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)

We previously reported cDNA cloning of a novel oxidative stress protein termed A170 from murine macrophages. Further experiments have demonstrated that exposure of the cells to low levels of H2O2 produced by glucose/glucose oxidase markedly induced the 60-kDa A170 protein. This result suggests that the level of A170 protein can also be controlled at posttranscriptional levels, because we showed previously that H2O2 hardly increased the level of A170 mRNA. We have found that proteasome inhibitors markedly induced the A170 protein after 2 to 8 h similarly to glucose/glucose oxidase, suggesting rapid degradation of the A170 protein by proteasome under normal conditions. Activation of cellular signaling pathways either by epidermal growth factor, lipopolysaccharide or tumor necrosis factor-alpha did not enhance the level of the A170 protein. The levels of glucose oxidase-induced A170 protein did not decrease after the addition of cycloheximide. These results suggest that low levels of H2O2 may stabilize the A170 protein, allowing it to accumulate within cells.
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PMID:Low micromolar levels of hydrogen peroxide and proteasome inhibitors induce the 60-kDa A170 stress protein in murine peritoneal macrophages. 912 46

We synthesize a large gene expression data set using dbEST and UniGene. We use guilt-by-association (GBA) to analyze this data set and identify coexpressed genes. One module, or group of genes, was found to be coexpressed mainly in tissue extracted from breast and ovarian cancers, but also found in tissue from lung cancers, brain cancers, and bone marrow. This module contains at least six members that are believed to be involved in either transcritional regulation (PDEF, H2AFO, NUCKS) or the ubiquitin proteasome pathway (PSMD7, SQSTM1, FLJ10111). We confirm these observations of coexpression by real-time RT-PCR analysis of mRNA extracted from four model breast epithelial cell lines.
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PMID:Identification and confirmation of a module of coexpressed genes. 1236 43

A hallmark of most neurodegenerative diseases, including those caused by polyglutamine expansion, is the formation of ubiquitin (Ub)-positive protein aggregates in affected neurons. This finding suggests that the Ub system may be involved in common mechanisms underlying these otherwise unrelated diseases. Here we report the finding of ataxin-3 (Atx-3), whose mutation is implicated in the neurodegenerative disease spinocerebellar ataxia type 3, in a bioinformatics search of the human genome for components of the Ub system. We show that wild-type Atx-3 is a Ub-binding protein and that the interaction of Atx-3 with Ub is mediated by motifs homologous to those found in a proteasome subunit. Both wild-type Atx-3 and the otherwise unrelated Ub-binding protein p62/Sequestosome-1 have been shown to be sequestered into aggregates in affected neurons in several neurodegenerative diseases, but the mechanism for this recruitment has remained unclear. In this article, we show that functional Ub-binding motifs in Atx-3 and p62 proteins are required for the localization of both proteins into aggregates in a cell-based assay that recapitulates several features of polyglutamine disease. We propose that the Ub-mediated sequestration of essential Ub-binding protein(s) into aggregates may be a common mechanism contributing to the pathogenesis of neurodegenerative diseases.
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PMID:Ubiquitin-mediated sequestration of normal cellular proteins into polyglutamine aggregates. 1285 50

An integrated, bioinformatic analysis of three databases comprising tumor-cell-based small molecule screening data, gene expression measurements, and PDB (Protein Data Bank) ligand-target structures has been developed for probing mechanism of drug action (MOA). Clustering analysis of GI50 profiles for the NCI's database of compounds screened across a panel of tumor cells (NCI60) was used to select a subset of unique cytotoxic responses for about 4000 small molecules. Drug-gene-PDB relationships for this test set were examined by correlative analysis of cytotoxic response and differential gene expression profiles within the NCI60 and structural comparisons with known ligand-target crystallographic complexes. A survey of molecular features within these compounds finds thirteen conserved Compound Classes, each class exhibiting chemical features important for interactions with a variety of biological targets. Protein targets for an additional twelve Compound Classes could be directly assigned using drug-protein interactions observed in the crystallographic database. Results from the analysis of constitutive gene expressions established a clear connection between chemo-resistance and overexpression of gene families associated with the extracellular matrix, cytoskeletal organization, and xenobiotic metabolism. Conversely, chemo-sensitivity implicated overexpression of gene families involved in homeostatic functions of nucleic acid repair, aryl hydrocarbon metabolism, heat shock response, proteasome degradation and apoptosis. Correlations between chemo-responsiveness and differential gene expressions identified chemotypes with nonselective (i.e., many) molecular targets from those likely to have selective (i.e., few) molecular targets. Applications of data mining strategies that jointly utilize tumor cell screening, genomic, and structural data are presented for hypotheses generation and identifying novel anticancer candidates.
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PMID:Linking tumor cell cytotoxicity to mechanism of drug action: an integrated analysis of gene expression, small-molecule screening and structural databases. 1577 71

In eukaryotic cells short-lived proteins are degraded in a specific process by the ubiquitin-proteasome system (UPS), whereas long-lived proteins and damaged organelles are degraded by macroautophagy (hereafter referred to as autophagy). A growing body of evidence now suggests that autophagy is important for clearance of protein aggregates that form in cells as a consequence of ageing, oxidative stress, alterations that elevate the amounts of certain aggregation-prone proteins or expression of aggregating mutant variants of specific proteins. Autophagy is generally considered to be a non-specific, bulk degradation process. However, a recent study suggests that p62/SQSTM1 may link the recognition of polyubiquitinated protein aggregates to the autophagy machinery.(1) This protein is able to polymerize via its N-terminal PB1 domain and to recognize polyubiquitin via its C-terminal UBA domain. It can also recruit the autophagosomal protein LC3 and co-localizes with many types of polyubiquitinated protein aggregates.(1) Here we discuss possible implications of these findings and raise some questions for further investigation.
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PMID:p62/SQSTM1: a missing link between protein aggregates and the autophagy machinery. 1687 37

Paget's disease of bone (PDB) is a common condition with a strong genetic component that is characterized by focal increases in bone turnover, leading to bone deformity, pathological fractures, and various other complications. Several rare disorders have also been described that show phenotypic overlap with PDB. Genome-wide searches have identified several susceptibility loci for PDB and PDB-like disorders, and mutations that cause these disorders have now been identified in four genes, all of which are involved in the RANK-NF-kappaB signaling pathway. Mutations in SQSTM1, which encodes an important scaffold protein in this pathway, have been found to be a common cause of classical PDB. Thus far, all disease-causing mutations in SQSTM1 affect the ubiquitin-associated (UBA) domain of the gene product and cause loss of ubiquitin binding. The rare PDB-like disorders of familial expansile osteolysis, early-onset familial PDB, and expansile skeletal hyperphosphatasia are caused by duplication mutations in exon 1 of the TNFRSF11A gene, which encodes the RANK receptor. This gene does not seem to be involved in the pathogenesis of classical PDB. Inactivating mutations in the TNFRSF11B gene, which encodes osteoprotegerin, cause juvenile PDB, and TNFRSF11B polymorphisms seem to increase the risk of classical PDB. The rare syndrome of hereditary inclusion body myopathy, PDB, and frontotemporal dementia (IBMPFD) is caused by mutations in the VCP gene, which is involved in regulating I-kappaB degradation by the proteasome. The disease-causing mutations in VCP cluster in and around a domain involved in ubiquitin binding. Whereas SQSTM1 has emerged as an important gene for classical PDB, most kindreds with familial PDB do not carry SQSTM1 mutations, indicating that additional genes for PDB remain to be discovered. In light of the molecular defects that have been identified thus far, it seems likely that these genes will also be involved in the RANK-NF-kappaB signaling pathway or its interactions with the ubiquitin-proteasome system.
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PMID:Contribution of genetic factors to the pathogenesis of Paget's disease of bone and related disorders. 1722 6

UCH-L3 (ubiquitin C-terminal hydrolase-L3) is a de-ubiquitinating enzyme that is a component of the ubiquitin-proteasome system and known to be involved in programmed cell death. A previous study of high-throughput drug screening identified an isatin derivative as a UCH-L3 inhibitor. In this study, we attempted to identify a novel inhibitor with a different structural basis. We performed in silico structure-based drug design (SBDD) using human UCH-L3 crystal structure data (PDB code; 1XD3) and the virtual compound library (ChemBridge CNS-Set), which includes 32,799 chemicals. By a two-step virtual screening method using DOCK software (first screening) and GOLD software (second screening), we identified 10 compounds with GOLD scores of over 60. To address whether these compounds exhibit an inhibitory effect on the de-ubiquitinating activity of UCH-L3, we performed an enzymatic assay using ubiquitin-7-amido-4-methylcoumarin (Ub-AMC) as the substrate. As a result, we identified three compounds with similar basic dihydro-pyrrole skeletons as UCH-L3 inhibitors. These novel compounds may be useful for the research of UCH-L3 function, and in drug development for UCH-L3-associated diseases.
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PMID:Identification of novel chemical inhibitors for ubiquitin C-terminal hydrolase-L3 by virtual screening. 1776 21

Based on a functional categorization, proteins may be grouped into three types and sorted to either the proteasome or the macroautophagy pathway for degradation. The two pathways are mechanistically connected but their capacity seems different. Macroautophagy can degrade all forms of misfolded proteins whereas proteasomal degradation is likely limited to soluble ones. Unlike the bulk protein degradation that occurs during starvation, autophagic degradation of misfolded proteins can have a degree of specificity, determined by ubiquitin modification and the interactions of p62/SQSTM1 and HDAC6. Macroautophagy is initiated in response to endoplasmic reticulum (ER) stress caused by misfolded proteins, via the ER-activated autophagy (ERAA) pathway, which activates a partial unfolded protein response involving PERK and/or IRE1, and a calcium-mediated signaling cascade. ERAA serves the function of mitigating ER stress and suppressing cell death, which may be explored for controlling protein conformational diseases. Conversely, inhibition of ERAA may be explored for sensitizing resistant tumor cells to cytotoxic agents.
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PMID:Sorting, recognition and activation of the misfolded protein degradation pathways through macroautophagy and the proteasome. 1798 70

A role for ubiquitin in the pathogenesis of human diseases was first suggested some two decades ago, from studies that localized the protein to intracellular protein aggregates, which are a feature of the major human neurodegenerative disorders. Although several different mechanisms have been proposed to connect impairment of the UPS (ubiquitin-proteasome system) to the presence of these 'ubiquitin inclusions' within diseased neurones, their significance in the disease process remains to be fully clarified. Ubiquitin inclusions also contain ubiquitin-binding proteins, such as the p62 protein [also known as SQSTM1 (sequestosome 1)], which non-covalently interacts with the ubiquitinated protein aggregates and may serve to mediate their autophagic clearance. p62 is a multifunctional protein and, in the context of bone-resorbing osteoclasts, is an important scaffold in the RANK [receptor activator of NF-kappaB (nuclear factor kappaB)]-NF-kappaB signalling pathway. Further, mutations affecting the UBA domain (ubiquitin-associated domain) of p62 are commonly found in patients with the skeletal disorder PDB (Paget's disease of bone). These mutations impair the ability of p62 to bind to ubiquitin and result in disordered osteoclast NF-kappaB signalling that may underlie the disease aetiology. Recent structural insights into the unusual mechanism of ubiquitin recognition by the p62 UBA domain have helped rationalize the mechanisms by which different PDB mutations exert their negative effects on ubiquitin binding by p62, as well as providing an indication of the ubiquitin-binding selectivity of p62 and, by extension, its normal biological functions.
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PMID:Disruption of ubiquitin-mediated processes in diseases of the brain and bone. 1848 83

Osteoclasts are responsible for bone resorption and play a pivotal role in the pathogenesis of osteolytic disorders. NF-kappaB is a set of nuclear factors that bind to consensus DNA sequences called kappaB sites, and is essential for osteoclast formation and survival. NF-kappaB signalling pathways are strictly regulated to maintain bone homeostasis by cytokines such as RANKL, TNF-alpha and IL-1, which differentially regulate classical and/or alternative NF-kappaB pathways in osteoclastic cells. These pathways are also modulated by NF-kappaB mediators, including TRAF6, aPKC, p62/SQSTM1 and deubiquitinating enzyme CYLD that are involved in the ubiquitin-proteasome system during RANK-mediated osteoclastogenesis. Abnormal activation of NF-kappaB signalling in osteoclasts has been associated with excessive osteoclastic activity, and frequently observed in osteolytic conditions, including periprosthetic osteolysis, arthritis, Paget's disease of bone, and periodontitis. NF-kappaB modulators such as parthenolide and NEMO-binding domain peptide demonstrate therapeutic effects on inflammation-induced bone destruction in mouse models. Unravelling the structure and function of NF-kappaB pathways in osteoclasts and other cell types will be important in developing new strategies for treatments of bone diseases.
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PMID:NF-kappaB modulators in osteolytic bone diseases. 1904 22


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