Ubiquitin proteasome expression in Mulitple Myeloma cell lines
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE78884 | GEO | 2016/10/31
SECONDARY ACCESSION(S): PRJNA314296
REPOSITORIES: GEO
Similar Datasets
Project description:This study provides a genome-wide map of changes in degradative ubiquitination in response to proteasome inhibition in the multiple myeloma cell line MM.1S. Following proteasome inhibition with lactacystin, CUT and RUN assays were carried out to determine the genomic locations of ubiquitin in multiple myeloma cells stably expressing a flagged version of ubiquitin (MM.1S-3XFlag Ubiquitin cells). In addition, we report the DNA binding locations of the transcription factor c-MYC in basal conditions in MM.1S parental cells.
2022-11-21 | GSE193302 | GEO
Project description:Resistance to proteasome inhibitors has prompted interest in blocking upstream components of the ubiquitin-proteasome pathway for the treatment of multiple myeloma (MM). We therefore evaluated the activity of TAK-243, a novel and specific inhibitor of E1 ubiquitin activating enzyme (UAE) activity, in the MM cell line MM1.S. Treatment of MM1.S with 25 nM TAK-243 for 24 hr caused extensive changes in gene expression, highly uniform between triplicates.
2019-05-01 | GSE126254 | 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:Modulation of the activity of the ubiquitin-proteasome pathway with the proteasome inhibitor (PI) is an established component of therapy for plasma cell disorders. However, resistance emerges and the mechanism is incompletely understood. We generated carfilzomib-resistant (CR) myeloma cell lines by exposing drug-naive ANBL-6, KAS-6/1, U266, and OPM-2 cells to increasing concentrations of carfilzomib and then performed gene expression profiling (GEP) to identify prominent changes compared to their vehicle-treated counterparts, followed by exploration of the mechanism(s) of proteasome inhibitor resistance.
2016-10-09 | GSE62237 | GEO
Project description:The E3 Ubiquitin Ligase AFF1 targets ARF19 to the proteasome
| PRJNA723009 | ENA
Project description:Proctor2007 - Age related decline of proteolysis, ubiquitin-proteome system
This
is a stochastic model of the ubiquitin-proteasome system for a
generic pool of native proteins (NatP), which have a half-life of
about 10 hours under normal conditions. It is assumed that these
proteins are only degraded after they have lost their native
structure due to a damage event. This is represented in the model
by the misfolding reaction which depends on the level of reactive
oxygen species (ROS) in the cell. Misfolded proteins (MisP) are
first bound by an E3 ubiquitin ligase. Ubiquitin (Ub) is
activated by E1 (ubiquitin-activating enzyme) and then passed to
E2 (ubiquitin-conjugating enzyme). The E2 enzyme then passes the
ubiquitin molecule to the E3/MisP complex with the net effect
that the misfolded protein is monoubiquitinated and both E2 and
E3 are released. Further ubiquitin molecules are added in a
step-wise manner. When the chain of ubiquitin molecules is of
length 4 or more, the polyubiquitinated misfolded protein may
bind to the proteasome. The model also includes de-ubiquitinating
enzymes (DUB) which cleave ubiquitin molecules from the chain in
a step-wise manner. They work on chains attached to misfolded
proteins both unbound and bound to the proteasomes. Misfolded
proteins bound to the proteasome may be degraded releasing
ubiquitin. Misfolded proteins including ubiquitinated proteins
may also aggregate. Aggregates (AggP) may be sequestered
(Seq_AggP) which takes them out of harm's way or they may bind to
the proteasome (AggP_Proteasome). Proteasomes bound by aggregates
are no longer available for protein degradation.
Figure
2 and Figure 3 has been simulated using Gillespie2.
This model is described in the article:
An in silico model of the
ubiquitin-proteasome system that incorporates normal
homeostasis and age-related decline.
Proctor CJ, Tsirigotis M, Gray
DA.
BMC Syst Biol 2007; 1: 17
Abstract:
BACKGROUND: The ubiquitin-proteasome system is responsible
for homeostatic degradation of intact protein substrates as
well as the elimination of damaged or misfolded proteins that
might otherwise aggregate. During ageing there is a decline in
proteasome activity and an increase in aggregated proteins.
Many neurodegenerative diseases are characterised by the
presence of distinctive ubiquitin-positive inclusion bodies in
affected regions of the brain. These inclusions consist of
insoluble, unfolded, ubiquitinated polypeptides that fail to be
targeted and degraded by the proteasome. We are using a systems
biology approach to try and determine the primary event in the
decline in proteolytic capacity with age and whether there is
in fact a vicious cycle of inhibition, with accumulating
aggregates further inhibiting proteolysis, prompting
accumulation of aggregates and so on. A stochastic model of the
ubiquitin-proteasome system has been developed using the
Systems Biology Mark-up Language (SBML). Simulations are
carried out on the BASIS (Biology of Ageing e-Science
Integration and Simulation) system and the model output is
compared to experimental data wherein levels of ubiquitin and
ubiquitinated substrates are monitored in cultured cells under
various conditions. The model can be used to predict the
effects of different experimental procedures such as inhibition
of the proteasome or shutting down the enzyme cascade
responsible for ubiquitin conjugation. RESULTS: The model
output shows good agreement with experimental data under a
number of different conditions. However, our model predicts
that monomeric ubiquitin pools are always depleted under
conditions of proteasome inhibition, whereas experimental data
show that monomeric pools were depleted in IMR-90 cells but not
in ts20 cells, suggesting that cell lines vary in their ability
to replenish ubiquitin pools and there is the need to
incorporate ubiquitin turnover into the model. Sensitivity
analysis of the model revealed which parameters have an
important effect on protein turnover and aggregation kinetics.
CONCLUSION: We have developed a model of the
ubiquitin-proteasome system using an iterative approach of
model building and validation against experimental data. Using
SBML to encode the model ensures that it can be easily modified
and extended as more data become available. Important aspects
to be included in subsequent models are details of ubiquitin
turnover, models of autophagy, the inclusion of a pool of
short-lived proteins and further details of the aggregation
process.
This model is hosted on
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and identified by:
BIOMD0000000105.
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2007-04-02 | BIOMD0000000105 | BioModels
Project description:Oculopharyngeal muscular dystrophy (OPMD) is a late-onset progressive muscle disorder caused by a poly-alanine expansion mutation in PABPN1. The hallmark of OPMD is the accumulation of the mutant protein in insoluble nuclear inclusions. The molecular mechanisms associated with disease onset and progression are unknown. We performed a high-throughput cross-species transcriptome study of affected muscles from two OPMD animal models and from patients at pre-symptomatic and symptomatic stages. The most consistently and significantly OPMD-deregulated pathway across species is the ubiquitin-proteasome system (UPS). By analyzing expression profiles, we found that the majority of OPMD-deregulated genes are age-associated. Based on expression trends, disease onset can be separated from progression; the expression profiles of the proteasome-encoding genes are associated with onset but not with progression. In a muscle cell model, proteasome inhibition and the stimulation of immunoproteasome specifically affect the accumulation and aggregation of mutant PABPN1. We suggest that proteasome down-regulation during muscle aging triggers the accumulation of expPABPN1 that in turn enhances proteasome deregulation and leads to intranuclear inclusions (INI) formation.
2011-04-19 | GSE26605 | GEO
Project description:Proteasome inhibitors are important chemotherapeutics in the treatment of multiple myeloma, but they are currently used empirically as no markers of sensitivity have been validated. We have identified expression of tight junction protein (TJP) 1 as being associated with sensitivity of plasma cells in vitro and in vivo to proteasome inhibitors. TJP1 suppressed expression of genes in the major histocompatibility class II region, including two catalytically active immunoproteasome subunits, thereby decreasing proteasome activity, a critical determinant of proteasome inhibitor sensitivity. This occurred through suppression by TJP1 of signaling through the epidermal growth factor receptor/Janus kinase 1/signal transducer and activator of transcription 3 pathway. In the clinic, high TJP1 expression in myeloma patients was associated with a significantly higher likelihood of responding to bortezomib, and with a longer time-to-progression after treatment. Taken together, these data support the use of TJP1 as a biomarker of sensitivity and resistance to proteasome inhibitors. To further elucidate mechanisms of bortezomib resistance, we developed human-derived multiple myeloma cell lines with a 4-fold or greater resistance to bortezomib. Then total RNA for bortezomib resistant (BR) and wild type (WT) was extracted and used for comparison by gene expression profiling.
2015-12-31 | E-GEOD-52369 | biostudies-arrayexpress
Project description:Bortezomib (BTZ), Carfilzomib (CFZ) and Ixazomib (IXA) are proteasome inhibitors (PI) approved for Multiple Myeloma (MM) treatment. By design, they all target the rate-limiting proteasome beta 5 (B5) subunit. CFZ treatment increases the survival of patients with relapsed/refractory MM compared to BTZ but is associated with heart failure not commonly observed for BTZ. The molecular basis for CFZ-induced cardiotoxicity is poorly understood. We time to investigate the transcriptomic effects of acute proteasome inhibition in the murine heart.
2023-07-01 | E-MTAB-11028 | 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