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)

Previous studies using post-mortem human brain extracts demonstrated that PrP in Creutzfeldt-Jakob disease (CJD) brains is cleaved by a cellular protease to generate a C-terminal fragment, referred to as C2, which has the same molecular weight as PrP-(27-30), the protease-resistant core of PrP(Sc) (1). The role of this endoproteolytic cleavage of PrP in prion pathogenesis and the identity of the cellular protease responsible for production of the C2 cleavage product has not been explored. To address these issues we have taken a combination of pharmacological and genetic approaches using persistently infected scrapie mouse brain (SMB) cells. We confirm that production of C2 is the predominant cleavage event of PrP(Sc) in the brains of scrapie-infected mice and that SMB cells faithfully recapitulate the diverse intracellular proteolytic processing events of PrP(Sc) and PrP(C) observed in vivo. While increases in intracellular calcium (Ca(2+)) levels in prion-infected cell cultures stimulate the production of the PrP(Sc) cleavage product, pharmacological inhibitors of calpains and overexpression of the endogenous calpain inhibitor, calpastatin, prevent the production of C2. In contrast, inhibitors of lysosomal proteases, caspases, and the proteasome have no effect on C2 production in SMB cells. Calpain inhibition also prevents the accumulation of PrP(Sc) in SMB and persistently infected ScN2A cells, whereas bioassay of inhibitor-treated cell cultures demonstrates that calpain inhibition results in reduced prion titers compared with control-treated cultures assessed in parallel. Our observations suggest that calpain-mediated endoproteolytic cleavage of PrP(Sc) may be an important event in prion propagation.
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PMID:Calpain-dependent endoproteolytic cleavage of PrPSc modulates scrapie prion propagation. 1502 10

Because of recent studies showing linkage of type 2 diabetes with the calpain 10 gene, we investigated the ability of calpains to regulate GLUT4 expression in 3T3-L1 adipocytes. Treatment of 3T3-L1 adipocytes with the calpain inhibitor ALLN significantly decreased the mRNA and protein expression of GLUT4. GLUT4 expression was not affected by treatment with the more selective calpain inhibitors PD150606, calpeptin, or a calpastatin peptide. In contrast, treatment with the proteasome inhibitors lactacystin or MG132 repressed GLUT4 mRNA level to 35% (10 microM lactacystin) and 12% (10 microM MG132) of control levels. Therefore, the expression of GLUT4 in 3T3-L1 adipocytes was repressed by proteasome inhibition, but not by inhibition of calpains; the effect of ALLN was due to its ability to inhibit proteasome function, rather than its action to inhibit calpains. Concomitant with the repression of GLUT4 mRNA levels, proteasome inhibition decreased GLUT4 protein levels in 3T3-L1 adipocytes. The decrease in GLUT4 expression occurred at the transcriptional level, as treatment with proteasome inhibitors decreased GLUT4 transcription measured by a nuclear run-on assay. Thus, these data demonstrate a new pathway for the regulation of GLUT4 expression that involves proteasomal degradation of factors that regulate GLUT4 expression.
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PMID:GLUT4 expression in 3T3-L1 adipocytes is repressed by proteasome inhibition, but not by inhibition of calpains. 1573 67

Beta-catenin is a multifunctional protein serving both as a structural element in cell adhesion and as a signaling component in the Wnt pathway, regulating embryogenesis and tumorigenesis. The signaling fraction of beta-catenin is tightly controlled by the adenomatous polyposis coli-axin-glycogen synthase kinase 3beta complex, which targets it for proteasomal degradation. It has been recently shown that Ca(2+) release from internal stores results in nuclear export and calpain-mediated degradation of beta-catenin in the cytoplasm. Here we have highlighted the critical relevance of constitutive calpain pathway in the control of beta-catenin levels and functions, showing that small interference RNA knock down of endogenous calpain per se (i.e. in the absence of external stimuli) induces an increase in the free transcriptional competent pool of endogenous beta-catenin. We further characterized the role of the known calpain inhibitors, Gas2 and Calpastatin, demonstrating that they can also control levels, function, and localization of beta-catenin through endogenous calpain regulation. Finally we present Gas2 dominant negative (Gas2DN) as a new tool for regulating calpain activity, providing evidence that it counteracts the described effects of both Gas2 and Calpastatin on beta-catenin and that it works via calpain independently of the classical glycogen synthase kinase 3beta and proteasome pathway. Moreover, we provide in vitro biochemical evidence showing that Gas2DN can increase the activity of calpain and that in vivo it can induce degradation of stabilized/mutated beta-catenin. In fact, in a context where the classical proteasome pathway is impaired, as in colon cancer cells, Gas2DN biological effects accounted for a significant reduction in proliferation and anchorage-independent growth of colon cancer.
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PMID:The calpain system is involved in the constitutive regulation of beta-catenin signaling functions. 1581 86

Epidemiological studies have indicated that malnutrition during early life may programme chronic degenerative disease in adulthood. In an animal model of fetal malnutrition, rats received an isoenergetic, low-protein (LP) diet during gestation. This reduced fetal beta-cell proliferation and insulin secretion. Supplementation during gestation with taurine prevented these alterations. Since proteases are involved in secretion and proliferation, we investigated which proteases were associated with these alterations and their restoration in fetal LP islets. Insulin secretion and proliferation of fetal control and LP islets exposed to different protease modulators were measured. Lactacystin and calpain inhibitor I, but not isovaleryl-L-carnitine, raised insulin secretion in control islets, indicating that proteasome and cysteinyl cathepsin(s), but not mu-calpain, are involved in fetal insulin secretion. Insulin secretion from LP islets responded normally to lactacystin but was insensitive to calpain inhibitor I, indicating a loss of cysteinyl cathepsin activity. Taurine supplementation prevented this by restoring the response to calpain inhibitor I. Control islet cell proliferation was reduced by calpain inhibitor I and raised by isovaleryl-L-carnitine, indicating an involvement of calpain. Calpain activity appeared to be lost in LP islets and not restored by taurine. Most modifications in the mRNA expression of cysteinyl cathepsins, calpains and calpastatin due to maternal protein restriction were consistent with reduced protease activity and were restored by taurine. Thus, maternal protein restriction affected cysteinyl cathepsins and the calpain-calpastatin system. Taurine normalised fetal LP insulin secretion by protecting cysteinyl cathepsin(s), but the restoration of LP islet cell proliferation by taurine did not implicate calpains.
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PMID:Nutritional regulation of proteases involved in fetal rat insulin secretion and islet cell proliferation. 1587 69

The function of p73, a transcription factor belonging to the p53 family, is finely regulated by its steady-state protein stability. p73 protein degradation/stabilization can be regulated by mechanisms in part dependent on the ubiquitin proteasome system (UPS): (i) Itch/NEDD4-like UPS degradation, (ii) NEDD8 UPS degradation, and (iii) NQO1 20S proteasome-dependent (but ubiquitin-independent) breakdown. Here, we show that, in vitro, Calpain I can cleave p73 at two distinct sites: the first proline-rich region and within the oligomerization domain. Consequently, different p73 isoforms can be degraded by calpains, i.e., both N-terminal isoforms (TAp73 and DeltaNp73) as well as the C-terminal isoforms (alpha, beta, gamma, delta). Moreover, overexpression of the specific endogenous calpain inhibitor, calpastatin, in cultured cells increased the steady-state p73 level. This suggests that calpains may play a physiological role in the regulation of p73 protein stability.
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PMID:Calpain cleavage regulates the protein stability of p73. 1597 58

The goal of this study was to assess if neurons exposed to amyloid-beta peptide (Abeta) exclusively in distal axons, undergo apoptosis. This is relevant to the loss of cholinergic neurons in Alzheimer's disease. Using a three-compartmented culture system for rat sympathetic neurons, we demonstrate that exposure of axons to Abeta1-42 activates an independent destruction program in axons, which leads to nuclear apoptosis. Abeta-induced axonal degeneration does not involve local caspase activation, but causes caspase activation in cell bodies. Accordingly, inhibition of caspase activation blocks Abeta-induced apoptosis but not axonal degeneration. In agreement with previous suggestions that disruption of nerve growth factor (NGF)-mediated signaling might contribute to the loss of cholinergic neurons, we found that provision of NGF to cell bodies protects sympathetic neurons from Abeta-induced apoptosis. However, our data indicate that Abeta-induced axonal degeneration follows a mechanism different than that activated by NGF withdrawal. Only Abeta-induced axonal degeneration is prevented by the calpain inhibitor calpastatin and is insensitive to the inhibitor of the ubiquitin-proteasome system MG132. Importantly, inhibition of Abeta-induced axonal degeneration by calpastatin prevents nuclear apoptosis.
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PMID:Apoptosis is secondary to non-apoptotic axonal degeneration in neurons exposed to Abeta in distal axons. 1612 41

Muscle wasting in sepsis is associated with increased expression of messenger RNA for several genes in the ubiquitin-proteasome proteolytic pathway, indicating that increased gene transcription is involved in the development of muscle atrophy. Here we review the influence of sepsis on the expression and activity of the transcription factors activator protein-1, nuclear factor-kappaB (NF-kappaB), and CCAAT/enhancer binding protein, as well as the nuclear cofactor p300. These transcription factors may be important for sepsis-induced muscle wasting because several of the genes in the ubiquitin-proteasome proteolytic pathway have multiple binding sites for activating protein-1, nuclear factor-kappaB, and CCAAT/enhancer binding protein in their promoter regions. In addition, the potential role of increased muscle calcium levels for sepsis-induced muscle atrophy is reviewed. Calcium may regulate several mechanisms and factors involved in muscle wasting, including the expression and activity of the calpain-calpastatin system, proteasome activity, CCAAT/enhancer binding protein transcription factors, apoptosis and glucocorticoid-mediated muscle protein breakdown. Because muscle wasting is commonly seen in patients with sepsis and has severe clinical consequences, a better understanding of mechanisms regulating sepsis-induced muscle wasting may help improve the care of patients with sepsis and other muscle-wasting conditions as well.
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PMID:Novel aspects on the regulation of muscle wasting in sepsis. 1612 15

Muscle wasting in sepsis is a significant clinical problem because it results in muscle weakness and fatigue that may delay ambulation and increase the risk for thromboembolic and pulmonary complications. Treatments aimed at preventing or reducing muscle wasting in sepsis, therefore, may have important clinical implications. Recent studies suggest that sepsis-induced muscle proteolysis may be initiated by calpain-dependent release of myofilaments from the sarcomere, followed by ubiquitination and degradation of the myofilaments by the 26S proteasome. In the present experiments, treatment of rats with one of the calpain inhibitors calpeptin or BN82270 inhibited protein breakdown in muscles from rats made septic by cecal ligation and puncture. The inhibition of protein breakdown was not accompanied by reduced expression of the ubiquitin ligases atrogin-1/MAFbx and MuRF1, suggesting that the ubiquitin-proteasome system is regulated independent of the calpain system in septic muscle. When incubated muscles were treated in vitro with calpain inhibitor, protein breakdown rates and calpain activity were reduced, consistent with a direct effect in skeletal muscle. Additional experiments suggested that the effects of BN82270 on muscle protein breakdown may, in part, reflect inhibited cathepsin L activity, in addition to inhibited calpain activity. When cultured myoblasts were transfected with a plasmid expressing the endogenous calpain inhibitor calpastatin, the increased protein breakdown rates in dexamethasone-treated myoblasts were reduced, supporting a role of calpain activity in atrophying muscle. The present results suggest that treatment with calpain inhibitors may prevent sepsis-induced muscle wasting.
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PMID:Treatment of rats with calpain inhibitors prevents sepsis-induced muscle proteolysis independent of atrogin-1/MAFbx and MuRF1 expression. 1645 66

beta2-Adrenergic agonists (BAAs) act as repartitioning agents in domestic animals by redistributing nutrients away from adipose tissue and towards muscle accretion. The mechanism involves altering the rates of protein degradation and synthesis. The aim of this study was to test the effects of chronic feeding of the BAAs clenbuterol (CLEN) and ractopamine (RACT) on rainbow trout (RBT) muscle. Specifically, we examined the activities and mRNA levels of genes in the major proteolytic pathways including calpains, the multi-catalytic proteasome and cathepsins, and the mRNA levels of genes encoding the myofibrillar proteins, fast-twitch and slow-twitch myosin heavy chains (f-MHC and s-MHC, respectively), and the cytoskeletal protein, beta-actin. RACT feeding significantly increased mRNA transcripts of the calpain catalytic subunit (Capn1), the regulatory subunit (cpns), and the calpastatin large isoform (CAST-L), without affecting the calpain enzyme activity. CLEN feeding significantly increased mRNA levels of the proteasome alpha subunit without a corresponding change in 20S enzyme activity. RACT significantly decreased cathepsin D activity without affecting mRNA levels suggesting that the action of RACT may be at the post-transcriptional level. In addition, both CLEN and RACT significantly increased mRNA transcripts of f-MHC and beta-actin genes suggesting an anabolic role of BAAs on myofibrillar and cytoskeletal proteins. Neither CLEN nor RACT altered mRNA expression of the s-MHC gene indicating no transformation of muscle fiber-types. This study supports a role for BAAs in inducing RBT muscle accretion by altering both protein synthesis and degradation.
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PMID:Anabolic effects of feeding beta2-adrenergic agonists on rainbow trout muscle proteases and proteins. 1658 Aug 55

Members of the C/EBP transcription factor family regulate cell differentiation and multiple other cellular functions. The cellular levels of C/EBPalpha, gamma, delta, epsilon, and Gadd153/CHOP are regulated in part by proteasome-dependent degradation. In contrast, mechanisms regulating the degradation of C/EBPbeta are poorly understood. We tested the hypothesis that the degradation of C/EBPbeta is calpain-dependent. Studies were performed in cultured L6 myotubes (a rat skeletal muscle cell line) because we have found previously that C/EBPbeta may be involved in the regulation of muscle proteolysis. Treatment of cultured L6 myotubes with the calpain inhibitors calpeptin and Calpain Inhibitor I and II resulted in increased C/EBPbeta concentrations but did not influence cellular levels of the other C/EBP transcription factor family members. Transfection of myoblasts with a plasmid expressing the endogenous calpain inhibitor calpastatin resulted in increased cellular levels of C/EBPbeta whereas the opposite result was observed in myoblasts overexpressing micro- or m-calpain. Co-immunoprecipitation provided evidence for protein-protein interaction between C/EBPbeta and micro- and m-calpain suggesting that C/EBPbeta may be a calpain substrate. This notion was supported by experiments in which immunoprecipitated C/EBPbeta was incubated with purified micro-calpain in a cell-free system. The increase in C/EBPbeta levels caused by inhibition of calpain activity was accompanied by increased C/EBPbeta DNA-binding and gene activation. The present results suggest that C/EBPbeta is degraded by a calpain-dependent mechanism in skeletal muscle cells and that the role of calpains is specific for C/EBPbeta among different members of the C/EBP transcription factor family.
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PMID:Degradation of C/EBPbeta in cultured myotubes is calpain-dependent. 1664 84


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