106 results on '"Ubiquitin proteasome system (UPS)"'
Search Results
2. 5-HT4 receptor agonists treatment reduces tau pathology and behavioral de?cit in the PS19 mouse model of tauopathy.
- Author
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Shan Jiang, Sydney, Eric J., Runyan, Avery M., Serpe, Rossana, Figueroa, Helen Y., Mu Yang, and Natura Myeku
- Subjects
TAUOPATHIES ,TAU proteins ,NEST building ,LABORATORY mice ,ALZHEIMER'S disease ,ANIMAL disease models ,SYNAPSES - Abstract
Background: Accumulation of tau in synapses in the early stages of Alzheimer's disease (AD) has been shown to cause synaptic damage, synaptic loss, and the spread of tau pathology through trans-synaptically connected neurons. Moreover, synaptic loss correlates with a decline in cognitive function, providing an opportunity to investigate therapeutic strategies to target synapses and synaptic tau to rescue or prevent cognitive decline in AD. One of the promising synaptic targets is the 5-HT4 serotonergic receptor present postsynaptically in the brain structures involved in the memory processes. 5-HT4R stimulation exerts synaptogenic and pro-cognitive effects involving synapse-to-nucleus signaling essential for synaptic plasticity. However, it is not known whether 5-HT4R activation has a therapeutic effect on tau pathology. Methods: The goal of this study was to investigate the impact of chronic stimulation of 5-HT4R by two agonists, prucalopride and RS-67333, in PS19 mice, a model of tauopathy. We utilized gradient assays to isolate pre- and post-synaptic compartments, followed by biochemical analyses for tau species and ubiquitinated proteins in the synaptic compartments and total brain tissue. Next, we performed kinetic assays to test the proteasome's hydrolysis capacity in treatment conditions. Moreover, behavioral tests such as the open field and non-maternal nest-building tests were used to evaluate anxiety-like behaviors and hippocampal-related cognitive functioning in the treatment paradigm. Results: Our results show that 5-HT4R agonism reduced tauopathy, reduced synaptic tau, increased proteasome activity, and improved cognitive functioning in PS19 mice. Our data suggest that enhanced proteasome activity by synaptic mediated signaling leads to the enhanced turnover of tau initially within synapses where the receptors are localized, and over time, the treatment attenuated the accumulation of tau aggregation and improved cognitive functioning of the PS19 mice. Conclusion: Therefore, stimulation of 5-HT4R offers a promising therapy to rescue synapses from the accumulation of toxic synaptic tau, evident in the early stages of AD. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
3. A Survey on the Expression of the Ubiquitin Proteasome System Components HECT- and RBR-E3 Ubiquitin Ligases and E2 Ubiquitin-Conjugating and E1 Ubiquitin-Activating Enzymes during Human Brain Development.
- Author
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Magnati, Stefano, Alladio, Eugenio, and Bracco, Enrico
- Subjects
- *
UBIQUITIN ligases , *UBIQUITINATION , *NEURAL development , *UBIQUITIN , *MACHINE learning , *GENE expression profiling - Abstract
Human brain development involves a tightly regulated sequence of events that starts shortly after conception and continues up to adolescence. Before birth, neurogenesis occurs, implying an extensive differentiation process, sustained by changes in the gene expression profile alongside proteome remodeling, regulated by the ubiquitin proteasome system (UPS) and autophagy. The latter processes rely on the selective tagging with ubiquitin of the proteins that must be disposed of. E3 ubiquitin ligases accomplish the selective recognition of the target proteins. At the late stage of neurogenesis, the brain starts to take shape, and neurons migrate to their designated locations. After birth, neuronal myelination occurs, and, in parallel, neurons form connections among each other throughout the synaptogenesis process. Due to the malfunctioning of UPS components, aberrant brain development at the very early stages leads to neurodevelopmental disorders. Through deep data mining and analysis and by taking advantage of machine learning-based models, we mapped the transcriptomic profile of the genes encoding HECT- and ring-between-ring (RBR)-E3 ubiquitin ligases as well as E2 ubiquitin-conjugating and E1 ubiquitin-activating enzymes during human brain development, from early post-conception to adulthood. The inquiry outcomes unveiled some implications for neurodevelopment-related disorders. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
4. A Survey on the Expression of the Ubiquitin Proteasome System Components HECT- and RBR-E3 Ubiquitin Ligases and E2 Ubiquitin-Conjugating and E1 Ubiquitin-Activating Enzymes during Human Brain Development
- Author
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Stefano Magnati, Eugenio Alladio, and Enrico Bracco
- Subjects
brain development ,neurodevelopmental disorders ,neurodegenerative disorders ,ubiquitin proteasome system (UPS) ,proteome remodeling ,machine learning and model classification ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Human brain development involves a tightly regulated sequence of events that starts shortly after conception and continues up to adolescence. Before birth, neurogenesis occurs, implying an extensive differentiation process, sustained by changes in the gene expression profile alongside proteome remodeling, regulated by the ubiquitin proteasome system (UPS) and autophagy. The latter processes rely on the selective tagging with ubiquitin of the proteins that must be disposed of. E3 ubiquitin ligases accomplish the selective recognition of the target proteins. At the late stage of neurogenesis, the brain starts to take shape, and neurons migrate to their designated locations. After birth, neuronal myelination occurs, and, in parallel, neurons form connections among each other throughout the synaptogenesis process. Due to the malfunctioning of UPS components, aberrant brain development at the very early stages leads to neurodevelopmental disorders. Through deep data mining and analysis and by taking advantage of machine learning-based models, we mapped the transcriptomic profile of the genes encoding HECT- and ring-between-ring (RBR)-E3 ubiquitin ligases as well as E2 ubiquitin-conjugating and E1 ubiquitin-activating enzymes during human brain development, from early post-conception to adulthood. The inquiry outcomes unveiled some implications for neurodevelopment-related disorders.
- Published
- 2024
- Full Text
- View/download PDF
5. Proteasomes of Autophagy-Deficient Cells Exhibit Alterations in Regulatory Proteins and a Marked Reduction in Activity.
- Author
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Xiong, Qiuhong, Feng, Rong, Fischer, Sarah, Karow, Malte, Stumpf, Maria, Meßling, Susanne, Nitz, Leonie, Müller, Stefan, Clemen, Christoph S., Song, Ning, Li, Ping, Wu, Changxin, and Eichinger, Ludwig
- Subjects
- *
CHIMERIC proteins , *IMMUNOPRECIPITATION , *DICTYOSTELIUM discoideum , *PROTEINS , *ORGANELLES , *EUKARYOTIC cells , *PROTEASOMES - Abstract
Autophagy and the ubiquitin proteasome system are the two major processes for the clearance and recycling of proteins and organelles in eukaryotic cells. Evidence is accumulating that there is extensive crosstalk between the two pathways, but the underlying mechanisms are still unclear. We previously found that autophagy 9 (ATG9) and 16 (ATG16) proteins are crucial for full proteasomal activity in the unicellular amoeba Dictyostelium discoideum. In comparison to AX2 wild-type cells, ATG9−and ATG16− cells displayed a 60%, and ATG9−/16− cells a 90%, decrease in proteasomal activity. Mutant cells also showed a significant increase in poly-ubiquitinated proteins and contained large ubiquitin-positive protein aggregates. Here, we focus on possible reasons for these results. Reanalysis of published tandem mass tag-based quantitative proteomic results of AX2, ATG9−, ATG16−, and ATG9−/16− cells revealed no change in the abundance of proteasomal subunits. To identify possible differences in proteasome-associated proteins, we generated AX2 wild-type and ATG16− cells expressing the 20S proteasomal subunit PSMA4 as GFP-tagged fusion protein, and performed co-immunoprecipitation experiments followed by mass spectrometric analysis. The results revealed no significant differences in the abundance of proteasomes between the two strains. However, we found enrichment as well as depletion of proteasomal regulators and differences in the ubiquitination of associated proteins for ATG16−, as compared to AX2 cells. Recently, proteaphagy has been described as a means to replace non-functional proteasomes. We propose that autophagy-deficient D. discoideum mutants suffer from inefficient proteaphagy, which results in the accumulation of modified, less-active, and also of inactive, proteasomes. As a consequence, these cells exhibit a dramatic decrease in proteasomal activity and deranged protein homeostasis. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
6. Chaperone-assisted E3 ligase CHIP: A double agent in cancer
- Author
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Sunny Kumar, Malini Basu, and Mrinal K. Ghosh
- Subjects
Chaperones (HSC70/HSP70 & HSP90) ,CHIP ,Oncogene ,Therapy ,Tumor suppressor ,Ubiquitin proteasome system (UPS) ,Medicine (General) ,R5-920 ,Genetics ,QH426-470 - Abstract
The carboxy-terminus of Hsp70-interacting protein (CHIP) is a ubiquitin ligase and co-chaperone belonging to Ubox family that plays a crucial role in the maintenance of cellular homeostasis by switching the equilibrium of the folding-refolding mechanism towards the proteasomal or lysosomal degradation pathway. It links molecular chaperones viz. HSC70, HSP70 and HSP90 with ubiquitin proteasome system (UPS), acting as a quality control system. CHIP contains charged domain in between N-terminal tetratricopeptide repeat (TPR) and C-terminal Ubox domain. TPR domain interacts with the aberrant client proteins via chaperones while Ubox domain facilitates the ubiquitin transfer to the client proteins for ubiquitination. Thus, CHIP is a classic molecule that executes ubiquitination for degradation of client proteins. Further, CHIP has been found to be indulged in cellular differentiation, proliferation, metastasis and tumorigenesis. Additionally, CHIP can play its dual role as a tumor suppressor as well as an oncogene in numerous malignancies, thus acting as a double agent. Here, in this review, we have reported almost all substrates of CHIP established till date and classified them according to the hallmarks of cancer. In addition, we discussed about its architectural alignment, tissue specific expression, sub-cellular localization, folding-refolding mechanisms of client proteins, E4 ligase activity, normal physiological roles, as well as involvement in various diseases and tumor biology. Further, we aim to discuss its importance in HSP90 inhibitors mediated cancer therapy. Thus, this report concludes that CHIP may be a promising and worthy drug target towards pharmaceutical industry for drug development.
- Published
- 2022
- Full Text
- View/download PDF
7. Proteome Birthdating Reveals Age-Selectivity of Protein Ubiquitination.
- Author
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Meadow ME, Broas S, Hoare M, Alimohammadi F, Welle KA, Swovick K, Hryhorenko JR, Martinez JC, Biashad SA, Seluanov A, Gorbunova V, Buchwalter A, and Ghaemmaghami S
- Subjects
- Humans, Proteomics methods, Proteolysis, Ubiquitin metabolism, Ubiquitination, Proteome metabolism, Proteasome Endopeptidase Complex metabolism, Ubiquitinated Proteins metabolism
- Abstract
Within a cell, proteins have distinct and highly variable half-lives. As a result, the molecular ages of proteins can range from seconds to years. How the age of a protein influences its environmental interactions is a largely unexplored area of biology. To investigate the age-selectivity of cellular pathways, we developed a methodology termed "proteome birthdating" that barcodes proteins based on their time of synthesis. We demonstrate that this approach provides accurate measurements of protein turnover kinetics from a single biological sample encoding multiple labeling time-points. As a first application of the birthdated proteome, we investigated the age distribution of the human ubiquitinome. Our results indicate that the vast majority of ubiquitinated proteins in a cell consist of newly synthesized proteins and that these young proteins constitute the bulk of the degradative flux through the proteasome. Rapidly ubiquitinated nascent proteins are enriched in cytosolic subunits of large protein complexes. Conversely, proteins destined for the secretory pathway and vesicular transport have older ubiquitinated populations. Our data also identify a smaller subset of older ubiquitinated cellular proteins that do not appear to be targeted to the proteasome for rapid degradation. Together, our data provide an age census of the human ubiquitinome and establish proteome birthdating as a robust methodology for investigating the protein age-selectivity of diverse cellular pathways., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
- Full Text
- View/download PDF
8. Proteasomes of Autophagy-Deficient Cells Exhibit Alterations in Regulatory Proteins and a Marked Reduction in Activity
- Author
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Qiuhong Xiong, Rong Feng, Sarah Fischer, Malte Karow, Maria Stumpf, Susanne Meßling, Leonie Nitz, Stefan Müller, Christoph S. Clemen, Ning Song, Ping Li, Changxin Wu, and Ludwig Eichinger
- Subjects
autophagy ,ubiquitin proteasome system (UPS) ,Dictyostelium ,ATG9 ,ATG16 ,Cytology ,QH573-671 - Abstract
Autophagy and the ubiquitin proteasome system are the two major processes for the clearance and recycling of proteins and organelles in eukaryotic cells. Evidence is accumulating that there is extensive crosstalk between the two pathways, but the underlying mechanisms are still unclear. We previously found that autophagy 9 (ATG9) and 16 (ATG16) proteins are crucial for full proteasomal activity in the unicellular amoeba Dictyostelium discoideum. In comparison to AX2 wild-type cells, ATG9−and ATG16− cells displayed a 60%, and ATG9−/16− cells a 90%, decrease in proteasomal activity. Mutant cells also showed a significant increase in poly-ubiquitinated proteins and contained large ubiquitin-positive protein aggregates. Here, we focus on possible reasons for these results. Reanalysis of published tandem mass tag-based quantitative proteomic results of AX2, ATG9−, ATG16−, and ATG9−/16− cells revealed no change in the abundance of proteasomal subunits. To identify possible differences in proteasome-associated proteins, we generated AX2 wild-type and ATG16− cells expressing the 20S proteasomal subunit PSMA4 as GFP-tagged fusion protein, and performed co-immunoprecipitation experiments followed by mass spectrometric analysis. The results revealed no significant differences in the abundance of proteasomes between the two strains. However, we found enrichment as well as depletion of proteasomal regulators and differences in the ubiquitination of associated proteins for ATG16−, as compared to AX2 cells. Recently, proteaphagy has been described as a means to replace non-functional proteasomes. We propose that autophagy-deficient D. discoideum mutants suffer from inefficient proteaphagy, which results in the accumulation of modified, less-active, and also of inactive, proteasomes. As a consequence, these cells exhibit a dramatic decrease in proteasomal activity and deranged protein homeostasis.
- Published
- 2023
- Full Text
- View/download PDF
9. Pevonedistat, a NEDD8‐activating enzyme inhibitor, induces apoptosis and augments efficacy of chemotherapy and small molecule inhibitors in pre‐clinical models of diffuse large B‐cell lymphoma
- Author
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Pallawi Torka, Cory Mavis, Shalin Kothari, Sarah Belliotti, Juan Gu, Suchitra Sundaram, Matthew Barth, and Francisco J. Hernandez‐Ilizaliturri
- Subjects
Apoptosis ,MLN4924 ,NF‐κB ,non‐Hodgkin lymphoma ,ubiquitin proteasome system (UPS) ,Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Abstract We studied the biological activity of pevonedistat, a first‐in‐class NEDD8‐activating enzyme (NAE) inhibitor, in combination with various cytotoxic chemotherapy agents and small molecule inhibitors in lymphoma preclinical models. Pevonedistat induced cell death in activated B‐cell (ABC) diffuse large B‐cell lymphoma (DLBCL) cell lines and to a lesser degree in germinal center B‐cell (GCB) DLBCL cell lines. In pevonedistat sensitive cells, we observed inhibition of NF‐κB activity by p65 co‐localization studies, decreased expression of BCL‐2/Bcl‐XL, and upregulation of BAK levels. Pevonedistat enhanced the activity of cytarabine, cisplatin, doxorubicin, and etoposide in ABC‐, but not in the GCB‐DLBCL cell lines. It also exhibited synergy with ibrutinib, selinexor, venetoclax, and A‐1331852 (a novel BCL‐XL inhibitor). In vivo, the combination of pevonedistat and ibrutinib or pevonedistat and cytarabine prolonged survival in SCID mice xenograft models when compared with monotherapy controls. Our data suggest that targeting the neddylation pathway in DLBCL is a viable therapeutic strategy and support further clinical studies of pevonedistat as a single agent or in combination with chemotherapy or novel targeted agents.
- Published
- 2020
- Full Text
- View/download PDF
10. 5-HT4 receptor agonists treatment reduces tau pathology and behavioral deficit in the PS19 mouse model of tauopathy.
- Author
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Jiang S, Sydney EJ, Runyan AM, Serpe R, Srikanth M, Figueroa HY, Yang M, and Myeku N
- Abstract
Background: Accumulation of tau in synapses in the early stages of Alzheimer's disease (AD) has been shown to cause synaptic damage, synaptic loss, and the spread of tau pathology through trans-synaptically connected neurons. Moreover, synaptic loss correlates with a decline in cognitive function, providing an opportunity to investigate therapeutic strategies to target synapses and synaptic tau to rescue or prevent cognitive decline in AD. One of the promising synaptic targets is the 5-HT4 serotonergic receptor present postsynaptically in the brain structures involved in the memory processes. 5-HT4R stimulation exerts synaptogenic and pro-cognitive effects involving synapse-to-nucleus signaling essential for synaptic plasticity. However, it is not known whether 5-HT4R activation has a therapeutic effect on tau pathology., Methods: The goal of this study was to investigate the impact of chronic stimulation of 5-HT4R by two agonists, prucalopride and RS-67333, in PS19 mice, a model of tauopathy. We utilized gradient assays to isolate pre- and post-synaptic compartments, followed by biochemical analyses for tau species and ubiquitinated proteins in the synaptic compartments and total brain tissue. Next, we performed kinetic assays to test the proteasome's hydrolysis capacity in treatment conditions. Moreover, behavioral tests such as the open field and non-maternal nest-building tests were used to evaluate anxiety-like behaviors and hippocampal-related cognitive functioning in the treatment paradigm., Results: Our results show that 5-HT4R agonism reduced tauopathy, reduced synaptic tau, increased proteasome activity, and improved cognitive functioning in PS19 mice. Our data suggest that enhanced proteasome activity by synaptic mediated signaling leads to the enhanced turnover of tau initially within synapses where the receptors are localized, and over time, the treatment attenuated the accumulation of tau aggregation and improved cognitive functioning of the PS19 mice., Conclusion: Therefore, stimulation of 5-HT4R offers a promising therapy to rescue synapses from the accumulation of toxic synaptic tau, evident in the early stages of AD., Competing Interests: ES is currently employed at Mount Sinai Neuropathology Brain Bank. AR is currently employed at Recursion Pharmaceuticals. RS is currently employed at Garuda Therapeutics. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Jiang, Sydney, Runyan, Serpe, Srikanth, Figueroa, Yang and Myeku.)
- Published
- 2024
- Full Text
- View/download PDF
11. Exercise Training-Increased FBXO32 and FOXO1 in a Gender-Dependent Manner in Mild Cognitively Impaired African Americans: GEMS-1 Study
- Author
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Fikru B. Bedada, Oyonumo E. Ntekim, Evaristus O. Nwulia, Thomas V. Fungwe, Sheeba Raaj Nadarajah, and Thomas O. Obisesan
- Subjects
ubiquitin proteasome system (UPS) ,FBXO32/atrogin-1 ,FoxO transcription factor ,cellular clearance system ,aging ,immune cells ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
The ubiquitin proteasome system (UPS) and FOXOs transcription factors play a pivotal role in cellular clearance and minimizing the accumulation of Aβ in neurodegeneration (ND). In African Americans (AAs) with mild cognitive impairment (MCI), the role of components of UPS and FOXOs; and whether they are amenable to exercise effects is unknown. We hypothesized that exercise can enhance cellular clearance systems during aging and ND by increasing expressions of FBXO32 and FOXO1. To test this hypothesis, we used TaqMan gene expression analysis in peripheral blood (PB) to investigate the component of UPS and FOXOs; and provide mechanistic insight at baseline, during exercise, and in both genders. At baseline, levels of FBXO32 were higher in women than in men. In our attempt to discern gender-specific exercise-related changes, we observed that levels of FBXO32 increased in men but not in women. Similarly, levels of FOXO1 increased in men only. These data suggest that a graded dose of FBXO32 and FOXO1 may be beneficial when PB cells carrying FBXO32 and FOXO1 summon into the brain in response to Alzheimer’s disease (AD) perturbation (docking station PB cells). Our observation is consistent with emerging studies that exercise allows the trafficking of blood factors. Given the significance of FBXO32 and FOXO1 to ND and associated muscle integrity, our findings may explain, at least in part, the benefits of exercise on memory, associated gait, and balance perturbation acknowledged to herald the emergence of MCI.
- Published
- 2021
- Full Text
- View/download PDF
12. Exercise Training-Increased FBXO32 and FOXO1 in a Gender-Dependent Manner in Mild Cognitively Impaired African Americans: GEMS-1 Study.
- Author
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Bedada, Fikru B., Ntekim, Oyonumo E., Nwulia, Evaristus O., Fungwe, Thomas V., Nadarajah, Sheeba Raaj, and Obisesan, Thomas O.
- Subjects
AFRICAN Americans ,TRANSCRIPTION factors ,AMERICAN studies ,ALZHEIMER'S disease ,UBIQUITIN - Abstract
The ubiquitin proteasome system (UPS) and FOXOs transcription factors play a pivotal role in cellular clearance and minimizing the accumulation of Aβ in neurodegeneration (ND). In African Americans (AAs) with mild cognitive impairment (MCI), the role of components of UPS and FOXOs ; and whether they are amenable to exercise effects is unknown. We hypothesized that exercise can enhance cellular clearance systems during aging and ND by increasing expressions of FBXO32 and FOXO1. To test this hypothesis, we used TaqMan gene expression analysis in peripheral blood (PB) to investigate the component of UPS and FOXOs ; and provide mechanistic insight at baseline, during exercise, and in both genders. At baseline, levels of FBXO32 were higher in women than in men. In our attempt to discern gender-specific exercise-related changes, we observed that levels of FBXO32 increased in men but not in women. Similarly, levels of FOXO1 increased in men only. These data suggest that a graded dose of FBXO32 and FOXO1 may be beneficial when PB cells carrying FBXO32 and FOXO1 summon into the brain in response to Alzheimer's disease (AD) perturbation (docking station PB cells). Our observation is consistent with emerging studies that exercise allows the trafficking of blood factors. Given the significance of FBXO32 and FOXO1 to ND and associated muscle integrity, our findings may explain, at least in part, the benefits of exercise on memory, associated gait, and balance perturbation acknowledged to herald the emergence of MCI. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
13. Molecular regulation of skeletal muscle mass and the contribution of nitric oxide: A review
- Author
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Jun Kobayashi, Hiroyuki Uchida, Ayaka Kofuji, Junta Ito, Maki Shimizu, Hyounju Kim, Yusuke Sekiguchi, and Seiji Kushibe
- Subjects
fork head box O (FoxO) ,mammalian target of rapamycin (mTOR) ,nitric oxide synthase (NOS) ,reactive oxygen species (ROS) ,ubiquitin proteasome system (UPS) ,Biology (General) ,QH301-705.5 - Abstract
Abstract A variety of internal and external factors such as exercise, nutrition, inflammation, and cancer‐associated cachexia affect the regulation of skeletal muscle mass. Because skeletal muscle functions as a crucial regulator of whole body metabolism, rather than just as a motor for locomotion, the enhancement and maintenance of muscle mass and function are required to maintain health and reduce the morbidity and mortality associated with diseases involving muscle wasting. Recent studies in this field have made tremendous progress; therefore, identification of the mechanisms that regulate skeletal muscle mass is necessary for the physical and nutritional management of both athletes and patients with muscle wasting disease. In this review, we present an overall picture of the interactions regulating skeletal muscle mass, particularly focusing on the insulin‐like growth factor‐I (IGF‐I)/insulin‐Akt‐mammalian target of rapamycin (mTOR) pathway, skeletal muscle inactivity, and endurance and resistance exercise. We also discuss the contribution of nitric oxide (NO) to the regulation of skeletal muscle mass based on the current knowledge of the novel role of NO in these processes.
- Published
- 2019
- Full Text
- View/download PDF
14. Classification of barley U-box E3 ligases and their expression patterns in response to drought and pathogen stresses
- Author
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Moon Young Ryu, Seok Keun Cho, Yourae Hong, Jinho Kim, Jong Hum Kim, Gu Min Kim, Yan-Jun Chen, Eva Knoch, Birger Lindberg Møller, Woo Taek Kim, Michael Foged Lyngkjær, and Seong Wook Yang
- Subjects
Barley ,Hordeum vulgare ,Ubiquitin proteasome system (UPS) ,Biotic stress ,Abiotic stress ,Biotechnology ,TP248.13-248.65 ,Genetics ,QH426-470 - Abstract
Abstract Background Controlled turnover of proteins as mediated by the ubiquitin proteasome system (UPS) is an important element in plant defense against environmental and pathogen stresses. E3 ligases play a central role in subjecting proteins to hydrolysis by the UPS. Recently, it has been demonstrated that a specific class of E3 ligases termed the U-box ligases are directly associated with the defense mechanisms against abiotic and biotic stresses in several plants. However, no studies on U-box E3 ligases have been performed in one of the important staple crops, barley. Results In this study, we identified 67 putative U-box E3 ligases from the barley genome and expressed sequence tags (ESTs). Similar to Arabidopsis and rice U-box E3 ligases, most of barley U-box E3 ligases possess evolutionary well-conserved domain organizations. Based on the domain compositions and arrangements, the barley U-box proteins were classified into eight different classes. Along with this new classification, we refined the previously reported classifications of U-box E3 ligase genes in Arabidopsis and rice. Furthermore, we investigated the expression profile of 67 U-box E3 ligase genes in response to drought stress and pathogen infection. We observed that many U-box E3 ligase genes were specifically up-and-down regulated by drought stress or by fungal infection, implying their possible roles of some U-box E3 ligase genes in the stress responses. Conclusion This study reports the classification of U-box E3 ligases in barley and their expression profiles against drought stress and pathogen infection. Therefore, the classification and expression profiling of barley U-box genes can be used as a platform to functionally define the stress-related E3 ligases in barley.
- Published
- 2019
- Full Text
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15. Arabidopsis RING‐type E3 ubiquitin ligase XBAT35.2 promotes proteasome‐dependent degradation of ACD11 to attenuate abiotic stress tolerance.
- Author
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Li, Qiaomu, Serio, Renata J., Schofield, Andrew, Liu, Hongxia, Rasmussen, Sheena R., Hofius, Daniel, and Stone, Sophia L.
- Subjects
- *
PROTEASOMES , *ABIOTIC stress , *UBIQUITIN ligases , *ABSCISIC acid , *ARABIDOPSIS , *DROUGHT tolerance , *UBIQUITIN - Abstract
SUMMARY: Plants employ multiple mechanisms to cope with a constantly changing and challenging environment, including using the ubiquitin proteasome system (UPS) to alter their proteome to assist in initiating, modulating and terminating responses to stress. We previously reported that the ubiquitin ligase XBAT35.2 mediates the proteasome‐dependent degradation of Accelerated Cell Death 11 (ACD11) to promote pathogen defense. Here, we demonstrate roles for XBAT35.2 and ACD11 in abiotic stress tolerance. As seen in response to pathogen infection, abiotic stress stabilizes XBAT35.2 and the abundance of ACD11 rose consistently with increasing concentrations of abscisic acid (ABA) and salt. Surprisingly, exposure to ABA and salt increased the stability of ACD11, and the overexpression of ACD11 improves plant survival of salt and drought stress, suggesting a role for ACD11 in promoting tolerance. Prolonged exposure to high concentrations of ABA or salt resulted in ubiquitination and the proteasome‐dependent degradation of ACD11, however. The stress‐induced turnover of ACD11 requires XBAT35.2, as degradation is slowed in the absence of the E3 ubiquitin ligase. Consistent with XBAT35.2 mediating the proteasome‐dependent degradation of ACD11, the loss of E3 ubiquitin ligase function enhances the tolerance of salt and drought stress, whereas overexpression increases sensitivity. A model is presented where, upon the perception of abiotic stress, ACD11 abundance increases to promote tolerance. Meanwhile, XBAT35.2 accumulates and in turn promotes the degradation of ACD11 to attenuate the stress response. The results characterize XBAT35.2 as an E3 ubiquitin ligase with opposing roles in abiotic and biotic stress. Significance Statement: Ubiquitin ligases are the substrate‐selecting component of the essential ubiquitin proteasome system. Arabidopsis RING‐type ubiquitin ligase XBAT35.2 was previously reported to promote pathogen defense via mediating the proteasome‐dependent degradation of ACD11. Here, ACD11 is shown to promote salt and drought tolerance, whereas stress‐stabilized XBAT35.2 targets ACD11 for degradation to attenuate the abiotic stress responses. This report identifies XBAT35.2 as a ubiquitin ligase with multiple and opposing roles in plant responses to biotic and abiotic stresses. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
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16. An In-Silico Investigation of Key Lysine Residues and Their Selection for Clearing off Aβ and Holo-AβPP Through Ubiquitination.
- Author
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Kumar, Dhiraj and Kumar, Pravir
- Subjects
AMYLOID beta-protein ,GLUTAMINE ,LYSINE ,UBIQUITINATION ,GLUTAMIC acid ,ALZHEIMER'S disease ,POST-translational modification ,AMINO acids - Abstract
Malicious progression of neurodegeneration is a consequence of toxic aggregates of proteins or peptides such as amyloid beta (Aβ) reported in Alzheimer's disease (AD). These aggregates hinder the electrochemical transmission at neuronal junctions and thus deteriorate neuronal-health by triggering dementia. Electrostatic and hydrophobic interactions among amino-acid residues are the governing principle behind the self-assembly of aforesaid noxious oligomers or agglomerate. Interestingly, lysine residues are crucial for these interactions and for facilitating the clearance of toxic metabolites through the ubiquitination process. The mechanisms behind lysine selectivity and modifications of target proteins are very intriguing process and an avenue to explore the clearance of unwanted proteins from neurons. Therefore, it is fascinating for the researchers to investigate the role of key lysine, their selectivity and interactions with other amino acids to clear-off toxic products in exempting the progression of Neurodegenerative disorders (NDDs). Herein, (1) we identified the aggregation prone sequence in Aβ40 and Aβ42 as 'HHQKLVFFAE' and 'SGYEVHHQKLVFFAEDVG/KGAIIGLMVGGV' respectively with critical lysine (K) at 16 and 28 for stabilizing the aggregates; (2) elucidated the interaction pattern of AβPP with other Alzheimer's related proteins BACE1, APOE, SNCA, APBB1, CASP8, NAE1, ADAM10, and PSEN1 to describe the pathophysiology; (3) found APOE as commonly interacting factor between amyloid beta and Tau for governing AD pathogenesis; (4) reported K224, K351, K363, K377, K601, K662, K751, and K763 as potential putative lysine for facilitating AβPP clearance through ubiquitination thereby arresting Aβ formation; and (5) observed conserved glutamine (Q), glutamic acid (E), and alpha-helical conformation as few crucial factors for lysine selectivity in the ubiquitination of AβPP. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
17. Ubiquitin-protein ligase E3A (UBE3A) mediation of viral infection and human diseases.
- Author
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Chaudhary, Pankaj, Proulx, Jessica, and Park, In-Woo
- Subjects
- *
VIRUS diseases , *UBIQUITIN ligases , *VIRAL proteins , *LIFE cycles (Biology) , *STEROID receptors , *ANGELMAN syndrome , *DELETION mutation - Abstract
• The Ubiquitin-protein ligase E3A, UBE3A, also known as E6-associated protein (E6-AP), plays an essential role in determination of the stability of various proteins, using the proteasomal degradation system. • UBE3A decays key viral proteins in the virus-infected cells and, thereby, impacts on the infected virus life cycle followed by the viral diseases. • Mutations or deletions in the maternally inherited gene in the brain cause human neurodevelopmental disorders such as Angelman syndrome and autism. The Ubiquitin-protein ligase E3A, UBE3A, also known as E6-associated protein (E6-AP), is known to play an essential role in regulating the degradation of various proteins by transferring Ub from E2 Ub conjugating enzymes to the substrate proteins. Several studies indicate that UBE3A regulates the stabilities of key viral proteins in the virus-infected cells and, thereby, the infected virus-mediated diseases, even if it were reported that UBE3A participates in non-viral-related human diseases. Furthermore, mutations such as deletions and duplications in the maternally inherited gene in the brain cause human neurodevelopmental disorders such as Angelman syndrome (AS) and autism. It is also known that UBE3A functions as a transcriptional coactivator for the expression of steroid hormone receptors. These reports establish that UBE3A is distinguished by its multitudinous functions that are paramount to viral pathology and human diseases. This review is focused on molecular mechanisms for such intensive participation of UBE3A in disease formation and virus regulation. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
18. Loss of Cdh1 Triggers Premature Senescence in Part via Activation of Both the RB/E2F1 and the CLASPIN/CHK1/P53 Tumor Suppressor Pathways
- Author
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Shaik, Shavali, Liu, Pengda, Wang, Zhiwei, Wei, Wenyi, Hayat, M. A., Series editor, and Hayat, M.A., editor
- Published
- 2014
- Full Text
- View/download PDF
19. Nucleotides regulate the common molecular mechanisms that underlie neurodegenerative diseases; Therapeutic implications.
- Author
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Sebastián-Serrano, Álvaro, de Diego-García, Laura, di Lauro, Caterina, Bianchi, Carolina, and Díaz-Hernández, Miguel
- Subjects
- *
NEURODEGENERATION , *NUCLEOTIDES , *PURINERGIC receptors , *ALKALINE phosphatase , *DISEASE progression - Abstract
• Progression of neurodegenerative diseases is guided by common molecular mechanisms. • Extracellular nucleotides may regulate these common molecular mechanisms. • New therapeutic strategies might be based on enhancing or inhibiting these regulatory actions. Neurodegenerative diseases (ND) are a heterogeneous group of neurological disorders characterized by a progressive loss of neuronal function which results in neuronal death. Although a specific toxic factor has been identified for each ND, all of them share common pathological molecular mechanisms favouring the disease development. In the final stages of ND, patients become unable to take care of themselves and decline to a total functional incapacitation that leads to their death. Some of the main factors which contribute to the disease progression include proteasomal dysfunction, neuroinflammation, synaptic alterations, protein aggregation, and oxidative stress. Over recent years, evidence has been accumulated to suggest that purinergic signaling plays a key role in the aforementioned molecular pathways. In this review, we revise the implications of the purinergic signaling in the common molecular mechanism underlying the ND. In particular, we focus on the role of the purinergic receptors P2X7, P2Y 2 and the ectoenzyme tissue-nonspecific alkaline phosphatase (TNAP). [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
20. Molecular regulation of skeletal muscle mass and the contribution of nitric oxide: A review.
- Author
-
Kobayashi, Jun, Uchida, Hiroyuki, Kofuji, Ayaka, Ito, Junta, Shimizu, Maki, Kim, Hyounju, Sekiguchi, Yusuke, and Kushibe, Seiji
- Abstract
A variety of internal and external factors such as exercise, nutrition, inflammation, and cancer‐associated cachexia affect the regulation of skeletal muscle mass. Because skeletal muscle functions as a crucial regulator of whole body metabolism, rather than just as a motor for locomotion, the enhancement and maintenance of muscle mass and function are required to maintain health and reduce the morbidity and mortality associated with diseases involving muscle wasting. Recent studies in this field have made tremendous progress; therefore, identification of the mechanisms that regulate skeletal muscle mass is necessary for the physical and nutritional management of both athletes and patients with muscle wasting disease. In this review, we present an overall picture of the interactions regulating skeletal muscle mass, particularly focusing on the insulin‐like growth factor‐I (IGF‐I)/insulin‐Akt‐mammalian target of rapamycin (mTOR) pathway, skeletal muscle inactivity, and endurance and resistance exercise. We also discuss the contribution of nitric oxide (NO) to the regulation of skeletal muscle mass based on the current knowledge of the novel role of NO in these processes. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
21. Comprehensive analysis of ubiquitin-proteasome system genes related to prognosis and immunosuppression in head and neck squamous cell carcinoma
- Author
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Fengyu Zhang, Huihong Chen, Zhifeng Liu, Xin Zhang, Rulong Hu, Juncheng Wang, Jianing Li, Luan Zhang, Yuxi Tian, Yuexiang Qin, and Yongquan Tian
- Subjects
Adult ,Male ,Aging ,Proteasome Endopeptidase Complex ,medicine.medical_treatment ,ubiquitin proteasome system (UPS) ,Regulator ,head and neck squamous cell carcinoma (HNSCC) ,Immune system ,Biomarkers, Tumor ,Medicine ,Humans ,Aged ,PSMD2 ,Aged, 80 and over ,Immunosuppression Therapy ,immunosuppression ,business.industry ,Squamous Cell Carcinoma of Head and Neck ,Ubiquitin ,Immunosuppression ,Cell Biology ,Immunotherapy ,Middle Aged ,medicine.disease ,Prognosis ,Head and neck squamous-cell carcinoma ,gene expression omnibus (GEO) database ,the cancer genome atlas (TCGA) database ,Gene Expression Regulation, Neoplastic ,Proteasome ,Tumor progression ,Head and Neck Neoplasms ,Cancer research ,Female ,business ,Research Paper - Abstract
The ubiquitin-proteasome system (UPS) with a capacity of degrading multiple intracellular proteins is an essential regulator in tumor immunosurveillance. Tumor cells that escape from recognition and destruction of immune system have been consistently characterized an important hallmark in the setting of tumor progression. Little know about the exact functions of UPS-related genes (UPSGs) and their relationships with antitumor immunity in head and neck squamous cell carcinoma (HNSCC) patients. In this study, for the first time, we comprehensively identified 114 differentially expressed UPSGs (DEUPSGs) and constructed a prognostic risk model based on the eight DEUPSGs (BRCA1, OSTM1, PCGF2, PSMD2, SOCS1, UCHL1, UHRF1, and USP54) in the TCGA-HNSCC database. This risk model was validated using multiple data sets (all P < 0.05). The high-risk score was found to be an independently prognostic factor in HNSCC patients and was significantly correlated with T cells suppression. Accordingly, our risk model can act as a prognostic signature and provide a novel concept for improving the precise immunotherapy for patients with HNSCC.
- Published
- 2021
22. A novel ALS-associated variant in UBQLN4 regulates motor axon morphogenesis
- Author
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Brittany M Edens, Jianhua Yan, Nimrod Miller, Han-Xiang Deng, Teepu Siddique, and Yongchao C Ma
- Subjects
UBQLN4 ,beta-catenin ,ubiquitin proteasome system (UPS) ,ALS ,axon morphogenesis ,neurodegeneration ,Medicine ,Science ,Biology (General) ,QH301-705.5 - Abstract
The etiological underpinnings of amyotrophic lateral sclerosis (ALS) are complex and incompletely understood, although contributions to pathogenesis by regulators of proteolytic pathways have become increasingly apparent. Here, we present a novel variant in UBQLN4 that is associated with ALS and show that its expression compromises motor axon morphogenesis in mouse motor neurons and in zebrafish. We further demonstrate that the ALS-associated UBQLN4 variant impairs proteasomal function, and identify the Wnt signaling pathway effector beta-catenin as a UBQLN4 substrate. Inhibition of beta-catenin function rescues the UBQLN4 variant-induced motor axon phenotypes. These findings provide a strong link between the regulation of axonal morphogenesis and a new ALS-associated gene variant mediated by protein degradation pathways.
- Published
- 2017
- Full Text
- View/download PDF
23. Functional Characterization of Ubiquitin-Like Core Autophagy Protein ATG12 in Dictyostelium discoideum
- Author
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Sarah Fischer, Ramesh Rijal, Peter Frommolt, Prerana Wagle, Roman Konertz, Jan Faix, Susanne Meßling, and Ludwig Eichinger
- Subjects
ATG12 ,ATG16 ,autophagy ,Dictyostelium ,ubiquitin-like protein ,post-translational modifier ,phagocytosis ,pinocytosis ,proteasome ,ubiquitin proteasome system (UPS) ,Cytology ,QH573-671 - Abstract
Autophagy is a highly conserved intracellular degradative pathway that is crucial for cellular homeostasis. During autophagy, the core autophagy protein ATG12 plays, together with ATG5 and ATG16, an essential role in the expansion of the autophagosomal membrane. In this study we analyzed gene replacement mutants of atg12 in Dictyostelium discoideum AX2 wild-type and ATG16‾ cells. RNAseq analysis revealed a strong enrichment of, firstly, autophagy genes among the up-regulated genes and, secondly, genes implicated in cell motility and phagocytosis among the down-regulated genes in the generated ATG12‾, ATG16‾ and ATG12‾/16‾ cells. The mutant strains showed similar defects in fruiting body formation, autolysosome maturation, and cellular viability, implying that ATG12 and ATG16 act as a functional unit in canonical autophagy. In contrast, ablation of ATG16 or of ATG12 and ATG16 resulted in slightly more severe defects in axenic growth, macropinocytosis, and protein homeostasis than ablation of only ATG12, suggesting that ATG16 fulfils an additional function in these processes. Phagocytosis of yeast, spore viability, and maximal cell density were much more affected in ATG12‾/16‾ cells, indicating that both proteins also have cellular functions independent of each other. In summary, we show that ATG12 and ATG16 fulfil autophagy-independent functions in addition to their role in canonical autophagy.
- Published
- 2019
- Full Text
- View/download PDF
24. The double faced role of copper in Aβ homeostasis: A survey on the interrelationship between metal dyshomeostasis, UPS functioning and autophagy in neurodegeneration.
- Author
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Grasso, Giuseppe, Santoro, Anna Maria, Lanza, Valeria, Sbardella, Diego, Tundo, Grazia Raffaella, Ciaccio, Chiara, Marini, Stefano, Coletta, Massimo, and Milardi, Danilo
- Subjects
- *
NEURODEGENERATION , *COPPER , *HOMEOSTASIS , *AUTOPHAGY , *METALS in medicine , *PROTEIN folding - Abstract
Substantial evidence has accumulated over the last decade indicating that diverse age-related neurodegenerative disorders share a common pathogenic mechanism: the misfolding, aggregation and accumulation of proteins (termed “amyloid”) in neuronal tissues. The latest studies suggest that, in principle, any deficiency in protein homeostasis (proteostasis) may lead to cell dysfunction thus underscoring the protective key role played by systems regulating the clearance of misfolded or defective proteins in the cell. On the other hand, an altered metal homeostasis (metallostasis) is thought to be tightly linked to the malfunction of the “quality control” machinery of the cell. Metal ions have long been thought to catalyze amyloid aggregation by initiating protein misfolding. More specifically, redox active metal ions such as copper have been demonstrated to be majorly involved in a cascade of events resulting in oxidative damage and neurodegeneration. However, drugs aimed at merely removing excess of such metal ions from the cell have proven to be unsuccessful thus forcing scientists to amend these traditional views. In particular, a comprehensive vision of the interplay between metal dyshomeostasis and systems engaged in proteome maintenance, e.g. proteases, ubiquitin proteasome system (UPS) and autophagy, emerges as a critical requirement to single out the many culprits of cell dysfunction occurring in aging and in neurodegenerative pathologies such as Alzheimer’s disease. Here, we will first provide a chemical perspective of the role of copper in Aβ homeostasis, thus giving the necessary outline to the problem of age-related protein misfolding and altered metallostasis which lead to accumulation processes and consequent decline of neuron functions. Secondly, we will focus on the proteome maintenance system (UPS and autophagy) and to the issues related to copper-mediated disturbances of the latter in AD. Finally, we will discuss the therapeutic potential of copper chelating agents in the treatment of neurodegenerative disorders. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
25. New potential targeted strategies in small cell lung cancer.
- Author
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de Toro M, Pangua C, Serrano-Montero G, Lara MÁ, and Rogado J
- Abstract
Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-23-64/coif). The authors have no conflicts of interest to declare.
- Published
- 2023
- Full Text
- View/download PDF
26. Activities of proteasome and m-calpain are essential for Chikungunya virus replication.
- Author
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Karpe, Yogesh, Pingale, Kunal, and Kanade, Gayatri
- Abstract
Replication of many viruses is dependent on the ubiquitin proteasome system. The present study demonstrates that Chikungunya virus replication increases proteasome activity and induces unfolded protein response (UPR) in cultured cells. Further, it was seen that the virus replication was dependent on the activities of proteasomes and m-calpain. Proteasome inhibition induced accumulation of polyubiquitinated proteins and earlier visualization of UPR. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
27. An assay for 26S proteasome activity based on fluorescence anisotropy measurements of dye-labeled protein substrates.
- Author
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Bhattacharyya, Sucharita, Renn, Jonathan P., Yu, Houqing, Marko, John F., and Matouschek, Andreas
- Subjects
- *
PROTEASOMES , *DENATURATION of proteins , *PROTEOLYTIC enzymes , *FLUORESCENCE anisotropy , *MOLECULAR machinery (Technology) - Abstract
The 26S proteasome is the molecular machine at the center of the ubiquitin proteasome system and is responsible for adjusting the concentrations of many cellular proteins. It is a drug target in several human diseases, and assays for the characterization of modulators of its activity are valuable. The 26S proteasome consists of two components: a core particle, which contains the proteolytic sites, and regulatory caps, which contain substrate receptors and substrate processing enzymes, including six ATPases. Current high-throughput assays of proteasome activity use synthetic fluorogenic peptide substrates that report directly on the proteolytic activity of the proteasome, but not on the activities of the proteasome caps that are responsible for protein recognition and unfolding. Here, we describe a simple and robust assay for the activity of the entire 26S proteasome using fluorescence anisotropy to follow the degradation of fluorescently labeled protein substrates. We describe two implementations of the assay in a high-throughput format and show that it meets the expected requirement of ATP hydrolysis and the presence of a canonical degradation signal or degron in the target protein. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
28. Function of ubiquitin (Ub) specific protease 15 (USP15) in HIV-1 replication and viral protein degradation.
- Author
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Pyeon, Dohun, Timani, Khalid Amine, Gulraiz, Fahad, He, Johnny J., and Park, In-Woo
- Subjects
- *
UBIQUITIN , *VIRAL proteins , *AIDS prevention , *IMMUNOPRECIPITATION , *NEF gene , *UBIQUITINATION , *THERAPEUTICS - Abstract
HIV-1 Nef is necessary and may be sufficient for HIV-1-associated AIDS pathogenicity, in that knockout of Nef alone can protect HIV-infected patients from AIDS. We therefore investigated the feasibility of physical knockout of Nef, using the host ubiquitin proteasome system in HIV-1-infected cells. Our co-immunoprecipitation analysis demonstrated that Nef interacted with ubiquitin specific protease 15 (USP15), and that USP15, which is known to stabilize cellular proteins, degraded Nef. Nef could also cause decay of USP15, although Nef-mediated degradation of USP15 was weaker than USP15-mediated Nef degradation. Direct interaction between Nef and USP15 was essential for the observed reciprocal decay of the proteins. Further, USP15 degraded not only Nef but also HIV-1 structural protein, Gag, thereby substantially inhibiting HIV-1 replication. However, Gag did not degrade USP15, indicating that the Nef and USP15 complex, in distinction to other viral proteins, play an integral role in coordinating viral protein degradation and hence HIV-1 replication. Moreover, Nef and USP15 globally suppressed ubiquitylation of cellular proteins, indicating that these proteins are major determinants for the stability of cellular as well as viral proteins. Taken together, these data indicate that Nef and USP15 are vital in regulating degradation of viral and cellular proteins and thus HIV-1 replication, and specific degradation of viral, not cellular proteins, by USP15 points to USP15 as a candidate therapeutic agent to combat AIDS by eliminating viral proteins from the infected cells via USP15-mediated proteosomal degradation. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
29. Molecular regulation of skeletal muscle mass and the contribution of nitric oxide: A review
- Author
-
Hiroyuki Uchida, Seiji Kushibe, Hyounju Kim, Ayaka Kofuji, Jun Kobayashi, Maki Shimizu, Yusuke Sekiguchi, and Junta Ito
- Subjects
Cancer Research ,medicine.medical_specialty ,Physiology ,ubiquitin proteasome system (UPS) ,Regulator ,Inflammation ,Disease ,reactive oxygen species (ROS) ,Biochemistry, Genetics and Molecular Biology (miscellaneous) ,Cachexia ,Nitric oxide ,chemistry.chemical_compound ,nitric oxide synthase (NOS) ,Internal medicine ,medicine ,lcsh:QH301-705.5 ,Wasting ,Research Articles ,PI3K/AKT/mTOR pathway ,business.industry ,mammalian target of rapamycin (mTOR) ,Skeletal muscle ,medicine.disease ,Endocrinology ,medicine.anatomical_structure ,lcsh:Biology (General) ,chemistry ,fork head box O (FoxO) ,Molecular Medicine ,medicine.symptom ,business ,Research Article - Abstract
A variety of internal and external factors such as exercise, nutrition, inflammation, and cancer‐associated cachexia affect the regulation of skeletal muscle mass. Because skeletal muscle functions as a crucial regulator of whole body metabolism, rather than just as a motor for locomotion, the enhancement and maintenance of muscle mass and function are required to maintain health and reduce the morbidity and mortality associated with diseases involving muscle wasting. Recent studies in this field have made tremendous progress; therefore, identification of the mechanisms that regulate skeletal muscle mass is necessary for the physical and nutritional management of both athletes and patients with muscle wasting disease. In this review, we present an overall picture of the interactions regulating skeletal muscle mass, particularly focusing on the insulin‐like growth factor‐I (IGF‐I)/insulin‐Akt‐mammalian target of rapamycin (mTOR) pathway, skeletal muscle inactivity, and endurance and resistance exercise. We also discuss the contribution of nitric oxide (NO) to the regulation of skeletal muscle mass based on the current knowledge of the novel role of NO in these processes., This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- Published
- 2019
30. Classification of barley U-box E3 ligases and their expression patterns in response to drought and pathogen stresses
- Author
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Woo Taek Kim, Seong Wook Yang, Michael F. Lyngkjær, Moon Young Ryu, Jinho Kim, Seok Keun Cho, Yan-Jun Chen, Gu Min Kim, Yourae Hong, Birger Lindberg Møller, Eva Knoch, and Jong Hum Kim
- Subjects
0106 biological sciences ,lcsh:QH426-470 ,Ubiquitin-Protein Ligases ,lcsh:Biotechnology ,Arabidopsis ,01 natural sciences ,Host-Parasite Interactions ,03 medical and health sciences ,Ascomycota ,Biotic stress ,Gene Expression Regulation, Plant ,Barley ,lcsh:TP248.13-248.65 ,Genetics ,Plant defense against herbivory ,Amino Acid Sequence ,Ubiquitin proteasome system (UPS) ,Phylogeny ,Plant Proteins ,030304 developmental biology ,Hordeum vulgare ,0303 health sciences ,Expressed sequence tag ,biology ,Abiotic stress ,food and beverages ,Hordeum ,Oryza ,biology.organism_classification ,Droughts ,Ubiquitin ligase ,lcsh:Genetics ,Proteasome ,Seedlings ,biology.protein ,Sequence Alignment ,Genome, Plant ,Research Article ,010606 plant biology & botany ,Biotechnology - Abstract
Background Controlled turnover of proteins as mediated by the ubiquitin proteasome system (UPS) is an important element in plant defense against environmental and pathogen stresses. E3 ligases play a central role in subjecting proteins to hydrolysis by the UPS. Recently, it has been demonstrated that a specific class of E3 ligases termed the U-box ligases are directly associated with the defense mechanisms against abiotic and biotic stresses in several plants. However, no studies on U-box E3 ligases have been performed in one of the important staple crops, barley. Results In this study, we identified 67 putative U-box E3 ligases from the barley genome and expressed sequence tags (ESTs). Similar to Arabidopsis and rice U-box E3 ligases, most of barley U-box E3 ligases possess evolutionary well-conserved domain organizations. Based on the domain compositions and arrangements, the barley U-box proteins were classified into eight different classes. Along with this new classification, we refined the previously reported classifications of U-box E3 ligase genes in Arabidopsis and rice. Furthermore, we investigated the expression profile of 67 U-box E3 ligase genes in response to drought stress and pathogen infection. We observed that many U-box E3 ligase genes were specifically up-and-down regulated by drought stress or by fungal infection, implying their possible roles of some U-box E3 ligase genes in the stress responses. Conclusion This study reports the classification of U-box E3 ligases in barley and their expression profiles against drought stress and pathogen infection. Therefore, the classification and expression profiling of barley U-box genes can be used as a platform to functionally define the stress-related E3 ligases in barley. Electronic supplementary material The online version of this article (10.1186/s12864-019-5696-z) contains supplementary material, which is available to authorized users.
- Published
- 2019
31. PROTACs: Novel approach for cancer breakdown by breaking proteins.
- Author
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Memon, Humera and Patel, Bhoomika M.
- Subjects
- *
SCHWANNOMAS , *PROTEOLYSIS , *PROTEIN synthesis , *SMALL molecules , *MULTIPLE myeloma , *CHIMERIC proteins - Abstract
Ubiquitination defects have been reported in various diseases, including neurodegenerative diseases, metabolic disorders and cancer. Balance between degradation and synthesis of the proteins to treat cancer can be managed by designing a chimeric molecule, known as Proteolysis Targeting Chimeric molecule (Lee, Kim et al. 2021). Proteolysis-targeting chimeras (PROTACs) acts as a tool for conducting therapeutic intervention. It eradicates or reduces the proteins that are responsible for causing diseases. Each PROTAC contains a target warhead, an E3 ligand and a linker. E3 ligases are recruited by these bifunctional molecules, and the Ubiquitin (Ub) Proteasome System (UPS) is used to target the degradation of specific proteins. As compared to inhibition, this degradation offers several advantages in the drug resistance, selectivity, and potency. Thus, numerous small molecule PROTACs are identified so far. In this review, the development of PROTACs, historical milestones, the biological mechanism, advantages and recent progress, and role of PROTAC in prostate cancer, breast cancer, non-hodgkin lymphoma, multiple myeloma, and malignant peripheral nerve sheath tumors are summarized. [Display omitted] [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
32. Molecular mechanisms of Nrf2 regulation and how these influence chemical modulation for disease intervention.
- Author
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Harder, Bryan, Tao Jiang, Tongde Wu, Shasha Tao, de la Vega, Montserrat Rojo, Wang Tian, Chapman, Eli, and Zhang, Donna D.
- Subjects
- *
TRANSCRIPTION factors , *HOMEOSTASIS , *UBIQUITIN , *PROTEASOMES , *TRANSDUCIN , *AUTOPHAGY - Abstract
Nrf2 (nuclear factor erytheroid-derived-2-like 2) transcriptional programmes are activated by a variety of cellular stress conditions to maintain cellular homoeostasis. Under non-stress conditions, Nrf2 is under tight regulation by the ubiquitin proteasome system (UPS). Detailed mechanistic investigations have shown the Kelch-like ECH-associated protein 1 (Keap1)-cullin3 (Cul3)-ring-box1 (Rbx1) E3-ligase to be the primary Nrf2 regulatory system. Recently, both beta-transducin repeat-containing E3 ubiquitin protein ligase (β-TrCP) and E3 ubiquitin-protein ligase synoviolin (Hrd1) have been identified as novel E3 ubiquitin ligases that negatively regulate Nrf2 through Keap1-independent mechanisms. In addition to UPS-mediated regulation of Nrf2, investigations have revealed a cross-talk between Nrf2 and the autophagic pathway resulting in activation of Nrf2 in a non-canonical manner. In addition to regulation at the protein level, Nrf2 was recently shown to be regulated at the transcriptional level by oncogenic K-rat sarcoma (Ras). A consequence of these differential regulatory mechanisms is the dual role of Nrf2 in cancer: the canonical, protective role and the non-canonical 'dark-side' of Nrf2. Based on the protective role of Nrf2, a vast effort has been dedicated towards identifying novel chemical inducers of Nrf2 for the purpose of chemoprevention. On the other hand, upon malignant transformation, some cancer cells have a constitutively high level of Nrf2 offering a growth advantage, as well as rendering cancer cells resistant to chemotherapeutics. This discovery has led to a new paradigm in cancer treatment; the initially counterintuitive use of Nrf2 inhibitors as adjuvants in chemotherapy. Herein, we will discuss the mechanisms of Nrf2 regulation and how this detailed molecular understanding can be leveraged to develop Nrf2modulators to prevent diseases, mitigate disease progression or overcome chemoresistance. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
33. Inhibitory effect on the proteasome regulatory subunit, RPN11/POH1, with the use of Capzimin-PROTAC to trigger apoptosis in cancer cells
- Abstract
Most patients diagnosed with cancer will receive systematic chemotherapy at some point during their illness, which almost always cause severe side effects for the patients such as, anemia, nausea and vomiting. The problems with today’s chemotherapy is not only that it cause severe side effects, but also that the cancer may develop resistance to the therapy, which is why the development of a new type of therapeutic agent is in dire need. The ubiquitin proteasome system (UPS) is a vital machinery for the cancer cells to maintain protein homeostasis, which also make them vulnerable to any disruption of this system. In recent years, a new technology has been developed that utilize the UPS by chemically bringing an E3 ubiquitin ligase into close proximity of a protein of choice and tagging the protein with ubiquitin for degradation. This technology is called proteolysis targeting chimera (PROTAC). In this project, we managed to theoretically develop a new type of cancer therapeutic agent, that utilize the PROTAC system together with the first-in-class proteasome regulatory subunit, POH1, inhibitor Capzimin as a warhead. By using Capzimin as a warhead it should be possible to polyubiquitinate POH1, and thus induce proteotoxic stress in the cancer cells to trigger apoptosis. This theoretically developed drug is therefore called Capzimin-PROTAC, which should be able to trigger apoptosis in cancer cells, and at the same time being relatively safe to normal healthy cells.
- Published
- 2020
34. Inhibitory effect on the proteasome regulatory subunit, RPN11/POH1, with the use of Capzimin-PROTAC to trigger apoptosis in cancer cells
- Abstract
Most patients diagnosed with cancer will receive systematic chemotherapy at some point during their illness, which almost always cause severe side effects for the patients such as, anemia, nausea and vomiting. The problems with today’s chemotherapy is not only that it cause severe side effects, but also that the cancer may develop resistance to the therapy, which is why the development of a new type of therapeutic agent is in dire need. The ubiquitin proteasome system (UPS) is a vital machinery for the cancer cells to maintain protein homeostasis, which also make them vulnerable to any disruption of this system. In recent years, a new technology has been developed that utilize the UPS by chemically bringing an E3 ubiquitin ligase into close proximity of a protein of choice and tagging the protein with ubiquitin for degradation. This technology is called proteolysis targeting chimera (PROTAC). In this project, we managed to theoretically develop a new type of cancer therapeutic agent, that utilize the PROTAC system together with the first-in-class proteasome regulatory subunit, POH1, inhibitor Capzimin as a warhead. By using Capzimin as a warhead it should be possible to polyubiquitinate POH1, and thus induce proteotoxic stress in the cancer cells to trigger apoptosis. This theoretically developed drug is therefore called Capzimin-PROTAC, which should be able to trigger apoptosis in cancer cells, and at the same time being relatively safe to normal healthy cells.
- Published
- 2020
35. Post-translational modification of mitochondria as a novel mode of regulation.
- Author
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Hofer, Annette and Wenz, Tina
- Subjects
- *
POST-translational modification , *MITOCHONDRIAL membranes , *CELLULAR control mechanisms , *CELL metabolism , *APOPTOSIS , *IMMUNE response - Abstract
Abstract: Mitochondria not only form the metabolic hub, but also are crucial players in many cellular pathways, like apoptosis and innate immune response, putting the organelle in a central position in controlling cellular function and fate. As novel and powerful regulators of mitochondrial processes and hence mitochondrial-controlled pathways, post-translational modifications (PTMs) have emerged in the last years. In this review, we will summarize the current state of knowledge on PTMs occurring in mammalian mitochondria with a focus on phosphorylation, acetylation, succinylation and ubiquitination. We will highlight their regulatory role in metabolism, autophagy and apoptosis as well as communicating element to cellular stress response pathways such as the immune response. Finally, we will discuss open questions in this exciting research area and point out how mitochondrial PTMs might impact age-associated pathologies. [Copyright &y& Elsevier]
- Published
- 2014
- Full Text
- View/download PDF
36. Dynamic interplay between breast cancer cells and normal endothelium mediates the expression of matrix macromolecules, proteasome activity and functional properties of endothelial cells.
- Author
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Gialeli, Ch., Viola, M., Barbouri, D., Kletsas, D., Passi, A., and Karamanos, N.K.
- Subjects
- *
BREAST cancer , *CANCER cells , *MACROMOLECULES , *GENE expression , *ENDOTHELIAL cells , *CANCER invasiveness - Abstract
Abstract: Background: Breast cancer–endothelium interactions provide regulatory signals facilitating tumor progression. The endothelial cells have so far been mainly viewed in the context of tumor perfusion and relatively little is known regarding the effects of such paracrine interactions on the expression of extracellular matrix (ECM), proteasome activity and properties of endothelial cells. Methods: To address the effects of breast cancer cell (BCC) lines MDA-MB-231 and MCF-7 on the endothelial cells, two cell culture models were utilized; one involves endothelial cell culture in the presence of BCCs-derived conditioned media (CM) and the other co-culture of both cell populations in a Transwell system. Real-time PCR was utilized to evaluate gene expression, an immunofluorescence assay for proteasome activity, and functional assays (migration, adhesion and invasion) and immunofluorescence microscopy for cell integrity and properties. Results: BCC-CM decreases the cell migration of HUVEC. Adhesion and invasion of BCCs are favored by HUVEC and HUVEC-CM. HA levels and the expression of CD44 and HA synthase-2 by HUVEC are substantially upregulated in both cell culture approaches. Adhesion molecules, ICAM-1 and VCAM-1, are also highly upregulated, whereas MT1-MMP and MMP-2 expressions are significantly downregulated in both culture systems. Notably, the expression and activity of the proteasome β5 subunit are increased, especially by the action of MDA-MB-231-CM on HUVEC. Conclusions and general significance: BCCs significantly alter the expression of matrix macromolecules, proteasome activity and functional properties of endothelial cells. Deep understanding of such paracrine interactions will help to design novel drugs targeting breast cancer at the ECM level. This article is part of a Special Issue entitled Matrix-mediated cell behaviour and properties. [Copyright &y& Elsevier]
- Published
- 2014
- Full Text
- View/download PDF
37. Nrf2 enhances myocardial clearance of toxic ubiquitinated proteins.
- Author
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Wang, Wenjuan, Li, Siying, Wang, Hui, Li, Bin, Shao, Lei, Lai, Yimu, Horvath, Gary, Wang, Qian, Yamamoto, Masayuki, Janicki, Joseph S., Wang, Xing Li, Tang, Dongqi, and Cui, Taixing
- Subjects
- *
ERYTHROCYTE membranes , *TRANSCRIPTION factors , *GENE expression , *ANTIOXIDANTS , *HEART cells , *HEART failure , *OXIDATIVE stress - Abstract
Abstract: Nuclear factor erythroid-2 related factor 2 (Nrf2) is a master transcription factor that controls the basal and inducible expression of a battery of antioxidant genes and other cytoprotective phase II detoxifying enzymes. While knockout of Nrf2 exaggerates cardiac pathological remodeling and dysfunction in diverse pathological settings, pharmacological activation of Nrf2 protects against cardiomyocyte injury and cardiac dysfunction. In contrast, there is also a concern that the chronic activation of Nrf2 secondary to oxidative stress is a contributing mechanism for the reductive stress-mediated heart failure. However, a direct link between cardiac specific activation of Nrf2 and cardiac protection or dysfunction in vivo remains to be established. Therefore, we investigated the effect of cardiomyocyte-specific transgenic activation of Nrf2 (Nrf2ctg) on cardiac pathological remodeling and dysfunction. We found that the cardiomyocyte-specific activation of Nrf2 suppressed myocardial oxidative stress as well as cardiac apoptosis, fibrosis, hypertrophy, and dysfunction in a setting of sustained pressure overload induced by transverse aortic arch constriction (TAC) in mice. Notably, the constitutive activation of Nrf2 increased the steady level of autophagosomes while decreasing the ubiquitinated protein aggregates in the heart after TAC. Nrf2 gene gain- and loss-of-function approaches revealed that Nrf2 enhances autophagosome formation and autophagic flux in cardiomyocytes. Unexpectedly, while Nrf2 minimally regulated apoptosis, it suppressed significantly the proteotoxic necrosis in cardiomyocytes. In addition, Nrf2 attenuated the proteocytotoxicity presumably via enhancing autophagy-mediated clearance of ubiquitinated protein aggregates in cardiomyocytes. Taken together, we demonstrated for the first time that cardiac specific activation of Nrf2 suppresses cardiac maladaptive remodeling and dysfunction most likely by enhancing autophagic clearance of toxic protein aggregates in the heart. [Copyright &y& Elsevier]
- Published
- 2014
- Full Text
- View/download PDF
38. Going against the flow: A case for peroxisomal protein export.
- Author
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Williams, Chris
- Subjects
- *
PEROXISOME proliferator-activated receptors , *ENDOPLASMIC reticulum , *MALATE synthase , *GLUTAMIC acid , *UBIQUITIN , *EXTRACELLULAR matrix proteins - Abstract
Abstract: Peroxisomes play a crucial role in regulating cellular metabolism, providing compartments where metabolic pathways can be contained and controlled. Their importance is underlined by the developmental brain disorders caused by peroxisome malfunction, while disturbances in peroxisome function also contribute to ageing. As peroxisomes do not contain DNA, they rely on an active transport system to obtain the full quota of proteins required for function. Organelle protein transport however, is rarely a one-way process and exciting recent data have demonstrated that peroxisomes can selectively export membrane and matrix proteins to fulfil specific functions. This review will summarise the current knowledge on peroxisomal membrane and matrix protein export, discussing the mechanisms underlying export as well as the role of peroxisomal protein export in peroxisomal and cellular function. [Copyright &y& Elsevier]
- Published
- 2014
- Full Text
- View/download PDF
39. Striated muscle laminopathies.
- Author
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Azibani, Feriel, Muchir, Antoine, Vignier, Nicolas, Bonne, Gisèle, and Bertrand, Anne T.
- Subjects
- *
STRIATED muscle , *LAMINS , *INTERMEDIATE filament proteins , *NUCLEAR proteins , *PATHOLOGICAL physiology , *MUSCULAR dystrophy , *GENETIC mutation , *DISEASES - Abstract
Highlights: [•] A-type lamins are intermediate filaments that polymerize with B-type lamins to form the nuclear lamina. [•] LMNA mutations are responsible for a range of cardiac and muscular dystrophies including Emery–Dreifuss muscular dystrophy (EDMD). [•] We review the pathophysiological mechanisms of lamin A/C in striated muscles and the potential pharmacological treatments for striated muscle laminopathies. [Copyright &y& Elsevier]
- Published
- 2014
- Full Text
- View/download PDF
40. Long-term heat shock proteins (HSPs) induction by carbenoxolone improves hallmark features of Parkinson's disease in a rotenone-based model.
- Author
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Thakur, Poonam and Nehru, Bimla
- Subjects
- *
HEAT shock proteins , *CARBENOXOLONE , *PARKINSON'S disease , *ROTENONE , *UBIQUITIN , *PROTEIN folding , *BODY weight - Abstract
Abstract: Protein aggregation and dysfunction of ubiquitin proteasome system (UPS) have been implicated in Parkinson's disease (PD) pathology for a long time. Heat shock proteins (HSPs) have neuro-protective effects in PD as they assist in protein refolding and targeting of irreparable proteins to UPS. To realize their benefits in a chronically progressing disease like PD, it is imperative to maintain slightly up-regulated levels of HSPs consistently over a longer period of time. Here, we evaluate the possible beneficial effects of HSP inducer carbenoxolone (cbx) in a rotenone-based rat model of PD. Simultaneously with rotenone, a low dose of cbx (20 mg/kg body weight) was administered for five weeks to male SD rats. Weekly behavioral analysis along with end-point evaluation of HSPs, UPS activity, apoptosis, and oxidative stress were performed. The activation of heat shock factor-1 (HSF-1) and up-regulation of HSP70, HSP40, and HSP27 levels in mid-brain following cbx administration resulted in the reduction of α-synuclein and ubiquitin aggregation. This decrease seems to be mediated by reduction in protein carbonylation as well as up-regulation of UPS activity. In addition, the decrease in apoptosis and oxidative stress following HSP upregulation prevented the decline in tyrosine hydroxylase (TH) and dopamine levels in mid-brain region, which in turn resulted in improved motor functions. Thus, persistent HSP induction at low levels by cbx could improve the PD pathophysiology. [Copyright &y& Elsevier]
- Published
- 2014
- Full Text
- View/download PDF
41. Ubiquitin-conjugating enzyme E2C: A potential cancer biomarker.
- Author
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Xie, Chanlu, Powell, Chris, Yao, Mu, Wu, Jianmin, and Dong, Qihan
- Subjects
- *
UBIQUITIN-conjugating enzymes , *TUMOR markers , *PROTEASOMES , *ANAPHASE , *PROTEIN folding , *N-terminal residues - Abstract
Abstract: The ubiquitin-conjugating enzymes 2C (UBE2C) is an integral component of the ubiquitin proteasome system. UBE2C consists of a conserved core domain containing the catalytic Cys residue and an N-terminal extension. The core domain is required for ubiquitin adduct formation by interacting with the ubiquitin-fold domain in the E1 enzyme, and contributes to the E3 enzyme binding. UBE2C N-terminal extension regulates E3 enzyme activity as a part of an intrinsic inhibitory mechanism. UBE2C is required for the destruction of mitotic cyclins and securin, which are essential for spindle assembly checkpoint and mitotic exit. The UBE2C mRNA and/or protein levels are aberrantly increased in many cancer types with poor clinical outcomes. Accumulation of UBE2C stimulates cell proliferation and anchorage-independent growth. UBE2C transgenic mice are prone to develop spontaneous tumors and carcinogen-induced tumor with evidence of chromosome aneuploidy. [Copyright &y& Elsevier]
- Published
- 2014
- Full Text
- View/download PDF
42. Inhibitory effect on the proteasome regulatory subunit, RPN11/POH1, with the use of Capzimin-PROTAC to trigger apoptosis in cancer cells
- Author
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Holmqvist, Andreas
- Subjects
Organisk kemi ,Organic Chemistry ,Chemotherapy ,Proteasome inhibitor ,Capzimin ,Cancer therapeutics ,Ubiquitin proteasome system (UPS) ,Proteolysis targeting chimera (PROTAC) ,Cancer - Abstract
Most patients diagnosed with cancer will receive systematic chemotherapy at some point during their illness, which almost always cause severe side effects for the patients such as, anemia, nausea and vomiting. The problems with today’s chemotherapy is not only that it cause severe side effects, but also that the cancer may develop resistance to the therapy, which is why the development of a new type of therapeutic agent is in dire need. The ubiquitin proteasome system (UPS) is a vital machinery for the cancer cells to maintain protein homeostasis, which also make them vulnerable to any disruption of this system. In recent years, a new technology has been developed that utilize the UPS by chemically bringing an E3 ubiquitin ligase into close proximity of a protein of choice and tagging the protein with ubiquitin for degradation. This technology is called proteolysis targeting chimera (PROTAC). In this project, we managed to theoretically develop a new type of cancer therapeutic agent, that utilize the PROTAC system together with the first-in-class proteasome regulatory subunit, POH1, inhibitor Capzimin as a warhead. By using Capzimin as a warhead it should be possible to polyubiquitinate POH1, and thus induce proteotoxic stress in the cancer cells to trigger apoptosis. This theoretically developed drug is therefore called Capzimin-PROTAC, which should be able to trigger apoptosis in cancer cells, and at the same time being relatively safe to normal healthy cells.
- Published
- 2020
43. Sesamol and naringenin reverse the effect of rotenone-induced PD rat model.
- Author
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Sonia Angeline, M., Sarkar, A., Anand, K., Ambasta, R.K., and Kumar, P.
- Subjects
- *
NARINGENIN , *ORGANIC compounds , *PARKINSON'S disease , *ROTENONE , *BIOFLAVONOIDS , *ANTIOXIDANTS , *HEAT shock proteins , *LABORATORY rats , *THERAPEUTICS - Abstract
Highlights: [•] Neuroprotective effect of the sesamol and naringenin on rotenone-induced model of PD. [•] Bioflavonoids improve body weight and motor impairment of rotenone-induced PD model. [•] Antioxidant property of flavonoids protects neurons and muscles against degeneration. [•] Sesamol and naringenin restore level of protective proteins parkin, DJ1, TH and CHIP. [•] Sesamol and naringenin reduced caspase activation, ubiquitin expression in PD model. [Copyright &y& Elsevier]
- Published
- 2013
- Full Text
- View/download PDF
44. Specificity in the actions of the UBR1 ubiquitin ligase in the degradation of nuclear receptors.
- Author
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Sultana, Rasheda, Theodoraki, Maria A., and Caplan, Avrom J.
- Subjects
UBIQUITIN ligases ,NUCLEAR receptors (Biochemistry) ,PROTEIN conformation ,PROTEIN folding ,GLUCOCORTICOID receptors ,DIMETHYL sulfoxide ,HEMAGGLUTININ - Abstract
Abstract: The UBR1 ubiquitin ligase promotes degradation of proteins via the N-end rule and by another mechanism that detects a misfolded conformation. Although UBR1 was shown recently to act on protein kinases whose misfolding was promoted by inhibition of Hsp90, it was unknown whether this ubiquitin ligase targeted other client types of the chaperone. We analyzed the role of UBR1 in the degradation of nuclear receptors that are classical clients of Hsp90. Our results showed that UBR1 deletion results in impaired degradation of the glucocorticoid receptor and the androgen receptor but not the estrogen receptor α. These findings demonstrate specificity in the actions of the UBR1 ubiquitin ligase in the degradation of Hsp90 clients in the presence of small molecule inhibitors that promote client misfolding. [Copyright &y& Elsevier]
- Published
- 2013
- Full Text
- View/download PDF
45. The BAG2 protein stabilises PINK1 by decreasing its ubiquitination.
- Author
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Che, Xiangqian, Tang, Beisha, Wang, Xuejing, Chen, Dong, Yan, Xinxiang, Jiang, Hong, Shen, Lu, Xu, Qian, Wang, Guanghui, and Guo, Jifeng
- Subjects
- *
UBIQUITINATION , *GENETIC mutation , *MEDICAL sciences , *HUMAN genetics , *MEDICAL genetics , *GENETIC disorders - Abstract
Highlights: [•] BAG2 colocalizes with PINK1 and R492X PINK1 mutation in vivo. [•] BAG2 binds with PINK1 directly and stabilizes PINK1 by decreasing its ubiquitination. [•] BAG2 also binds with R492X PINK1 mutation, directly and more tightly. [•] BAG2 stabilizes R492X PINK1 mutation by decreasing its ubiquitination more obviously. [Copyright &y& Elsevier]
- Published
- 2013
- Full Text
- View/download PDF
46. Molecular mechanisms and signaling pathways of angiotensin II-induced muscle wasting: Potential therapeutic targets for cardiac cachexia.
- Author
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Yoshida, Tadashi, Tabony, A. Michael, Galvez, Sarah, Mitch, William E., Higashi, Yusuke, Sukhanov, Sergiy, and Delafontaine, Patrice
- Subjects
- *
ANGIOTENSIN II , *WASTING syndrome , *CACHEXIA treatment , *HEART failure , *MUSCULAR atrophy , *RENIN-angiotensin system - Abstract
Abstract: Cachexia is a serious complication of many chronic diseases, such as congestive heart failure (CHF) and chronic kidney disease (CKD). Many factors are involved in the development of cachexia, and there is increasing evidence that angiotensin II (Ang II), the main effector molecule of the renin–angiotensin system (RAS), plays an important role in this process. Patients with advanced CHF or CKD often have increased Ang II levels and cachexia, and angiotensin-converting enzyme (ACE) inhibitor treatment improves weight loss. In rodent models, an increase in systemic Ang II leads to weight loss through increased protein breakdown, reduced protein synthesis in skeletal muscle and decreased appetite. Ang II activates the ubiquitin–proteasome system via generation of reactive oxygen species and via inhibition of the insulin-like growth factor-1 signaling pathway. Furthermore, Ang II inhibits 5′ AMP-activated protein kinase (AMPK) activity and disrupts normal energy balance. Ang II also increases cytokines and circulating hormones such as tumor necrosis factor-α, interleukin-6, serum amyloid-A, glucocorticoids and myostatin, which regulate muscle protein synthesis and degradation. Ang II acts on hypothalamic neurons to regulate orexigenic/anorexigenic neuropeptides, such as neuropeptide-Y, orexin and corticotropin-releasing hormone, leading to reduced appetite. Also, Ang II may regulate skeletal muscle regenerative processes. Several clinical studies have indicated that blockade of Ang II signaling via ACE inhibitors or Ang II type 1 receptor blockers prevents weight loss and improves muscle strength. Thus the RAS is a promising target for the treatment of muscle atrophy in patients with CHF and CKD. This article is part of a Directed Issue entitled: Molecular basis of muscle wasting. [Copyright &y& Elsevier]
- Published
- 2013
- Full Text
- View/download PDF
47. Glucocorticoid-induced skeletal muscle atrophy.
- Author
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Schakman, O., Kalista, S., Barbé, C., Loumaye, A., and Thissen, J.P.
- Subjects
- *
GLUCOCORTICOIDS , *SKELETAL muscle , *MUSCULAR atrophy , *PROTEASOMES , *MYOSTATIN , *GHRELIN receptors - Abstract
Abstract: Many pathological states characterized by muscle atrophy (e.g., sepsis, cachexia, starvation, metabolic acidosis and severe insulinopenia) are associated with an increase in circulating glucocorticoids (GC) levels, suggesting that GC could trigger the muscle atrophy observed in these conditions. GC-induced muscle atrophy is characterized by fast-twitch, glycolytic muscles atrophy illustrated by decreased fiber cross-sectional area and reduced myofibrillar protein content. GC-induced muscle atrophy results from increased protein breakdown and decreased protein synthesis. Increased muscle proteolysis, in particular through the activation of the ubiquitin proteasome and the lysosomal systems, is considered to play a major role in the catabolic action of GC. The stimulation by GC of these two proteolytic systems is mediated through the increased expression of several Atrogenes (“genes involved in atrophy”), such as FOXO, Atrogin-1, and MuRF-1. The inhibitory effect of GC on muscle protein synthesis is thought to result mainly from the inhibition of the mTOR/S6 kinase 1 pathway. These changes in muscle protein turnover could be explained by changes in the muscle production of two growth factors, namely Insulin-like Growth Factor (IGF)-I, a muscle anabolic growth factor and Myostatin, a muscle catabolic growth factor. This review will discuss the recent progress made in the understanding of the mechanisms involved in GC-induced muscle atrophy and consider the implications of these advancements in the development of new therapeutic approaches for treating GC-induced myopathy. This article is part of a Directed Issue entitled: Molecular basis of muscle wasting. [Copyright &y& Elsevier]
- Published
- 2013
- Full Text
- View/download PDF
48. Deciphering the ubiquitin proteome: Limits and advantages of high throughput global affinity purification-mass spectrometry approaches.
- Author
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Polge, Cécile, Uttenweiler-Joseph, Sandrine, Leulmi, Roza, Heng, Anne-Elisabeth, Burlet-Schiltz, Odile, Attaix, Didier, and Taillandier, Daniel
- Subjects
- *
UBIQUITIN , *PROTEASOMES , *MASS spectrometry , *CELL metabolism , *UBIQUITIN ligases , *UBIQUITINATION - Abstract
Abstract: Ubiquitination is a posttranslational modification of proteins that involves the covalent attachment of ubiquitin, either as a single moiety or as polymers. This process controls almost every cellular metabolic pathway through a variety of combinations of linkages. Mass spectrometry now allows high throughput approaches for the identification of the thousands of ubiquitinated proteins and of their ubiquitination sites. Despite major technological improvements in mass spectrometry in terms of sensitivity, resolution and acquisition speed, the use of efficient purification methods of ubiquitinated proteins prior to mass spectrometry analysis is critical to achieve an efficient characterization of the ubiquitome. This critical step is achieved using different approaches that possess advantages and pitfalls. Here, we discuss the limits that can be encountered when deciphering the ubiquitome. This article is part of a Directed Issue entitled: Molecular basis of muscle wasting. [Copyright &y& Elsevier]
- Published
- 2013
- Full Text
- View/download PDF
49. Modulation of histone deacetylase, the ubiquitin proteasome system, and autophagy underlies the neuroprotective effects of venlafaxine in a rotenone-induced Parkinson's disease model in rats.
- Author
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El-Saiy, Khalid A., Sayed, Rabab H., El-Sahar, Ayman E., and Kandil, Esraa A.
- Subjects
- *
PARKINSON'S disease , *HISTONE deacetylase , *BRAIN-derived neurotrophic factor , *VENLAFAXINE , *UBIQUITIN , *DOPAMINERGIC neurons , *SUBTHALAMIC nucleus , *SIRTUINS - Abstract
Parkinson's disease (PD) is a neurodegenerative disease characterized by motor and non-motor symptoms. Impairment of the ubiquitin proteasome system (UPS) and autophagy has been suggested to contribute to α-synuclein accumulation, which is identified as the pathological hallmark of PD. Recently, alteration in histone-3 acetylation has also been found to be correlated to PD. Interestingly, the histone deacetylase 6 (HDAC6) enzyme, which regulates the acetylation of histone-3, was shown to be involved in autophagy. Venlafaxine is an antidepressant that was proposed to inhibit HDAC expression in depressive rats' hippocampi. In this study, we aimed to examine the ability of venlafaxine to inhibit striatal HDAC6 and to enhance α-synuclein clearance through the activation of the UPS and autophagy, in addition to treating depression, which is the most debilitating non-motor symptom, in a rotenone model of PD. Venlafaxine administration was noted to decrease α-synuclein accumulation and preserve dopaminergic neurons along with restoration of striatal dopamine levels and motor recovery. Its administration augmented the UPS and autophagic markers (beclin-1, p62, and LC3) with consequent modulation of apoptotic indicators (Bax/Bcl-2 ratio, cytochrome c , and caspase-3). Additionally, venlafaxine inhibited HDAC6 with further enhancement of autophagy and restoration of histone-3 acetylation with subsequent increases in survival gene expressions (Bcl-2 and brain-derived neurotrophic factor). Chloroquine (autophagy inhibitor) was used to indicate the proposed pathway. Moreover, venlafaxine hampered depressive symptoms and improved hippocampal noradrenaline and serotonin levels. Collectively, venlafaxine is suggested to display neuroprotective effects with improvement of motor and non-motor PD symptoms. [Display omitted] • Venlafaxine decreased α-synuclein accumulation and preserved dopaminergic neurons. • Venlafaxine recovered motor activity of rats. • Venlafaxine augmented the UPS and autophagic markers with consequent modulation of apoptotic indicators. • Venlafaxine inhibited HDAC6 with restoration of histone-3 acetylation. • The proposed pathway was evidenced by the use of autophagy inhibitor chloroquine. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
50. Reprint of: Revisiting oxidative stress and mitochondrial dysfunction in the pathogenesis of Parkinson disease—resemblance to the effect of amphetamine drugs of abuse.
- Author
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Perfeito, Rita, Cunha-Oliveira, Teresa, and Rego, Ana Cristina
- Subjects
- *
OXIDATIVE stress , *MITOCHONDRIAL pathology , *PARKINSON'S disease , *AMPHETAMINE abuse , *NEURODEGENERATION , *CYTOPLASM , *NEUROTOXICOLOGY - Abstract
Abstract: Parkinson disease (PD) is a chronic and progressive neurological disease associated with a loss of dopaminergic neurons. In most cases the disease is sporadic but genetically inherited cases also exist. One of the major pathological features of PD is the presence of aggregates that localize in neuronal cytoplasm as Lewy bodies, mainly composed of α-synuclein (α-syn) and ubiquitin. The selective degeneration of dopaminergic neurons suggests that dopamine itself may contribute to the neurodegenerative process in PD. Furthermore, mitochondrial dysfunction and oxidative stress constitute key pathogenic events of this disorder. Thus, in this review we give an actual perspective to classical pathways involving these two mechanisms of neurodegeneration, including the role of dopamine in sporadic and familial PD, as well as in the case of abuse of amphetamine-type drugs. Mutations in genes related to familial PD causing autosomal dominant or recessive forms may also have crucial effects on mitochondrial morphology, function, and oxidative stress. Environmental factors, such as MPTP and rotenone, have been reported to induce selective degeneration of the nigrostriatal pathways leading to α-syn-positive inclusions, possibly by inhibiting mitochondrial complex I of the respiratory chain and subsequently increasing oxidative stress. Recently, increased risk for PD was found in amphetamine users. Amphetamine drugs have effects similar to those of other environmental factors for PD, because long-term exposure to these drugs leads to dopamine depletion. Moreover, amphetamine neurotoxicity involves α-syn aggregation, mitochondrial dysfunction, and oxidative stress. Therefore, dopamine and related oxidative stress, as well as mitochondrial dysfunction, seem to be common links between PD and amphetamine neurotoxicity. [Copyright &y& Elsevier]
- Published
- 2013
- Full Text
- View/download PDF
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