Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.25.1 (proteasome)
28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Polyphenols are characterized by the presence of more than one phenolic group and are widely distributed in many fruits and vegetables. They possess antioxidant properties and interact with cellular defense systems through the antioxidant-responsive element/electrophile-responsive element (ARE/EpRE) although the precise mechanism by which polyphenols influence transcription factor complexes to target ARE is poorly understood. In the present study, we chose a typical polyphenol, quercetin, to investigate the mechanism in human HepG2 cells. Quercetin enhanced the ARE binding activity and Nrf2-mediated transcription activity. Molecular evidence revealed that quercetin not only up-regulated the expression of Nrf2 mRNA and protein, but also stabilized Nrf2 protein by inhibiting the ubiquitination and proteasomal turnover of Nrf2. At the same time, quercetin markedly reduced the level of Keap1 protein in posttranslational levels through the formation of modified Keap1 protein, rather than 26S proteasome-dependent degradation mechanisms, without affecting the dissociation of Keap1-Nrf2. Silencing Keap1 using Keap1 siRNA significantly increased the Nrf2-dependent ARE activity, whereas silencing Nrf2 using Nrf2 siRNA markedly reduced the ARE activity under both baseline and quercetin-induced conditions. Thus, we conclude that the pathway of quercetin-induced ARE activity involves up-regulation of Nrf2 through the regulation of both transcription and posttranscription sites and repression of Keap1 by affecting the posttranscription site, revealing some substantial differences between oxidative inducers. Thus, the findings provide an insight into the mechanisms underlying polyphenolic compounds in cytoprotection and cancer chemoprevention.
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PMID:Action of Nrf2 and Keap1 in ARE-mediated NQO1 expression by quercetin. 1746 37

The 26S proteasome is responsible for degradation of abnormal proteins and may play a role in cell survival upon oxidative stress. The indirect antioxidant sulforaphane (SFN) protects animal tissues from chemical toxicants by increasing the expression of several families of Nrf2-regulated genes. The role of induction of the 26S proteasome in cytoprotection by SFN was investigated in murine neuroblastoma Neuro2A cells. SFN enhanced the expression of the catalytic subunits of the proteasome, as well as proteasomal peptidase activities in these cells. Such treatment with SFN protected cells from hydrogen peroxide-mediated cytotoxicity in a manner dependent on proteasomal function. Inhibition of proteasome activities using pharmacological interventions significantly attenuated the protective effects of SFN against hydrogen peroxide cytotoxicity, as well as protein oxidation. Moreover, overexpression of the catalytic subunit PSMB5 enhanced proteasome function and led to elevated resistance against hydrogen peroxide toxicity and extent of protein oxidation compared to blank-plasmid-transfected cells. Pretreatment of PSMB5-overexpressing cells with SFN did not further enhance this resistance. Collectively, these results suggest that the cytoprotective effects of SFN against oxidative stress are in part due to up-regulation of the proteasome system. Therefore, inducers of proteasome expression may ameliorate the accumulation of damaged proteins associated with neurodegeneration and other diseases in whose etiologies protein oxidation plays a role.
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PMID:Role of increased expression of the proteasome in the protective effects of sulforaphane against hydrogen peroxide-mediated cytotoxicity in murine neuroblastoma cells. 1766 44

Parkinson's disease (PD) may be caused by a complex interaction of environmental insults and genetic susceptibilities. Previous studies of DJ-1-deficient mice have noted dopaminergic dysfunction mainly in older mice. To simulate the interaction of genetic factors and environmental factors, we treated DJ-1-deficient mice with paraquat. Even in relatively young mice, this combination produced dopamine loss and motor dysfunction. To determine the potential mechanism for the dopaminergic dysfunction, we investigated the proteasome function and ubiquitinated protein levels. DJ-1-deficient mice treated with paraquat showed decreased proteasome activities and increased ubiquitinated protein levels. To further investigate the mechanism of proteasome dysfunction, ATP levels and subunit protein levels of 19S ATPase Rpt6 and 20S beta5 were measured and noted to be decreased in the ventral midbrain, but not in the striatum. Finally, a transcription factor, Nrf2 that has been previously shown to be regulated by DJ-1 and to regulate 20S beta5 levels was decreased. These pathologies were not observed in brain regions of normal mice treated with paraquat. In conclusion, this study raises the possibility that environmental and genetic factors might cooperatively involve the mechanisms underlying proteasome impairment in PD brains.
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PMID:Paraquat induces dopaminergic dysfunction and proteasome impairment in DJ-1-deficient mice. 1782 2

Oxidative injury has been found to be associated with proteasomal inactivity. In this study, the extent of oxidative damage and its effects on proteasomal function has been critically assessed. Left anterior descending coronary artery was occluded (ischemia) and reperfused with or without preconditioning in male Sprague-Dawley rats. For further validation, H9c2 cardiac myoblasts cultures were used. We demonstrate that ischemia-reperfusion causes extensive endoplasmic reticulum stress as evident from the degradation of GRP78 transcript followed by its rapid induction. Western blot analysis and immunohistochemistry showed that increasing duration of ischemia and reperfusion causes accumulation of phosphorylated IkappaB (p-IkappaB), thereby suggesting proteasomal inactivity. However, similar analysis for Nrf2, a key mediator of antioxidant defense, showed sustained activation, suggesting intact proteasomal function. Preconditioning of the myocardium preserves the degradation of p-IkappaB, suggesting effective functioning of proteasome after preconditioning. Further analysis with specific proteosomal inhibitors like epoxomicin (100 nM, inhibits chymotrypsin-like activities of proteasomes) and lactacystin (2 microM, inhibits chymotrypsin as well as some trypsin-like activities of proteasomes) suggests that degradation of p-IkappaB and Keap-1 in the proteasome occurs by independent mechanisms. This study gives further insight into interrelationship between oxidative injury and catalytic function of the proteasome in heart, where oxidative injury causes selective rather than global inhibition of proteasome.
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PMID:Oxidative injury induces selective rather than global inhibition of proteasomal activity. 1807 53

Prothymosin alpha (ProTalpha) is a highly conserved protein in vertebrates that possesses a number of biological functions. One of these functions of ProTalpha is the ability to enhance antioxidant defence system of a cell via its interaction with Keap1 protein. Keap1 is a repressor of Nrf2, a transcription factor responsible for activation of genes that code for defensive proteins. While bound to Nrf2, Keap1 exports Nrf2 from the nucleus to the cytoplasm and, being adaptor protein for ubiquitin ligase, promotes ubiquitination of Nrf2 and its subsequent degradation by 26S proteasome. ProTalpha and Nrf2 compete for interaction with Keap1, therefore ProTalpha is able to liberate Nrf2 from complex with Keap1 and hence contribute to Nrf2-dependent transcription. Here we were interested in elucidating possible consequences for ProTalpha of its interaction with Keap1. We have shown that, despite ProTalpha interaction with Keap1, ProTalpha is a stable protein. In contrast to Nrf2 ProTalpha was not subjected to Keap-dependent ubiquitination, degradation and export from the nucleus. Furthermore, ubiquitination of ProTalpha was undetectable even when Keap1 and ubiquitin were overexpressed. It appears that ProTalpha contribution to Nrf2-dependent transcription is accomplished via the increase of free Nrf2 rather then the increase of total intracellular amount of Nrf2.
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PMID:[Prothyomosin alpha interaction with KEAP1 doesn't lead to prothymosin alpha ubiquination and degradation]. 1824 May 69

The 26S proteasome plays a major role in degradation of abnormal proteins within the cell. The indirect antioxidant including sulforaphane (SFN) protects cells from oxidative damage by increasing the expression of Nrf2-target genes. It has been observed that the expression of multiple subunits of the proteasome was up-regulated by indirect antioxidants through the Nrf2 pathway. In the current study, the role of SFN in amyloid beta(1-42) (Abeta(1-42))-induced cytotoxicity has been investigated in murine neuroblastoma cells. Treatment with SFN protected cells from Abeta(1-42)-mediated cell death in Neuro2A and N1E 115 cells. Inhibition of proteasome activities by MG132 could abolish the protective effect of SFN against Abeta(1-42). Neuro2A cells, which were stably overexpressing the catalytic subunit of the proteasome PSMB5, showed an elevated resistance toward Abeta(1-42) toxicity compared to control cells. Furthermore, the in vitro assay demonstrated that the Abeta(1-42) peptide is degraded by the proteasome fraction. These results suggest that proteasome-inducing indirect antioxidants may facilitate the removal of the Abeta(1-42) peptide and lead to the amelioration of abnormal protein-associated etiologies.
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PMID:Protection against amyloid beta cytotoxicity by sulforaphane: role of the proteasome. 1918 83

Cigarette smoking is the major risk factor for developing chronic obstructive pulmonary disease, the fourth leading cause of deaths in the United States. Despite recent advances, the molecular mechanisms involved in the initiation and progression of this disease remain elusive. We used Affymetrix Gene Chip arrays to determine the temporal alterations in global gene expression during the progression of pulmonary emphysema in A/J mice. Chronic cigarette smoke (CS) exposure caused pulmonary emphysema in A/J mice, which was associated with pronounced bronchoalveolar inflammation, enhanced oxidative stress, and increased apoptosis of alveolar septal cells. Microarray analysis revealed the upregulation of 1,190, 715, 260, and 246 genes and the downregulation of 1,840, 730, 442, and 236 genes in the lungs of mice exposed to CS for 5 h, 8 days, and 1.5 and 6 mo, respectively. Most of the genes belong to the functional categories of phase I genes, Nrf2-regulated antioxidant and phase II genes, phase III detoxification genes, and others including immune/inflammatory response genes. Induction of the genes encoding multiple phase I enzymes was markedly higher in the emphysematous lungs, whereas reduced expression of various cytoprotective genes constituting ubiquitin-proteasome complex, cell survival pathways, solute carriers and transporters, transcription factors, and Nrf2-regulated antioxidant and phase II-responsive genes was noted. Our data indicate that the progression of CS-induced emphysema is associated with a steady decline in the expression of various genes involved in multiple pathways in the lungs of A/J mice. Many of the genes discovered in this study could rationally play an important role in the susceptibility to CS-induced emphysema.
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PMID:Cigarette smoke-induced emphysema in A/J mice is associated with pulmonary oxidative stress, apoptosis of lung cells, and global alterations in gene expression. 1928 29

Nrf2 (NF-E2-related factor 2) is a master transcription factor containing a powerful acidic transcriptional activation domain. Nrf2-dependent gene expression impacts cancer chemoprevention strategies, inflammatory responses, and progression of neurodegenerative diseases. Under basal conditions, association of Nrf2 with the CUL3 adaptor protein Keap1 results in the rapid Nrf2 ubiquitylation and proteasome-dependent degradation. Inhibition of Keap1 function blocks ubiquitylation of Nrf2, allowing newly synthesized Nrf2 to translocate into the nucleus, bind to ARE sites and direct target gene expression. Site-directed mutagenesis experiments coupled with proteomic analysis support a model in which Keap1 contains at least 2 distinct cysteine motifs. The first is located at Cys 151 in the BTB domain. The second is located in the intervening domain and centers around Cys 273 and 288. Adduction or oxidation at Cys151 has been shown to produce a conformational change in Keap1 that results in dissociation of Keap1 from CUL3, thereby inhibiting Nrf2 ubiquitylation. Thus, adduction captures specific chemical information and translates it into biochemical information via changes in structural conformation.
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PMID:Cysteine-based regulation of the CUL3 adaptor protein Keap1. 1956 Apr 82

Glutathione peroxidase-3 (GPx-3) is a key antioxidant enzyme in the plasma. GPx-3 was previously identified as the major antioxidative enzyme that was induced upon nontoxic proteasome inhibition in endothelial cells. Here, we investigated the determinants of the proteasome inhibitor-induced expression of GPx-3. Nontoxic proteasome inhibition massively upregulates GPx-3 RNA and protein in human umbilical cord vein cells within 24 h. Surprisingly, induction of GPx-3 was species-specific for human cells. The exponential upregulation of GPx-3 is mediated by transcriptional activation of the human GPx-3 promoter and, in addition, stabilization of GPx-3 mRNA: in reporter gene assays with full-length and deleted variants of the human GPx-3 promoter we identified a putative antioxidative response element (ARE) as essential and also sufficient for transcriptional activation of GPx-3 by proteasome inhibition. However, the ARE-specific antioxidative transcription factor Nrf2 is not involved in the activation of GPx-3. UV-crosslinking using the 3'UTR of GPx-3 revealed an altered protein binding pattern in the presence of proteasome inhibitors, thus indicating regulation of mRNA stability of human GPx-3. As GPx-3 is secreted into the plasma, our data point toward a borderline defense mechanism of endothelial cell-derived GPx-3 to protect the vasculature from oxidative stress.
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PMID:Human-specific induction of glutathione peroxidase-3 by proteasome inhibition in cardiovascular cells. 1976 14

Replicative senescence in human fibroblasts is accompanied with alterations of various biological processes, including the impaired function of the proteasome. The proteasome is responsible for the removal of both normal and damaged proteins. Due to its latter function, proteasome is also considered a representative secondary antioxidant cellular mechanism. Nrf2 is a basic transcription factor responsible for the regulation of the cellular antioxidant response that has also been shown to regulate several proteasome subunits in mice. We have established in this study the proteasome-related function of Nrf2 in human fibroblasts undergoing replicative senescence. We demonstrate that Nrf2 has a declined function in senescence, whereas its silencing leads to premature senescence. However, upon its activation by a novel Nrf2 inducer, elevated levels of proteasome activity and content are recorded only in cell lines possessing a functional Nrf2. Moreover, treatment by the Nrf2 inducer results in the enhanced survival of cells following oxidative stress, whereas continuous treatment leads to lifespan extension of human fibroblasts. Importantly the Nrf2-proteasome axis is functional in terminally senescent cultures as these cells retain their responsiveness to the Nrf2 stimuli. In conclusion, these findings open up new directions for future manipulation of the senescence phenotype.
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PMID:Nuclear erythroid factor 2-mediated proteasome activation delays senescence in human fibroblasts. 2006 43


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