Homo sapiens
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PROVIDER: PRJNA127685 | ENA |
REPOSITORIES: ENA
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Project description:Carbon monoxide (CO) abrogates TNF-alpha mediated inflammatory responses in endothelial cells, yet, the underlying mechanism hereof is still elusive. We sought to explore potential mechanisms by which CO down-regulates VCAM-1 expression on TNF-alpha stimulated human umbilical vein endothelial cells (HUVEC). By genome-wide gene expression profiling and pathway analysis we studied the relevance of particular pathways for the anti-inflammatory effect of CO. In CO-releasing molecules-3 (CORM-3) stimulated HUVEC, significant changes in gene expression were found for genes implicated in the proteasome and porphyrine pathways. Although proteasome activities were increased by CORM-3, proteasome inhibitors did not abolish CORM-3‘s effect. Likewise, HO-1 inhibitors did not abrogate the ability of CORM-3 to down-regulate VCAM-1 expression. MAPK p38 was inhibited by CORM-3. Accordingly, VCAM-1 expression was down-regulated by the p38 inhibitor SB203580. Down-regulation of VCAM-1 by CORM-3 only occurred at concentrations that partly inhibit ATP production. Sodium azide and oligomycin paralleled the effect of CORM-3 in this regard. In conclusion, down-regulation of VCAM-1 by CORM-3 seems to be mediated via inhibition of p38 and mitochondrial respiration. Although CORM-3 up-regulates several genes in the ubiquitin proteasome sytem (UPS) or porphyrin pathway, there is no evidence that these changes are involved in the anti-inflammatory properties of CORM-3. In this study we focused on the potential of CORM-3 to downregulate the expression of TNF-alpha mediated inflammataroy genes
2011-07-11 | E-GEOD-22175 | biostudies-arrayexpress
Project description:Carbon monoxide (CO) abrogates TNF-alpha mediated inflammatory responses in endothelial cells, yet, the underlying mechanism hereof is still elusive. We sought to explore potential mechanisms by which CO down-regulates VCAM-1 expression on TNF-alpha stimulated human umbilical vein endothelial cells (HUVEC). By genome-wide gene expression profiling and pathway analysis we studied the relevance of particular pathways for the anti-inflammatory effect of CO. In CO-releasing molecules-3 (CORM-3) stimulated HUVEC, significant changes in gene expression were found for genes implicated in the proteasome and porphyrine pathways. Although proteasome activities were increased by CORM-3, proteasome inhibitors did not abolish CORM-3‘s effect. Likewise, HO-1 inhibitors did not abrogate the ability of CORM-3 to down-regulate VCAM-1 expression. MAPK p38 was inhibited by CORM-3. Accordingly, VCAM-1 expression was down-regulated by the p38 inhibitor SB203580. Down-regulation of VCAM-1 by CORM-3 only occurred at concentrations that partly inhibit ATP production. Sodium azide and oligomycin paralleled the effect of CORM-3 in this regard. In conclusion, down-regulation of VCAM-1 by CORM-3 seems to be mediated via inhibition of p38 and mitochondrial respiration. Although CORM-3 up-regulates several genes in the ubiquitin proteasome sytem (UPS) or porphyrin pathway, there is no evidence that these changes are involved in the anti-inflammatory properties of CORM-3.
2011-07-11 | GSE22175 | GEO
Project description:Inhibition of VCAM-1 expression by CORM-3: the role of the ubiquitin proteasome system, p38 and mitochondrial respiration
| PRJNA127685 | ENA
Project description:We established an assay to localize DNA-associated proteins that are slated for degradation by the ubiquitin-proteasome system. The genome-wide map we describe here ties proteolysis to active enhancer elements and to transcription start sites of specific gene families. ChIP-sequencing of ubiquitin and transcription factors was performed in the presence or absence of proteasome inhibition.
2013-12-01 | E-GEOD-33821 | biostudies-arrayexpress
Project description:The ubiquitin proteasome system plays an important role in the pathophysiology of Multiple Myeloma, highlighted by the unique success of proteasome inhibitors in this malignancy. Using topic-defined microarrays we have looked at expression of ubiquitin proteasome system genes in 2 multiple myeloma cell lines and normal bone marrow samples.
2016-10-31 | GSE78884 | GEO
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
BioModels Database
and identified by:
BIOMD0000000105.
To cite BioModels Database, please use:
BioModels Database:
An enhanced, curated and annotated resource for published
quantitative kinetic models.
To the extent possible under law, all copyright and related or
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the public domain worldwide. Please refer to
CC0
Public Domain Dedication for more information.
2024-09-02 | BIOMD0000000105 | BioModels
Project description:This a model from the article:
Modelling the Role of UCH-L1 on Protein Aggregation in
Age-Related Neurodegeneration.
Proctor CJ, Tangeman PJ, Ardley HC. PLoS One.
2010 Oct 6;5(10):e13175 20949132
,
Abstract:
Overexpression of the de-ubiquitinating enzyme UCH-L1 leads to inclusion formation in response to proteasome impairment. These inclusions contain components of the ubiquitin-proteasome system and α-synuclein confirming that the ubiquitin-proteasome system plays an important role in protein aggregation. The processes involved are very complex and so we have chosen to take a systems biology approach to examine the system whereby we combine mathematical modelling with experiments in an iterative process. The experiments show that cells are very heterogeneous with respect to inclusion formation and so we use stochastic simulation. The model shows that the variability is partly due to stochastic effects but also depends on protein expression levels of UCH-L1 within cells. The model also indicates that the aggregation process can start even before any proteasome inhibition is present, but that proteasome inhibition greatly accelerates aggregation progression. This leads to less efficient protein degradation and hence more aggregation suggesting that there is a vicious cycle. However, proteasome inhibition may not necessarily be the initiating event. Our combined modelling and experimental approach show that stochastic effects play an important role in the aggregation process and could explain the variability in the age of disease onset. Furthermore, our model provides a valuable tool, as it can be easily modified and extended to incorporate new experimental data, test hypotheses and make testable predictions.
To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication
for more information.
In summary, you are entitled to use this encoded model in absolutely any manner you deem suitable, verbatim, or with modification, alone or embedded it in a larger context, redistribute it, commercially or not, in a restricted way or not.
To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.
2024-09-02 | BIOMD0000000293 | BioModels
Project description:Aging and neurodegeneration are often accompanied by a functionally impaired ubiquitin-proteasome system (UPS). In tauopathies and polyglutamine diseases a mutant form of Ubiquitin B, UBB+1, accumulates in disease-specific aggregates. UBB+1 mRNA is generated at low levels in vivo during transcription from the Ubiquitin B locus by molecular misreading. The resulting mutant protein has been shown to inhibit proteasome function. To elucidate causative effects and neuropathological consequences of UBB+1 accumulation, we used a UBB+1 expressing transgenic mouse line, that models UPS inhibition in neurons and exhibits behavioral phenotypes reminiscent of Alzheimer’s disease (AD). In order to reveal affected organs and functions, young and aged UBB+1 transgenic mice were comprehensively phenotyped for more than 240 parameters. This revealed unexpected changes in spontaneous breathing patterns and an altered response to hypoxic conditions. Our findings point to a central dysfunction of respiratory regulation in transgenic mice in comparison to wildtype littermate mice. Accordingly, UBB+1 was strongly expressed in brainstem regions of transgenic mice controlling respiration. These regions included, for example, the medial part of the nucleus of the tractus solitarius and the lateral subdivisions of the parabrachial nuclei. In addition, UBB+1 was also strongly expressed in these anatomical structures of AD patients (Braak stage #6) and was not expressed in non-demented controls. We conclude that long-term UPS inhibition due to UBB+1 expression causes central breathing dysfunction in a transgenic mouse model of AD. The UBB+1 expression pattern in humans is consistent with the contribution of bronchopneumonia as a cause of death in AD patients. 12 animals were analysed (6 Ubb+1 transgenic animals, 6 wildtype animals) on MOE430A/B arrays (for MOE430A one wt was omitted).
2012-06-12 | E-GEOD-13691 | biostudies-arrayexpress
Project description:VCP is an evolutionary conserved ubiquitin-dependent ATPase that mediates the degradation of proteins through the ubiquitin-proteasome pathway. Despite the central role of VCP in the regulation of protein homeostasis, identity and nature of its cellular substrates remain poorly defined. Here, we combined chemical inhibition of VCP and quantitative ubiquitin remnant profiling to assess the effect of VCP inhibition on the ubiquitin-modified proteome and to probe the substrate spectrum of VCP in human cells. We demonstrate that inhibition of VCP perturbs cellular ubiquitylation and increases ubiquitylation of a different subset of proteins compared to proteasome inhibition. VCP inhibition globally upregulates K6-linked ubiquitylation that is dependent on the HECT-type ubiquitin E3 ligase HUWE1. We report ~450 putative VCP substrates, many of which function in nuclear processes, including gene expression, DNA repair and cell cycle. Moreover, we identify that VCP regulates the level and activity of the transcription factor c-Myc.
2018-02-08 | GSE107313 | GEO
Project description:The proteasome is the main proteolytic system for targeted protein degradation in the cell. Its function is fine-tuned according to cellular needs. Inhibition of the respiratory chain impairs proteasome activity, regulation of proteasome function by mitochondrial metabolism, however, is unknown. Here, we demonstrate that mitochondrial dysfunction reduces the assembly and activity of the 26S proteasome. Defects in respiratory chain caused metabolic reprogramming of the Krebs cycle and deficiency in the amino acid aspartate resulting in reduced 26S proteasome function. Aspartate supplementation fully restored assembly and activity of 26S proteasome complexes. This metabolic reprogramming involved sensing of aspartate via the mTORC1 pathway and the mTORC1-dependent transcriptional activation of defined proteasome assembly factors. Metabolic regulation of 26S function was confirmed in patient-derived skin fibroblasts with respiratory dysfunction containing a single mitochondrial mutation. Importantly, treatment of primary human lung fibroblasts with the respiratory chain inhibitor and anti-diabetic drug metformin similarly reduced assembly and activity of 26S proteasome complexes, which was fully reversible and rescued by supplementation of aspartate or pyruvate. Of note, reduced 26S activity conferred increased resistance towards the proteasome inhibitor Bortezomib, which was reversible upon pyruvate supplementation. Our study uncovers a fundamental novel mechanism of how mitochondrial metabolism adaptively adjusts protein degradation by the proteasome. It thus unravels unexpected consequences of defective mitochondrial metabolism in disease or drug-targeted mitochondrial reprogramming for proteasomal protein degradation in the cell. As metabolic inhibition of proteasome function can be alleviated by treatment with aspartate or pyruvate, our results also have therapeutic implications.
2020-07-26 | GSE153983 | GEO