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Microarray to find CHOP dependent genes in response to proteasome inhibition

ABSTRACT: Environmental stresses that disrupt protein homeostasis induce phosphorylation of eIF2, triggering repression of global protein synthesis coincident with preferential translation of ATF4, a transcriptional activator of the Integrated stress response (ISR). Depending on the extent of protein disruption, ATF4 may not be able to restore proteostatic control and instead switch to a terminal outcome that features elevated expression of the transcription factor CHOP (GADD153/DDIT3). The focus of this study was to define the mechanisms by which CHOP directs gene regulatory networks that determine cell fate. We find that in response to proteasome inhibition, CHOP induces the expression of a collection of genes encoding transcription regulators, including ATF5, which is preferentially translated during eIF2 phosphorylation. Transcriptional expression of ATF5 is directly activated by both CHOP and ATF4. Knock-down of ATF5 increased cell survival in response to proteasome inhibition, supporting the idea that both ATF5 and CHOP have pro-apoptotic functions. Transcriptome analyses of ATF5-dependent genes revealed targets involved in apoptosis, including, NOXA, which is important for inducing cell death during proteasome inhibition. This study suggests that the ISR features a feed-forward loop of stress induced transcriptional regulators, each subject to transcriptional and translational control that can switch cell fate towards apoptosis.

ORGANISM(S): Mus musculus

PROVIDER: GSE43713 | GEO | 2013/09/05

SECONDARY ACCESSION(S): PRJNA187148

REPOSITORIES: GEO

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Microarray to find ATF5 dependent genes in response to proteasome inhibition

Project description:Environmental stresses that disrupt protein homeostasis induce phosphorylation of eIF2, triggering repression of global protein synthesis coincident with preferential translation of ATF4, a transcriptional activator of the Integrated stress response (ISR). Depending on the extent of protein disruption, ATF4 may not be able to restore proteostatic control and instead switch to a terminal outcome that features elevated expression of the transcription factor CHOP (GADD153/DDIT3). The focus of this study was to define the mechanisms by which CHOP directs gene regulatory networks that determine cell fate. We find that in response to proteasome inhibition, CHOP induces the expression of a collection of genes encoding transcription regulators, including ATF5, which is preferentially translated during eIF2 phosphorylation. Transcriptional expression of ATF5 is directly activated by both CHOP and ATF4. Knock-down of ATF5 increased cell survival in response to proteasome inhibition, supporting the idea that both ATF5 and CHOP have pro-apoptotic functions. Transcriptome analyses of ATF5-dependent genes revealed targets involved in apoptosis, including, NOXA, which is important for inducing cell death during proteasome inhibition. This study suggests that the ISR features a feed-forward loop of stress induced transcriptional regulators, each subject to transcriptional and translational control that can switch cell fate towards apoptosis. 8 plates (10cm) of WT and and 8 plates (10cm) of ATF5-KD MEF cells were subject to no stress (4 each for a total of 8) or treated for 8 hours with 1uM MG132 (4 each for a total of 8). Unstressed cells were harvested at the same time as the stressed cells

2013-09-05 | E-GEOD-43714 | biostudies-arrayexpress

Microarray to find CHOP dependent genes in response to proteasome inhibition

Project description:Environmental stresses that disrupt protein homeostasis induce phosphorylation of eIF2, triggering repression of global protein synthesis coincident with preferential translation of ATF4, a transcriptional activator of the Integrated stress response (ISR). Depending on the extent of protein disruption, ATF4 may not be able to restore proteostatic control and instead switch to a terminal outcome that features elevated expression of the transcription factor CHOP (GADD153/DDIT3). The focus of this study was to define the mechanisms by which CHOP directs gene regulatory networks that determine cell fate. We find that in response to proteasome inhibition, CHOP induces the expression of a collection of genes encoding transcription regulators, including ATF5, which is preferentially translated during eIF2 phosphorylation. Transcriptional expression of ATF5 is directly activated by both CHOP and ATF4. Knock-down of ATF5 increased cell survival in response to proteasome inhibition, supporting the idea that both ATF5 and CHOP have pro-apoptotic functions. Transcriptome analyses of ATF5-dependent genes revealed targets involved in apoptosis, including, NOXA, which is important for inducing cell death during proteasome inhibition. This study suggests that the ISR features a feed-forward loop of stress induced transcriptional regulators, each subject to transcriptional and translational control that can switch cell fate towards apoptosis. 8 plates (10cm) of WT and and 8 plates (10cm) of CHOP-/- MEF cells were subject to no stress (4 each for a total of 8) or treated for 8 hours with 1uM MG132 (4 each for a total of 8). Unstressed cells were harvested at the same time as the stressed cells

2013-09-05 | E-GEOD-43713 | biostudies-arrayexpress

Microarray to find ATF5 dependent genes in response to proteasome inhibition

2013-09-05 | GSE43714 | GEO

Project description:Microarray to find CHOP/ATF5 dependent genes in response to proteasome inhibition

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Genome wide binding of ATF4 and CEBPG bZIP transcription factors in MEFs under amino acid deprived (AAD) conditions

Project description:The integrated stress response (ISR) controls cellular adaptations to nutrient deprivation, redox imbalances and ER stress. ISR genes are upregulated in stressed cells, primarily by the bZIP transcription factor ATF4 through its recruitment to cis-regulatory C/EBP:ATF response elements (CAREs) together with a dimeric partner of uncertain identity. Here we show that C/EBPÎ³:ATF4 heterodimers, but not C/EBPÎ²:ATF4 dimers, are the predominant CARE binding species in stressed cells. C/EBPÎ³ and ATF4 associate with genomic CAREs in a mutually-dependent manner and co-regulate many ISR genes. By contrast, the C/EBP family members C/EBPÎ² and CHOP were largely dispensable for induction of stress genes. Cebpgâ/â MEFs proliferate poorly and exhibit oxidative stress due to reduced glutathione levels and impaired expression of several glutathione biosynthesis pathway genes. Cebpgâ/â mice (C57BL/6 background) display reduced body size and microphthalmia, similar to ATF4-null animals. In addition, C/EBPÎ³-deficient newborns die from atelectasis and respiratory failure which can be mitigated by in utero exposure to the anti-oxidant, N-acetyl-cysteine. Cebpgâ/â mice on a mixed strain background show improved viability but, upon aging, develop significantly fewer malignant solid tumors compared to WT animals. Our findings identify C/EBPÎ³ as a novel anti-oxidant regulator and an obligatory ATF4 partner that controls redox homeostasis in normal and cancerous cells. Evaluation of genomic binding of 2 bZIP transcription factors under amino acid deprivation conditions in mouse embryonic fibroblasts

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Whole genome expression data from WT, Atf4-/-, and Cebpg-/- MEFs under normal and amino acid deprived (AAD) growth conditions

Project description:The integrated stress response (ISR) controls cellular adaptations to nutrient deprivation, redox imbalances and ER stress. ISR genes are upregulated in stressed cells, primarily by the bZIP transcription factor ATF4 through its recruitment to cis-regulatory C/EBP:ATF response elements (CAREs) together with a dimeric partner of uncertain identity. Here we show that C/EBPÎ³:ATF4 heterodimers, but not C/EBPÎ²:ATF4 dimers, are the predominant CARE binding species in stressed cells. C/EBPÎ³ and ATF4 associate with genomic CAREs in a mutually-dependent manner and co-regulate many ISR genes. By contrast, the C/EBP family members C/EBPÎ² and CHOP were largely dispensable for induction of stress genes. Cebpgâ??/â?? MEFs proliferate poorly and exhibit oxidative stress due to reduced glutathione levels and impaired expression of several glutathione biosynthesis pathway genes. Cebpgâ??/â?? mice (C57BL/6 background) display reduced body size and microphthalmia, similar to ATF4-null animals. In addition, C/EBPÎ³-deficient newborns die from atelectasis and respiratory failure which can be mitigated by in utero exposure to the anti-oxidant, N-acetyl-cysteine. Cebpgâ??/â?? mice on a mixed strain background show improved viability but, upon aging, develop significantly fewer malignant solid tumors compared to WT animals. Our findings identify C/EBPÎ³ as a novel anti-oxidant regulator and an obligatory ATF4 partner that controls redox homeostasis in normal and cancerous cells. WT, Atf4-/-, and Cebpg-/- MEFs (passage 3) were cultured under normal and AAD conditions. RNA from each treatment condition was collected in triplicate for hybrization on Affymetrix Mouse Genome 430 2.0 microarrays.

2015-11-19 | E-GEOD-75150 | biostudies-arrayexpress

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Transcription profiling by array of human cell lines expressing high levels of tamoxifen-induced DDIT3

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