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)

Spinal and bulbar muscular atrophy (SBMA) and amyotrophic lateral sclerosis (ALS) are representative motor neuron diseases in which selective neuronal degeneration occurs. In this paper, some molecular aspects are discussed related to the pathogenesis of the neuronal degeneration. SBMA is a an X-linked neurodegenerative disease caused by the expansion of a CAG repeat in the first exon of the androgen receptor (AR) gene. To date, eight CAG repeat diseases have been identified, including spinal and bulbar muscular atrophy (SBMA), Huntington's disease (HD), dentatorubralpallidoluysian atrophy (DRPLA), and five spinocerebellar ataxias (SCAs 1, 2, 3, 6, 7). These disorders very likely share a common pathogenesis caused by the gain of a toxic function associated with the expanded polyglutamine tract. Several mechanisms have been postulated as a pathogenic process for neurodegeneration caused by the expanded polyglutamine tract. In SBMA, nuclear inclusions (NIs) containing mutant AR protein have been observed in regions of SBMA central nervous system susceptible to degenerations. Transcriptional factors or their cofactors, such as CREB or creb-binding protein (CBP) sequestrated in NIs, may alter the major intracellular transcriptional signal transduction and ultimately may result in neuronal degeneration. The components in the ubiquitin-proteasome pathway also colocalized in NIs and contribute to the path-ogenesis of SBMA. We generated two types of transgenic mice expressing 239Q under the control of human AR promoter and full-size AR containing 97Q. Marked neurological symptoms and extensive nuclear inclusions were observed in both transgenic lines, but there was no neuronal cell death, suggesting that major neurological phenotype was due to neuronal dysfunction instead of neuronal cell death. As for the therapeutic strategies, the overexpression of Hsp70 and Hsp40 chaperones acted together to protect a cultured neuronal cell model of SBMA from inclusion formation and cell death by mutant AR with expanded polyglutamine tract. In regard to ALS, we are screening the gene expression profiles of the motor neurons from the human ALS and SOD transgenic mouse spinal cord. Motor neurons were microdissected from the spinal cord samples by a lazer-captured microdissection system. Gene expression profiles were screened by cDNA microarray and molecular indexing. Several new molecules were cloned and characterized for their function and relation to neuronal cell dysfunction. Some molecules characterized in this procedure were briefly described.
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PMID:[Molecular pathogenesis of motor neuron diseases]. 1140 Mar 22

Spinal and bulbar muscular atrophy (SBMA) is an X-linked neurodegenerative disease caused by the expansion of a CAG repeat in the first exon of the androgen receptor (AR) gene. To date, eight CAG-repeat diseases have been identified, including spinal and bulbar muscular atrophy (SBMA). Huntington's disease (HD), dentatorubralpallidoluysian atrophy (DRPLA) and five spinocerebellar ataxias (SCAs 1, 2, 3, 6, 7). These disorders likely share a common pathogenesis caused by the gain of a toxic function associated with the expanded polyglutamine tract. Several mechanisms have been postulated as a pathogenic process for neurodegeneration caused by the expanded polyglutamine tract. Processing of the polyglutamine containing proteins by proteases liberate truncated polyglutamine tract, which may cause neurodegeneration as demonstrated in transgenic mice and transfected cells. In addition to cellular toxicity, truncated and expanded polyglutamine tracts have been shown to form intranuclear inclusions (NI). The NIs formed by the disease protein are a common pathological feature of these diseases. In SBMA, NIs containing AR protein have been observed in regions of SBMA central nervous system susceptible to degenerations. Transcriptional factors or their cofactors, such as cerb or creb-binding protein (CBP) sequestrated in the NI may alter the major intracellular transcriptional signal transduction, and ultimately may result in neuronal degeneration. The ubiquitin-proteasome pathway may also contribute to the pathogenesis of CAG-repeat diseases. As for the therapeutic strategies, many possibilities have been demonstrated. Overexpression of Hsp70 and Hsp40 chaperones act together to protect a cultured neuronal cell model of SBMA from a cellular toxicity of expanded polyglutamine tract.
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PMID:[Triplet repeat disease, with particular emphasis of spinal and bulbar muscular atrophy (SBMA)]. 1146 55

Polyglutamine diseases are inherited neurodegenerative diseases caused by the expansion of polyglutamine tract in the disease causing gene products. Studies of polyglutamine disease patients and transgenic mice have revealed that nuclear inclusions formed by the disease protein are a common pathological feature of these diseases. The finding that nuclear inclusions are ubiquitinated raises the possibility that alterations in the major intracellular system for degrading proteins, the ubiquitin-proteasome pathway, may be involved in the pathogenesis of polyglutamine diseases. Perturbations in proteasome function are associated with altered expression levels of stress-response or heat shock proteins. Heat shock proteins function as molecular chaperones, which recognize and renaturate misfolded protein (aggregate). In this article, we review the role of chaperones in the development of polyglutamine diseases. Overexpression of chaperones reduces aggregate formation and suppresses apoptosis in several polyglutamine disease models including spinal and bulbar muscular atrophy. These facts indicate that chaperones may be one of the key factors in the development of polyglutamine disease, and suggest that increasing expression level or enhancing the function of chaperones will provide an avenue for the treatment of polyglutamine disease.
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PMID:Protective effect of chaperones on polyglutamine diseases. 1171 46

Spinal and bulbar muscular atrophy (SBMA) is a heritable neurodegenerative disease caused by the expansion of a polyglutamine [poly(Q)] repeat within the androgen receptor (AR) protein. We studied SBMA in Drosophila using an N-terminal fragment of the human AR protein. Expression of a pathogenic AR protein with an expanded poly(Q) repeat in Drosophila results in nuclear and cytoplasmic inclusion formation, and cellular degeneration, preferentially in neuronal tissues. We have studied the influence of ubiquitin-dependent modification and the proteasome pathway on neural degeneration and AR protein fragment solubility. Compromising the ubiquitin/proteasome pathway enhances degeneration and decreases poly(Q) protein solubility. Our data further suggest that Hsp70 and the proteasome act in an additive manner to modulate neurodegeneration. Through the over-expression of a mutant of the SUMO-1 activating enzyme Uba2, we further show that poly(Q)-induced degeneration is intensified when the cellular SUMO-1 protein conjugation pathway is altered. These data suggest that post-translational protein modification, including the ubiquitin/proteasome and the SUMO-1 pathways, modulate poly(Q) pathogenesis.
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PMID:Genetic modulation of polyglutamine toxicity by protein conjugation pathways in Drosophila. 1239 1

It has been more than 10 years since the discovery that the expansion of a simple CAG trinucleotide repeat within the coding region of the androgen receptor gene leads to the motor neuronopathy spinal and bulbar muscular atrophy (SBMA). A flurry of investigation into this and the other, more recently discovered, polyglutamine diseases has led to an understanding of many aspects of the molecular pathogenesis of this family of diseases. A characteristics pathological feature of the polyglutamine diseases is the occurrence in affected neurons of ubiquitinated aggregates; such aggregates also contain, among others, proteins involved in the folding and degradation of the mutant proteins. Aggregates themselves are likely not directly cytotoxic, but rather mark the accumulation of all or part of the mutant protein. Furthermore, aggregation occurs because of the inefficient clearance of the mutant protein by the ubiquitin-proteasome pathway for protein degradation. These findings are common to the polyglutamine diseases and reflect the general problem of folding/degrading expanded polyglutamines. In SBMA, the altered metabolism of the androgen receptor is ligand dependent. How the accumulation of the mutant protein causes neuronal dysfunction and disease is not well understood, but several cellular processes have been implicated. Although these findings provide insight into the toxic function of the expanded polyglutamine protein, additional investigations have led to the finding that intrinsic AR transactivational function is somewhat diminished in the presence of the expanded polyglutamine; this likely leads to the partial androgen insensitivity that characterizes patients with SBMA. The recent development of useful animal and cell models of SBMA will lead to increased understanding of disease pathogenesis, as well as to the development of new and better therapeutic strategies.
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PMID:Trinucleotide repeat disease. The androgen receptor in spinal and bulbar muscular atrophy. 1248 45

Spinal and bulbar muscular atrophy (SBMA) is an inherited motor neuron disease caused by the expansion of the polyglutamine (polyQ) tract within the androgen receptor (AR). The nuclear inclusions consisting of the mutant AR protein are characteristic and combine with many components of ubiquitin-proteasome and molecular chaperone pathways, raising the possibility that misfolding and altered degradation of mutant AR may be involved in the pathogenesis. We have reported that the overexpression of heat shock protein (HSP) chaperones reduces mutant AR aggregation and cell death in a neuronal cell model (Kobayashi et al., 2000). To determine whether increasing the expression level of chaperone improves the phenotype in a mouse model, we cross-bred SBMA transgenic mice with mice overexpressing the inducible form of human HSP70. We demonstrated that high expression of HSP70 markedly ameliorated the motor function of the SBMA model mice. In double-transgenic mice, the nuclear-localized mutant AR protein, particularly that of the large complex form, was significantly reduced. Monomeric mutant AR was also reduced in amount by HSP70 overexpression, suggesting the enhanced degradation of mutant AR. These findings suggest that HSP70 overexpression ameliorates SBMA phenotypes in mice by reducing nuclear-localized mutant AR, probably caused by enhanced mutant AR degradation. Our study may provide the basis for the development of an HSP70-related therapy for SBMA and other polyQ diseases.
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PMID:Heat shock protein 70 chaperone overexpression ameliorates phenotypes of the spinal and bulbar muscular atrophy transgenic mouse model by reducing nuclear-localized mutant androgen receptor protein. 1265 79

Spinobulbar muscular atrophy (SBMA, Kennedy's disease) results from the dysfunction and degeneration of specific motor and sensory neurons. The underlying cause of this ligand-dependent neurodegenerative disease is expansion of the CAG trinucleotide repeat in the androgen receptor (AR) gene which leads to lengthening of the polyglutamine tract in the AR protein. Recently, the effects of the polyglutamine-expanded AR have been explored in a number of cellular and animal models. Common themes include research on polyglutamine-containing nuclear inclusions and the effect of molecular chaperone overexpression on their formation. In addition, investigations have highlighted the role that abnormal transcriptional regulation, proteasome dysfunction and altered axonal transport may play in disease pathogenesis. These studies suggest a number of potential treatments for restoring neuronal function. One of the most interesting advances in SBMA research has been the creation of mouse models that recapitulate the key features of SBMA progression in men. Lowering testosterone levels in affected transgenic male mice rescued, and even reversed the polyglutamine-induced neuromuscular phenotype, indicating that manipulating androgen levels in men could be of therapeutic benefit. Although the question of why only a distinct subset of neurons is affected by polyglutamine expansion of the AR remains unsolved, future research will provide further insights into the mechanisms contributing to disease progression in SBMA.
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PMID:Progress in Spinobulbar muscular atrophy research: insights into neuronal dysfunction caused by the polyglutamine-expanded androgen receptor. 1589 56

Prostate cancer is the second leading cause of death in men in western countries and is usually treated by surgery and/or radiotherapy. More recently, hyperthermia has been introduced into clinical trials investigating a possible effect in the first-line treatment of prostate cancer. However, the molecular mechanisms of hyperthermia are not completely understood. In this study, we investigated the effects of hyperthermia on proteasome function and its significance for signal transduction, cell death and androgen receptor (AR) expression in PC-3, LnCaP, and DU-145 human and TRAMP-C2 murine prostate cancer cells. Hyperthermia caused apoptosis and radiosensitization and decreased 26S proteasome activity in all three human cell lines to about 40% of untreated control cells. 20S proteasome activity was not affected by heat. Heat treatment inhibited constitutive and radiation-induced activation of nuclear factor kappaB caused by stabilization of IkappaB. Although stabilization of AR by proteasome inhibitors has been reported previously, AR protein levels in LnCaP cells decreased dramatically after heat. Our data suggest that inhibition of proteasome function and dependent signal transduction pathways might be a major molecular mechanisms of heat-induced apoptosis and radiosensitization. Hyperthermia abrogates AR expression in androgen-dependent cells and might thus promote malignant progression of prostate cancer.
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PMID:Hyperthermia-induced proteasome inhibition and loss of androgen receptor expression in human prostate cancer cells. 1593 Mar 4

The effect of exercise on beta-adrenergic receptor (beta-AR) trafficking was investigated in rat adipocytes. The binding sites of a hydrophilic ligand, [(3)H]CGP12177, increased immediately (0 h) and at 3 h after exercise (3 h) but decreased at 24 h after exercise (24 h). The data of immunoblotting revealed that the alterations in the binding sites mainly paralleled the alterations in the beta2-AR proteins in membrane fractions. The protein expressions of both G-protein-coupled receptor kinase (GRK)-2 and beta-arrestin-2 were reduced, with a decline in beta2-AR ubiquitination at 0 h and 3 h. The protein expressions of beta2-AR, GRK-2, beta-arrestin-2, the beta2-AR/beta-arrestin-2 complex, and beta2-AR ubiquitination returned to their respective control levels at 24 h, whereas the beta2-AR mRNA level was reduced. Administration of either lactacystin or propranolol did not alter GRK-2 and beta2-AR protein expressions after exercise. Thus, the mechanism underlying the increased density of beta2-AR up to at least 3 h may involve alterations in a multistep event involving the coordinate interaction among proteins mediating beta2-AR trafficking, in which both the receptor-agonist interactions and ubiquitin-proteasome pathway have a key role. However, the decreased protein expression of beta2-AR at 24 h might be due to some change occurring at the translational levels.
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PMID:Beta-adrenergic receptor trafficking by exercise in rat adipocytes: roles of G-protein-coupled receptor kinase-2, beta-arrestin-2, and the ubiquitin-proteasome pathway. 1636 19

Interest in the use of traditional medicines for cancer prevention and treatment is increasing. In vitro, in vivo, and clinical studies suggest the potential use of proteasome inhibitors as novel anticancer drugs. Celastrol, an active compound extracted from the root bark of the Chinese medicine "Thunder of God Vine" (Tripterygium wilfordii Hook F.), was used for years as a natural remedy for inflammatory conditions. Although Celastrol has been shown to induce leukemia cell apoptosis, the molecular target involved has not been identified. Furthermore, whether Celastrol has antitumor activity in vivo has never been conclusively shown. Here, we report, for the first time, that Celastrol potently and preferentially inhibits the chymotrypsin-like activity of a purified 20S proteasome (IC(50) = 2.5 micromol/L) and human prostate cancer cellular 26S proteasome (at 1-5 micromol/L). Inhibition of the proteasome activity by Celastrol in PC-3 (androgen receptor- or AR-negative) or LNCaP (AR-positive) cells results in the accumulation of ubiquitinated proteins and three natural proteasome substrates (IkappaB-alpha, Bax, and p27), accompanied by suppression of AR protein expression (in LNCaP cells) and induction of apoptosis. Treatment of PC-3 tumor-bearing nude mice with Celastrol (1-3 mg/kg/d, i.p., 1-31 days) resulted in significant inhibition (65-93%) of the tumor growth. Multiple assays using the animal tumor tissue samples from both early and end time points showed in vivo inhibition of the proteasomal activity and induction of apoptosis after Celastrol treatment. Our results show that Celastrol is a natural proteasome inhibitor that has a great potential for cancer prevention and treatment.
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PMID:Celastrol, a triterpene extracted from the Chinese "Thunder of God Vine," is a potent proteasome inhibitor and suppresses human prostate cancer growth in nude mice. 1665 29


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