectedly, ATF6 interference disabled Wnt and Myc signaling and reduced stemness. ATF6 inhibition attenuated growth of organoids derived from malignant but not normal human intestinal tissue, decreasing Wnt-pathway activity and driving cellular differentiation. Wnt-surrogate agonism in a Wnt-dependent CRC organoid restored pathway activity and rescued growth under ATF6 blockade. Our findings identify ATF6 as an unexpected facilitator of oncogenic Wnt signaling in CRC.
2024-08-06 | GSE273988 | GEO
Project description:The unfolded protein response maintains endoplasmic reticulum (ER) homeostasis by sensing protein-folding stress and orchestrating cellular adaptation via the ER-transmembrane proteins IRE1, PERK and ATF6. Malignant cells can co-opt IRE1 and PERK to sustain growth; however, the importance of ATF6 in cancer remains poorly deciphered. We observed elevated ATF6 transcriptional activity in several cancers including colorectal carcinoma (CRC). Genetic silencing or small molecule inhibition of ATF6 blocked cell cycle progression and reduced viability of several human CRC cell lines in vitro and disrupted tumor progression in vivo. Unexpectedly, ATF6 interference disabled Wnt and Myc signaling and reduced stemness. ATF6 inhibition attenuated growth of organoids derived from malignant but not normal human intestinal tissue, decreasing Wnt-pathway activity and driving cellular differentiation. Wnt-surrogate agonism in a Wnt-dependent CRC organoid restored pathway activity and rescued growth under ATF6 blockade. Our findings identify ATF6 as an unexpected facilitator of oncogenic Wnt signaling in CRC.
2024-08-08 | GSE274172 | GEO
Project description:Disruptions of the endoplasmic reticulum (ER) that perturb protein folding cause ER stress and elicit an unfolded protein response (UPR) that involves translational and transcriptional changes in gene expression aimed at expanding the ER processing capacity and alleviating cellular injury. Three ER stress sensors PERK, ATF6, and IRE1 implement the UPR. PERK phosphorylation of eIF2 during ER stress represses protein synthesis, which prevents further influx of ER client proteins, along with preferential translation of ATF4, a transcription activator of the integrated stress response. In this study we show that the PERK/eIF2α~P/ATF4 pathway is required not only for translational control, but also activation of ATF6 and its target genes. The PERK pathway facilitates both the synthesis of ATF6 and trafficking of ATF6 from the ER to the Golgi for intramembrane proteolysis and activation of ATF6. As a consequence, liver-specific depletion of PERK significantly reduces both the translational and transcriptional phases of the UPR, leading to reduced protein chaperone expression, disruptions of lipid metabolism, and enhanced apoptosis. These findings show that the regulatory networks of the UPR are fully integrated, and helps explain the diverse pathologies associated with loss of PERK. 14 gene expression arrays, 3 WT control arrays; 3 lsPERK control arrays; 4 WT Treated arrays; 4 lsPERK treated arrays. Comparison of gene expression profiles for treated vs control in wildtype and knock-out.
2012-01-20 | E-GEOD-29929 | biostudies-arrayexpress
Project description: Not available
| S-EPMC8784167 | biostudies-literature