Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA290443 | ENA |
REPOSITORIES: ENA
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Project description:Here we use an integrated systems-level examination of transcription, translation, and proteolysis to explore how cancer cells struggle with a chemotherapeutic drug prior to succumbing to apoptosis. As a model system we study myeloma cells exposed to the proteasome inhibitor bortezomib, a first-line clinical treatment. Despite robust transcriptional changes, unbiased quantitative proteomics detects production of only a few critical anti-apoptotic proteins against a background of general translation inhibition. Ribosome profiling further reveals potential translational regulation of stress response genes following bortezomib treatment. Once the apoptotic machinery is engaged, degradation by caspases is largely independent of changes at the transcriptional level. Moreover, previously uncharacterized non-caspase proteolytic events also participate in cellular deconstruction. As suggested by these data, we find that inhibition of the anti-apoptotic response regulator HSF1 promotes cell death by bortezomib. Thus, monitoring global cellular dynamics after chemotherapy offers in-depth insight into apoptosis and can also guide potential therapeutic combinations. We examined MM1.S myeloma cells exposed to 20 nM bortezomib across a time course with independent samples of poly(A) mRNA and ribosome footprints isolated at each of six time points (0h (untreated), 1.5h, 3h, 6h, 9h, 12h). Sequencing was performed on a Illumina HiSeq 2000 with single-end.
2013-10-17 | E-GEOD-48785 | biostudies-arrayexpress
Project description:Analysis of the coordinated transcriptional reponse to proteasome inhibition mRNA profiles of NIH3T3 cells which stably expressing DD-sfGFP were generated by deep sequencing using Illumina HiSeq. The samples were collected from indicated timepoints after exposed to proteasome inhibition by Bortezomib.
2015-09-04 | E-GEOD-71145 | biostudies-arrayexpress
Project description:This study provides a genome-wide map of changes in histone mark modifications and HDAC3 binding in response to protesome inhibition in the multiple myeloma cell line MM.1S. Chromatin immunoprecipitation assays were carried out to determine the genomic locations of histone modifications (H3K27ac, H3K4me1, H3K4me3) and histone deacetylase 3 (HDAC3) binding locations in multiple myeloma cells following proteasome inhibition with either lactacystin, bortezomib or carfilzomib. In addition, we report the effects of the overexpression of the E3-ubiquitin ligase Siah2 and the impact of HDAC3 knockdown on H3K27 acetylation levels in multiple myeloma cells treated with lactacystin. Our global ChIP-seq analysis of histone marks showed that enhancer and promoter marks (H3K4me1 and H3K4me3, respectively) present little response to proteasome inhibition, while the acetylation of histone H3K27 was significantly up- or down-regulated after three-hour treatment with proteasome inhibitors. Treatment of the cells with lactacystin, bortezomib or carfilzomib strongly increased HDAC3 recruitment at cell cycle and mitochondrial promoters, indicating that proteasome inhibition stabilized HDAC3 locally at the promoter of these genes to induce their repression. Furthermore, genome-wide ChIP-seq analysis of H3K27ac profiles showed that overexpression of Siah2 enhanced H3K27 acetylation levels at cell cycle and mitochondrial promoters.
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Project description:Here we use an integrated systems-level examination of transcription, translation, and proteolysis to explore how cancer cells struggle with a chemotherapeutic drug prior to succumbing to apoptosis. As a model system we study myeloma cells exposed to the proteasome inhibitor bortezomib, a first-line clinical treatment. Despite robust transcriptional changes, unbiased quantitative proteomics detects production of only a few critical anti-apoptotic proteins against a background of general translation inhibition. Ribosome profiling further reveals potential translational regulation of stress response genes following bortezomib treatment. Once the apoptotic machinery is engaged, degradation by caspases is largely independent of changes at the transcriptional level. Moreover, previously uncharacterized non-caspase proteolytic events also participate in cellular deconstruction. As suggested by these data, we find that inhibition of the anti-apoptotic response regulator HSF1 promotes cell death by bortezomib. Thus, monitoring global cellular dynamics after chemotherapy offers in-depth insight into apoptosis and can also guide potential therapeutic combinations.
2013-10-17 | GSE48785 | GEO
Project description:Microarray to find CHOP dependent genes in response to proteasome inhibition
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Project description:Microarray to find ATF5 dependent genes in response to proteasome inhibition
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Project description:The KMT2A rearranged B lineage infant ALL cell line SEM was treated with the proteasome inhibitor bortezomib followed by a multiplexed mass spectrometry-based proteomic analysis at multiple time points (0, 6, 12, 16, and 20 hours) over 20 hours to further understand the cellular response of these cells to proteasome inhibition.
2023-02-15 | PXD038845 | Pride
Project description:Germline and somatic mutations in BRCA1predispose to breast cancer. We found that proteasome inhibitors can selectively kill BRCA1-depleted cells. The toxic response involves a deregulation of the G1/S cell cycle checkpoint via hyperphosphorylation of RB1, 53BP1-mediated arrest at G2/M checkpoint, and ERN1-mediated unfolded protein response, culminating in a TNF receptor-mediated apoptosis. The study new unexpected molecular functions for BRCA1 protein and opens a novel possibility for the treatment of BRCA1-deficient cancers. We used microarrays to detail the global programme of gene expression underlying the response of BRCA1-deficient cells to proteasome inhibitor bortezomib. We aimed to identify genes that are strongly up- or down-regulated with a combination of BRCA1 knockdown and proteasome inhibition, but none of these treatments alone before the onset of apoptosis. HeLa and U2OS cells were transfected either with a non-targeting or anti-BRCA1 siRNAs (siControl or siBRCA1, respectively), treated with bortezomib for 8 hours, after which RNA was extracted for hybridization on Affymetrix microarray. The following treatments have been performed: (T1) siControl; (T2) siControl + 20 nM bortezomib for 8h; (T3) siBRCA1; (T4) siBRCA1 + 20 nM bortezomib for 8h. All samples were used without replicas. However, all genes showing inconsistent expression pattern between the two cell lines were excluded from further consideration. Selected candidate genes were subject to validation by qRT-PCR.
2015-01-01 | E-GEOD-56280 | biostudies-arrayexpress
Project description:The ubiquitin-proteasome system (UPS) has recently emerged as a major target for drug development in cancer therapy. The proteasome inhibitor bortezomib has clinical activity in multiple myeloma and mantle cell lymphoma. Here we report that Eeyarestatin I (EerI), a chemical inhibitor that blocks ER-associated protein degradation (ERAD), has anti-tumor and biologic activities similar to bortezomib, and can synergize with bortezomib. Like bortezomib, EerI-induced cytotoxicity requires the upregulation of the BH3 only pro-apoptotic protein NOXA. We further demonstrate that both EerI and bortezomib activate NOXA via an unanticipated mechanism that requires cooperation between two processes: First, these agents elicit an integrated stress response program at the ER to activate the CREB/ATF transcription factors ATF3 and ATF4. We show that ATF3 and ATF4 form a complex capable of binding to the NOXA promoter, which is required for NOXA activation. Second, EerI and bortezomib also block ubiquitination of histone H2A to relieve its inhibition on NOXA transcription. Our results identify a class of anti-cancer agents that integrate ER stress response with an epigenetic mechanism to induce cell death. Experiment Overall Design: 1. EerI 10 vs 0 Experiment Overall Design: 2. EerI 10 vs 0 Experiment Overall Design: 3. Bzm 10 vs 0 Experiment Overall Design: 4. Bzm 10 vs 0
2009-02-28 | E-GEOD-14003 | biostudies-arrayexpress