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)

The beta-amyloid precursor protein undergoes a physiological cleavage by alpha-secretase that leads to the release of a secreted C-terminally truncated fragment called APP alpha and likely concomitantly reduces the formation of the amyloidogenic A beta peptide. Here we demonstrate that APP alpha secretion is increased by the protein kinase A (PKA) effectors 8-bromo cyclic AMP and forskolin in human embryonic kidney cells (HK293), and that this can be prevented by a proteasome inhibitor. Furthermore, we establish that PKA effectors but not protein kinase C agonists increase the chymotrypsin-like activity and phosphorylation state of the proteasome in vitro and in vivo in HK293 cells. Altogether, this report demonstrates that the alpha-secretase pathway is under the control of PKA in human cells and that the proteasome likely contributes, either directly or through yet unknown intermediates, to the PKA-stimulated APP alpha secretion in human cells.
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PMID:Protein kinase A phosphorylation of the proteasome: a contribution to the alpha-secretase pathway in human cells. 893 98

A major histopathological hallmark in Alzheimer's disease consists of the extracellular deposition of the amyloid beta-peptide (A beta) that is proteolytically derived from the beta-amyloid precursor protein (beta APP). An alternative, nonamyloidogenic cleavage, elicited by a protease called alpha-secretase, occurs inside the A beta sequence and gives rise to APP alpha, a major secreted C-terminal-truncated form of beta APP. Here, we demonstrate that human embryonic kidney 293 (HK293) cells contain a chymotryptic-like activity that can be ascribed to the proteasome and that selective inhibitors of this enzyme reduce the phorbol 12,13-dibutyrate-sensitive APP alpha secretion by these cells. Furthermore, we establish that a specific proteasome blocker, lactacystin, also induces increased secretion of A beta peptide in stably transfected HK293 cells overexpressing wild-type beta APP751. Altogether, this study represents the first identification of a proteolytic activity, namely, the proteasome, contributing likely through yet unknown intracellular relays, to the alpha-secretase pathway in human cells.
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PMID:Proteasome contributes to the alpha-secretase pathway of amyloid precursor protein in human cells. 900 58

The physiological processing of the beta-amyloid precursor protein (betaAPP) by a protease called alpha-secretase gives rise to APP alpha, a C-terminally truncated fragment of betaAPP with known neurotrophic and cytoprotective properties. Several lines of evidence indicate that protein kinase C (PKC)-mediated events regulate this physiological pathway. We show here that the proteasome multicatalytic complex modulates the phorbol 12,13-dibutyrate-stimulated APP alpha secretion at several levels in human kidney 293 (HK293) cells. Two blocking agents of the proteasome, namely, Z-IE(Ot-Bu)A-leucinal and lactacystin, elicit a dual effect on PKC-regulated APP alpha secretion by metabolically labeled HK293 cells. Thus, short periods of preincubation (2-5 h) of the cells with the inhibitors trigger a drastic potentiation of APP alpha recovery, whereas long-term treatment of the cells (15-20 h) with the blocking agents leads to an overall decrease in the secretion of APP alpha. Such a dual effect was not observed on constitutive APP alpha secretion and intracellular formation generated by HK293 cells, which both only increase upon inhibitor treatments. Similar effects on the constitutive and PKC-regulated APP alpha secretion were observed with PC12 cells. Altogether, these data suggest distinct mechanisms underlying basal and PKC-regulated APP alpha production, indicating that this multicatalytic complex appears as a key contributor of the alpha-secretase pathway.
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PMID:Constitutive and protein kinase C-regulated secretory cleavage of Alzheimer's beta-amyloid precursor protein: different control of early and late events by the proteasome. 937 83

The deposition of amyloid-beta peptides (Abeta) in senile plaques (SPs) is a central pathological feature of Alzheimer's disease (AD). Since SPs are composed predominantly of Abeta1-42, which is more amyloidogenic in vitro, the enzymes involved in generating Abeta1-42 may be particularly important to the pathogenesis of AD. In contrast to Abeta1-40, which is generated in the trans-Golgi network and other cytoplasmic organelles, intracellular Abeta1-42 is produced in the endoplasmic reticulum/intermediate compartment (ER/IC), where it accumulates in a stable insoluble pool. Since this pool of insoluble Abeta1-42 may play a critical role in AD amyloidogenesis, we sought to determine how the production of intracellular Abeta is regulated. Surprisingly, the production of insoluble intracellular Abeta1-42 was increased by a putative gamma-secretase inhibitor as well as by an inhibitor of the proteasome. We further demonstrate that this increased generation of Abeta1-42 in the ER/IC is due to a reduction in the turnover of Abeta-containing APP C-terminal fragments. We conclude that the proteasome is a novel site for degradation of ER/IC-generated APP fragments. Proteasome inhibitors may augment the availability of APP C-terminal fragments for gamma-secretase cleavage and thereby increase production of Abeta1-42 in the ER/IC. Based on the organelle-specific differences in the generation of Abeta by gamma-secretase, we conclude that intracellular ER/IC-generated Abeta1-42 and secreted Abeta1-40 are produced by different gamma-secretases. Further, the fact that a putative gamma-secretase inhibitor had opposite effects on the production of secreted and intracellular Abeta may have important implications for AD drug design.
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PMID:A distinct ER/IC gamma-secretase competes with the proteasome for cleavage of APP. 1065 47

Processing of integral membrane proteins in order to liberate active proteins is of exquisite cellular importance. Examples are the processing events that govern sterol regulation, Notch signaling, the unfolded protein response, and APP fragmentation linked to Alzheimer's disease. In these cases, the proteins are thought to be processed by regulated intramembrane proteolysis, involving site-specific, membrane-localized proteases. Here we show that two homologous yeast transcription factors SPT23 and MGA2 are made as dormant ER/nuclear membrane-localized precursors and become activated by a completely different mechanism that involves ubiquitin/proteasome-dependent processing. SPT23 and MGA2 are relatives of mammalian NF-kappaB and control unsaturated fatty acid levels. Intriguingly, proteasome-dependent processing of SPT23 is regulated by fatty acid pools, suggesting that the precursor itself or interacting partners are sensors of membrane composition or fluidity.
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PMID:Activation of a membrane-bound transcription factor by regulated ubiquitin/proteasome-dependent processing. 1100 76

The accumulation of altered proteins is a common pathogenic mechanism in several neurodegenerative disorders. A causal role of protein aggregation was originally proposed in Alzheimer's disease (AD) where extracellular deposition of beta-amyloid (Abeta) is the main neuropathological feature. It is now believed that intracellular deposition of aggregated proteins may be relevant in Parkinson's disease (PD), amyotrophic lateral sclerosis and polyglutamine disorders. An impairment of ubiquitin-proteasome system (UPS) appears directly involved in these disorders. We reviewed the results on the role of protein misfolding in AD and PD and the influence of mutations associated with these diseases on the expression of amyloidogenic proteins. Results of genetic screening of familial cases of AD and PD are summarized. In the familial AD population (70 subjects) we found several mutations of the presenilin 1 (PS1) gene with a frequency of 12.8% and one mutation in the gene encoding the protein precursor of amyloid (APP) (1.4%). One mutation of Parkin in the homozygous form and two in the heterozygous form were identified in our PD population. We also reported data obtained with synthetic peptides and other experimental models, for evaluation of the pathogenic role of mutations in terms of protein misfolding.
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PMID:Protein misfolding in Alzheimer's and Parkinson's disease: genetics and molecular mechanisms. 1239 98

gamma-Secretase activity is involved in the generation of Abeta and therefore likely contributes to the pathology of Alzheimer's disease. Blocking this activity was seen as a major therapeutic target to slow down or arrest Abeta-related AD progression. This strategy seemed more doubtful when it was established that gamma-secretase also targets other substrates including Notch, a particularly important transmembrane protein involved in vital functions, at both embryonic and adulthood stages. We have described previously new non-peptidic inhibitors able to selectively inhibit Abeta cellular production in vitro without altering Notch pathway. We show here that in vivo, these inhibitors do not alter the Notch pathway responsible for somitogenesis in the zebrafish embryo. In addition, we document further the selectivity of JLK inhibitors by showing that, unlike other described gamma-secretase inhibitors, these agents do not affect E-cadherin processing. Finally, we establish that JLKs do not inhibit beta-site APP cleaving enzymes (BACE) 1 and BACE2, alpha-secretase, the proteasome, and GSK3beta kinase. Altogether, JLK inhibitors are the sole agents to date that are able to prevent Abeta production without triggering unwanted cleavages of other proteins.
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PMID:JLK isocoumarin inhibitors: selective gamma-secretase inhibitors that do not interfere with notch pathway in vitro or in vivo. 1459 13

We previously showed that specific strains of human immunodeficiency virus (HIV)-1 infect the brain and contribute to Neuropathology, Cognitive Distress, and Neuropsychiatric Disease. To study further brain disease that results from HIV-1 infection, we commenced analysis of changes in gene expression in brain. We analyzed RNA purified from Frontal Cortex of 5 HIV-1 infected and 4 HIV-1 negative control subjects RNA was amplified and Affymetrix technology was used to analyze gene expression using the 12,585 gene Affymetrix Human Genome U95A chip. The expressed genes showed highly significant Pearsons correlations with each other within the two groups. Expression intensities were transferred to Microsoft Excel and Spotfire was used to analyze the results. Twenty-group K-means cluster analysis was done for HIV+ and HIV- subjects. Genes that were expressed in the same cluster numbers in the two groups were removed from further analysis. Analysis of Gene expression in the top 13 HIV+ clusters showed expression in the 40 gene categories designated in our prior studies. Genes from several categories occurred in more than one K-means cluster. Genes identified in these lists included several genes that have been previously studied: MBP, Myelin-PLP, NMDA receptor, MAG, astrocytic protein, Notch 3, APP, Senescence, proteasome, Ferritin, signaling, cell cycle, iNOS, Chemokine, splicing, synapse, protein tags, and ribosomal proteins. The first (primary significant) axis of both Principal Component Analyses ordered the genes in the same patient groups as the K-means cluster analysis for the respective patient groups. PCA was thus not more informative than K-Means cluster analysis. Ratios of HIV+ to HIV- intensities were calculated for all the averaged gene expression intensities. The ratio range was 0.14 to 9.26. The genes at the extremes (ad extrema) did not correspond to the gene order by K-means clustering (or PCA). The genes in the top 13 K-means clusters showed low-level changes by expression ratio. Genes ad extrema by ratio were in clusters with very large memberships. Mann-Whitney analysis confirmed expression ratio results. Several inferences result from our preliminary study. First, study design will be different in future studies involving additional replicates. Second, ratios inform us of the extent of changes in gene expression quantitatively. Third, Cluster methodology provides us with more subtle information, how bunches (clusters) of genes behave in terms of their centroids (attractors). Fourth, genes that change extensively by ratio tend to be in the larger k-Means clusters. We conclude that ranking gene expression with the use of expression ratio or by K-means clustering, yield different representations of the data.
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PMID:Analytic approaches to differential gene expression in AIDS versus control brains. 1535 27

Abeta (beta-amyloid) peptides are found aggregated in the cortical amyloid plaques associated with Alzheimer's disease neuropathology. Inhibition of the proteasome alters the amount of Abeta produced from APP (amyloid precursor protein) by various cell lines in vitro. Proteasome activity is altered during aging, a major risk factor for Alzheimer's disease. In the present study, a human neuroblastoma cell line expressing the C-terminal 100 residues of APP (SH-SY5Y-SPA4CT) was used to determine the effect of proteasome inhibition, by lactacystin and Bz-LLL-COCHO (benzoyl-Leu-Leu-Leu-glyoxal), on APP processing at the gamma-secretase site. Proteasome inhibition caused a significant increase in Abeta peptide levels in medium conditioned by SH-SY5Y-SPA4CT cells, and was also associated with increased cell death. APP is a substrate of the apoptosis-associated caspase 3 protease, and we therefore investigated whether the increased Abeta levels could reflect caspase activation. We report that caspase activation was not required for proteasome-inhibitor-mediated effects on APP (SPA4CT) processing. Cleavage of Ac-DEVD-AMC (N-acetyl-Asp-Glu-Val-Asp-7-amino-4-methylcoumarin), a caspase substrate, was reduced following exposure of SH-SY5Y-SPA4CT cells to lactacystin, and co-treatment of cells with lactacystin and a caspase inhibitor [Z-DEVD-FMK (benzyloxycarbonyl-Val-Ala-DL-Asp-fluoromethylketone)] resulted in higher Abeta levels in medium, augmenting those seen with lactacystin alone. This study indicated that proteasome inhibition could increase APP processing specifically at the gamma-secretase site, and increase release of Abeta, in the absence of caspase activation. This indicates that the decline in proteasome function associated with aging would contribute to increased Abeta levels.
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PMID:Proteasome-mediated effects on amyloid precursor protein processing at the gamma-secretase site. 1547 68

Alzheimer's disease is a genetically complex disorder associated with multiple genetic defects, either mutational or of susceptibility. Although potentially associated with an accelerated stochastically driven aging process, Alzheimer's disease is an independent clinical entity in which the aging process exerts a deleterious effect on brain activity in conjunction with polymodal genetic factors and other pathological conditions (i.e., age-related cerebrovascular deterioration) and environmental factors (i.e., nutrition). Alzheimer's disease genetics does not explain in full the etiopathogenesis of this disease. Therefore, it is likely that environmental factors and/or epigenetic phenomena also contribute to Alzheimer's disease pathology and phenotypic expression of dementia. The genomics of Alzheimer's disease is still in its infancy, but this field is aiding the understanding of novel aspects of this disease, including genetic epidemiology, multifactorial risk factors, pathogenic mechanisms associated with genetic networks and genetically regulated metabolic cascades. Alzheimer's disease genomics is also helping to develop new strategies in pharmacogenomic research and prevention. Functional genomics, proteomics, pharmacogenomics, high-throughput methods, combinatorial chemistry and modern bioinformatics will greatly contribute to accelerate drug development for Alzheimer's disease and other complex disorders. The multifactorial genetic dysfunction in dementia includes mutational loci (APP, PS1, PS2, TAU) and diverse susceptibility loci (APOE, alpha2M, alphaACT, LRP1, IL1 alpha, TNF, ACE, BACE, BCHE, CST3, MTHFR, GSK3 beta, NOS3 and many other genes) distributed across the human genome, probably converging in a common pathogenic mechanism that leads to premature neuronal death, in which mitochondrial DNA mutations may contribute to increased genetic variability and heterogeneity. In Alzheimer's disease, multiple pathogenic events, including genetic factors, accumulation of aberrant or misfolded proteins, protofibril formation, ubiquitin-proteasome system dysfunction, excitotoxic reactions, oxidative and nitrosative stress, mitochondrial injury, synaptic failure, altered metal homeostasis, dysfunction of axonal and dendritic transport, and chaperone misoperation may converge in pathogenic pathways leading to premature death and neurodegeneration. Some of these mechanisms are common to several neurodegenerative disorders, which differ depending upon the gene(s) affected and the involvement of specific genetic networks, together with epigenetic factors and environmental events. Many genes potentially associated with Alzheimer's disease in some studies cannot be confirmed as candidate genes in replication studies, indicating that methodological problems and genomic complexity are leading to erroneous conclusions. A different approach to Alzheimer's disease functional genomics is to integrate individual genetic information in polygenic genotypes (haplotype-like model) and to investigate genotype-phenotype correlations and genotype-related pharmacogenomic behaviors. The application of functional genomics to Alzheimer's disease can be a suitable strategy for molecular diagnosis and for understanding pathophysiological mechanisms associated with Alzheimer's disease-related neurodegeneration. Furthermore, the pharmacogenomics of Alzheimer's disease may contribute in the future to optimize drug development and therapeutics, increasing efficacy and safety, and reducing side-effects and unnecessary costs.
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PMID:Molecular genetics of Alzheimer's disease and aging. 1647 Feb 48


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