Comparative global transcriptomic profiling of low and high concentration of lactacystin-mediated neuronal death
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE23155 | GEO | 2013/12/31
SECONDARY ACCESSION(S): PRJNA131567
REPOSITORIES: GEO
Similar Datasets
Project description:Inhibition of proteasome degradation pathway has been implicated in neuronal cell death leading to neurodegenerative diseases such as Parkinson’s disease and Alzheimer’s disease. Pharmacological proteasomal inhibitors such as lactacystin can induce apoptosis in cultured mouse cortical neurons through the activation of caspase-3. However, Meiners et al., 2003 suggested that low dose of lactacystin induces a concerted expression of proteasome genes and de novo formation of proteasomes. We discovered by microarray analysis that lactacystin treatment induces a dose-dependent biphasic modulation of both potentially neuroprotective as well as pro-apoptotic genes in neurons. Microarray analysis was carried out using 24 Illumina mouse Ref8V1.1 genechip arrays. The assignment of the arrays was as follows: Controls (n=6); exposure to 1 ?M (High) lactacystin for 5h, 8h, 15h and 24 h (n=3 respectively) and 0.1uM (Low) for 15h and 24h (n=3 respectively).
2013-12-31 | E-GEOD-23155 | biostudies-arrayexpress
Project description:Inhibition of proteasome degradation pathway has been implicated in neuronal cell death leading to neurodegenerative diseases such as Parkinson’s disease and Alzheimer’s disease. Pharmacological proteasomal inhibitors such as lactacystin can induce apoptosis in cultured mouse cortical neurons through the activation of caspase-3. Furthermore, proteasomal inhibitors are also reported to mediate deleterious alterations in cell cycle regulation, inflammatory processes and protein aggregation and trigger the cell death pathway. We discovered by microarray analysis that lactacystin treatment modulates the expression of both potentially neuroprotective as well as pro-apoptotic genes in neurons. However, the genes, upon transcriptional modulation, contribute to proteasomal inhibition-induced apoptosis, remains unidentified. By employing microarray analysis to decipher the time-dependent changes in transcription of these genes in cultured cortical neurons, we discovered different groups of genes were transcriptionally regulated at different phases of lactacystin-induced cell death.
2012-01-03 | GSE22465 | GEO
Project description:Inhibition of proteasome degradation pathway has been implicated in neuronal cell death leading to neurodegenerative diseases such as ParkinsonM-bM-^@M-^Ys disease and AlzheimerM-bM-^@M-^Ys disease. Pharmacological proteasomal inhibitors such as lactacystin can induce apoptosis in cultured mouse cortical neurons through the activation of caspase-3. Furthermore, proteasomal inhibitors are also reported to mediate deleterious alterations in cell cycle regulation, inflammatory processes and protein aggregation and trigger the cell death pathway. We discovered by microarray analysis that lactacystin treatment modulates the expression of both potentially neuroprotective as well as pro-apoptotic genes in neurons. However, the genes, upon transcriptional modulation, contribute to proteasomal inhibition-induced apoptosis, remains unidentified. By employing microarray analysis to decipher the time-dependent changes in transcription of these genes in cultured cortical neurons, we discovered different groups of genes were transcriptionally regulated at different phases of lactacystin-induced cell death. Microarray analysis was carried out using 10 murine genome U74A and U74Av2 Genechips array (Affymetrix, Santa Clara, CA). The assignment of the arrays (GeneChip) was as follows: Control at 24 h (n=2), 48 h (n=2); exposure to 1 M-NM-<M lactacystin for 24 h (n=3) and 48 h (n=3).
2012-01-03 | E-GEOD-22465 | biostudies-arrayexpress
Project description:Purpose: We report the NGS-derived transcriptome profiling (paired-end RNA-seq) following proteasome inhibition in the multiple myeloma cell line MM.1S. Methods: MM.1S cells were treated for six hours with the synthetic proteasome inhibitor lactacystin or clinically-approved proteasome inhibitor bortezomib and RNA expression changes were quantified and compared to DMSO control-treated cells by RNA-sequencing.
2021-03-06 | GSE166122 | GEO
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.
2022-11-21 | GSE193301 | GEO
Project description:Purpose: We report the NGS-derived transcriptome profiling (paired-end RNA-seq) following proteasome inhibition in the multiple myeloma cell line MM.1S. Methods: MM.1S cells were treated for six hours with the synthetic proteasome inhibitor lactacystin and RNA expression changes were quantified and compared to DMSO control-treated cells by RNA-sequencing.
2022-11-21 | GSE193300 | GEO
Project description:Proteasomes degrade most intracellular proteins. Several different forms of proteasomes are known. Proteasome inhibitors targeting different proteasome forms are used in clinical practice and were shown to modulate long-term potentiation (LTP) in hippocampal slices of untreated animals. Here we studied the effect of chronic administration of non-constitutive proteasome inhibitor ONX-0914 on the LTP induced by two different protocols: tetanic stimulation and theta-burst stimulation (TBS). Excitatory postsynaptic potentials (fEPSPs) in hippocampal slices from control animals and animals treated with DMSO or ONX-0914 were compared. The TBS stimulation did not change LTP kinetics in hippocampal slices, however chronic administration of ONX-0914 led to the decrease in fEPSP slopes after tetanic stimulation. Observed effects correlated with differential expression of genes involved in synaptic plasticity, glutaminergic synapse and synaptic signaling. Obtained results indicate that non-constitutive proteasomes are likely involved in the tetanus-evoked LTP but not the LTP occurring after TBS, supporting the relevance and complexity of the role of proteasomes in the synaptic plasticity.
2023-04-05 | GSE229000 | GEO
Project description:Sneppen2009 - Modeling proteasome dynamics in
Parkinson's disease
This model is described in the article:
Modeling proteasome dynamics
in Parkinson's disease.
Sneppen K, Lizana L, Jensen MH,
Pigolotti S, Otzen D.
Phys Biol 2009; 6(3): 036005
Abstract:
In Parkinson's disease (PD), there is evidence that
alpha-synuclein (alphaSN) aggregation is coupled to
dysfunctional or overburdened protein quality control systems,
in particular the ubiquitin-proteasome system. Here, we develop
a simple dynamical model for the on-going conflict between
alphaSN aggregation and the maintenance of a functional
proteasome in the healthy cell, based on the premise that
proteasomal activity can be titrated out by mature alphaSN
fibrils and their protofilament precursors. In the presence of
excess proteasomes the cell easily maintains homeostasis.
However, when the ratio between the available proteasome and
the alphaSN protofilaments is reduced below a threshold level,
we predict a collapse of homeostasis and onset of oscillations
in the proteasome concentration. Depleted proteasome opens for
accumulation of oligomers. Our analysis suggests that the onset
of PD is associated with a proteasome population that becomes
occupied in periodic degradation of aggregates. This behavior
is found to be the general state of a proteasome/chaperone
system under pressure, and suggests new interpretations of
other diseases where protein aggregation could stress elements
of the protein quality control system.
This model is hosted on
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and identified by:
BIOMD0000000548.
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To the extent possible under law, all copyright and related or
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2024-09-02 | BIOMD0000000548 | BioModels
Project description:A composition of proteasome complexes in WT yeast, and the changes these complexes undergo upon the deletion of Pre9 (Δα3) or of Sem1 (ΔSem1) based on whole-cell proteomic analysis and to activity-guided proteasome profiling of indicates that the amounts of proteasomal proteins and proteasome interacting proteins in the assembled active proteasomes differ significantly from their total amounts in the cell as a whole. This data set is of the activity-guided profiling of the proteasome LFQ analysis.
2024-02-15 | PXD045051 | Pride
Project description:Disruption in proteostasis is a hallmark of cancer, with aberrations in proteasome-mediated degradation highly implicated in this malignancy. Proteasomes further bear critical importance in tumor immunogenicity by regulating inflammatory signaling, promoting immune cell activation and playing a crucial role in antigen processing and presentation. Indeed, response to immunotherapy in melanoma patients has been recently linked to increased expression of immunoproteasomes, a specialized form of proteasomes that are upregulated under inflammatory conditions. Yet, the percentage of patients that respond to therapy remains low, and the underlying mechanisms driving resistance remain poorly understood. Further, comprehensive analysis of the role proteasomes play in the pathophysiology of cancer and as a modulator of anti-tumor immunity is remains lacking. Here, we show that proteasome complex composition varies across cancer types and can be used to stratify patient response to immunotherapy. Specifically, we found that the proteasome regulator PSME4 is upregulated in NSCLC and associated with poor prognosis. We show that PSME4 alters proteasome activity and antigen processing attenuating the antigenic diversity and presentation. Through exacting biochemical assays, proteasome profiling of patient-derived NSCLC samples, combined with scRNA-seq, immunopeptidomics and in vivo analyses we uncovered a novel mechanism of immune evasion mediated by PSME4, which promotes an immunosuppressive tumor microenvironment and abrogates anti-tumor immunity. Collectively, our approach may be adapted to other cancer types and pathological settings and affords a novel paradigm by which proteasome composition heterogeneity should be examined and targeted in the context of precision oncology.
2023-02-26 | GSE201460 | GEO