Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.25.1 (proteasome)
 28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Organisms produce reactive species throughout their lives, and this may result in damage to proteins and other biological molecules. Oxidatively damaged proteins are normally selectively degraded and replaced, but this process appears to be less efficient in senescent, long-lived, post-mitotic cells, as is evidenced by their accumulation in the form of lipofuscin inside the lysosomal compartment. A great deal of research has focused on changes to the proteolytic machinery in the ageing cell, in particular the proteasome, although failure of heat shock proteins (HSPs) to bind and deliver oxidised proteins efficiently to the degradation machinery could also contribute to their aggregation and accumulation. Oxidised proteins can be protease-resistant and may even directly inhibit the proteolytic machinery of the cell. The critical role that is played by HSPs in preventing accumulation of oxidised proteins is often overlooked. In this review, we examine the key role played by HSPs in recognising, removing and preventing the formation of oxidised and damaged proteins in cells. We also examine the evidence supporting the view that failure of one of these pathways could underlie ageing and age-related diseases. Finally, we discuss how modulation of HSP-activity could influence the ageing process and the progression of age-related diseases.
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PMID:Heat shock proteins: keys to healthy ageing? 1969 21

Previous studies have shown that inhibiting the activity of the proteasome leads to the accumulation of damaged or unfolded proteins within the cell. In this study, we report that proteasome inhibitors, lactacystin and carbobenzoxy-L-leucyl-L-leucyl-L-leucinal (MG132), induced the accumulation of ubiquitinated proteins as well as a dose- and time-dependent increase in the relative levels of heat shock protein (HSP)30 and HSP70 and their respective mRNAs in Xenopus laevis A6 kidney epithelial cells. In A6 cells recovering from MG132 exposure, HSP30 and HSP70 levels were still elevated after 24 h but decreased substantially after 48 h. The activation of heat shock factor 1 (HSF1) may be involved in MG132-induced hsp gene expression in A6 cells since KNK437, a HSF1 inhibitor, repressed the accumulation of HSP30 and HSP70. Exposing A6 cells to simultaneous MG132 and mild heat shock enhanced the accumulation of HSP30 and HSP70 to a much greater extent than with each stressor alone. Immunocytochemical studies determined that HSP30 was localized primarily in the cytoplasm of lactacystin- or MG132-treated cells. In some cells treated with higher concentrations of MG132 or lactacystin, we observed in the cortical cytoplasm (1) relatively large HSP30 staining structures, (2) colocalization of actin and HSP30, and (3) cytoplasmic areas that were devoid of HSP30. Lastly, MG132 treatment of A6 cells conferred a state of thermotolerance such that they were able to survive a subsequent thermal challenge.
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PMID:Proteasome inhibition induces hsp30 and hsp70 gene expression as well as the acquisition of thermotolerance in Xenopus laevis A6 cells. 1983 33

alphaB-crystallin, a small heat shock protein, plays an important role in muscle homeostasis. It gets up-regulated during muscle differentiation and mice lacking alphaB-crystallin die prematurely with extensive muscle wastage. We have examined the role of alphaB-crystallin in muscle development using C2C12 myoblasts as a model system. Over-expression of alphaB-crystallin delays the muscle differentiation program significantly. C2C12 myoblasts over-expressing alphaB-crystallin (CRYAB-C2C12) display defect in cell-cycle exit upon induction of differentiation. During differentiation, CRYAB-C2C12 cells exhibit sustained level of cyclin D1 and delay in p21 and myogenin expression as compared to C2C12 cells. We find less accumulation of MyoD in CRYAB-C2C12 cells than in C2C12 cells. In vivo protein stability studies reveal faster ubiquitin-proteasome-mediated MyoD degradation in CRYAB-C2C12 cells (t(1/2)=1.42 h) than in C2C12 cells (t(1/2)=2.37 h). Immuno-precipitation experiments showed that MyoD gets ubiquitinated at earlier time points in CRYAB-C2C12 cells than in C2C12 cells. Our data reveal alterations in the synthesis and degradation of MyoD in CRYAB-C2C12 cells. The level of alphaB-crystallin as well as its Ser-59 phosphorylated form increases with increasing time of differentiation. Our studies show, inter alia, that alphaB-crystallin modulates myogenesis by altering MyoD level and provide an interesting insight in its role in myogenesis.
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PMID:Ubiquitin-proteasome-mediated degradation and synthesis of MyoD is modulated by alphaB-crystallin, a small heat shock protein, during muscle differentiation. 2000 63

Plastid-targeted proteins pass through the cytosol as unfolded precursors. If proteins accumulate in the cytosol, they can form nonspecific aggregates that cause severe cellular damage. Here, we demonstrate that high levels of plastid precursors are degraded through the ubiquitin-proteasome system (UPS) in Arabidopsis thaliana cells. The cytosolic heat shock protein cognate 70-4 (Hsc70-4) and E3 ligase carboxy terminus of Hsc70-interacting protein (CHIP) were highly induced in plastid protein import2 plants, which had a T-DNA insertion at Toc159 and showed an albino phenotype and a severe defect in protein import into chloroplasts. Hsc70-4 and CHIP together mediated plastid precursor degradation when import-defective chloroplast-targeted reporter proteins were transiently expressed in protoplasts. Hsc70-4 recognized specific sequence motifs in transit peptides and thereby led to precursor degradation through the UPS. CHIP, which interacted with Hsc70-4, functioned as an E3 ligase in the Hsc70-4-mediated protein degradation. The physiological role of Hsc70-4 was confirmed by analyzing Hsc70-4 RNA interference plants in an hsc70-1 mutant background. Plants with lower Hsc70 levels exhibited abnormal embryogenesis, resulting in defective seedlings that displayed high levels of reactive oxygen species and monoubiquitinated Lhcb4 precursors. We propose that Hsc70-4 and CHIP mediate plastid-destined precursor degradation to prevent cytosolic precursor accumulation and thereby play a critical role in embryogenesis.
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PMID:Heat shock protein cognate 70-4 and an E3 ubiquitin ligase, CHIP, mediate plastid-destined precursor degradation through the ubiquitin-26S proteasome system in Arabidopsis. 2002 38

Missense mutant proteins, such as those produced in individuals with genetic diseases, are often misfolded and subject to processing by intracellular quality control systems. Previously, we have shown using a yeast system that enzymatic function could be restored to I278T cystathionine beta-synthase (CBS), a cause of homocystinuria, by treatments that affect the intracellular chaperone environment. Here, we extend these studies and show that it is possible to restore significant levels of enzyme activity to 17 of 18 (94%) disease causing missense mutations in human cystathionine beta-synthase (CBS) expressed in Saccharomyces cerevisiae by exposure to ethanol, proteasome inhibitors, or deletion of the Hsp26 small heat shock protein. All three of these treatments induce Hsp70, which is necessary but not sufficient for rescue. In addition to CBS, these same treatments can rescue disease-causing mutations in human p53 and the methylene tetrahydrofolate reductase gene. These findings do not appear restricted to S. cerevisiae, as proteasome inhibitors can restore significant CBS enzymatic activity to CBS alleles expressed in fibroblasts derived from homocystinuric patients and in a mouse model for homocystinuria that expresses human I278T CBS. These findings suggest that proteasome inhibitors and other Hsp70 inducing agents may be useful in the treatment of a variety of genetic diseases caused by missense mutations.
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PMID:Activation of mutant enzyme function in vivo by proteasome inhibitors and treatments that induce Hsp70. 2006 33

The accumulation of the intermediate filament protein, glial fibrillary acidic protein (GFAP), in astrocytes of Alexander disease (AxD) impairs proteasome function in astrocytes. We have explored the molecular mechanism that underlies the proteasome inhibition. We find that both assembled and unassembled wild type (wt) and R239C mutant GFAP protein interacts with the 20 S proteasome complex and that the R239C AxD mutation does not interfere with this interaction. However, the R239C GFAP accumulates to higher levels and forms more protein aggregates than wt protein. These aggregates bind components of the ubiquitin-proteasome system and, thus, may deplete the cytosolic stores of these proteins. We also find that the R239C GFAP has a greater inhibitory effect on proteasome system than wt GFAP. Using a ubiquitin-independent degradation assay in vitro, we observed that the proteasome cannot efficiently degrade unassembled R239C GFAP, and the interaction of R239C GFAP with proteasomes actually inhibits proteasomal protease activity. The small heat shock protein, alphaB-crystallin, which accumulates massively in AxD astrocytes, reverses the inhibitory effects of R239C GFAP on proteasome activity and promotes degradation of the mutant GFAP, apparently by shifting the size of the mutant protein from larger oligomers to smaller oligomers and monomers. These observations suggest that oligomeric forms of GFAP are particularly effective at inhibiting proteasome activity.
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PMID:Oligomers of mutant glial fibrillary acidic protein (GFAP) Inhibit the proteasome system in alexander disease astrocytes, and the small heat shock protein alphaB-crystallin reverses the inhibition. 2011 Mar 64

In eukaryotes, the ubiquitin-proteasome system (UPS) is responsible for the degradation of most proteins. Proteasome inhibition, which has been associated with various diseases, can cause alterations in various intracellular processes including the expression of heat shock protein (hsp) genes. In this study, we show that celastrol, a quinone methide triterpene and anti-inflammatory agent, inhibited proteasome activity and enhanced HSP accumulation in Xenopus laevis A6 kidney epithelial cells. Treatment of cells with celastrol induced the accumulation of ubiquitinated protein and inhibited chymotrypsin-like activity. This was accompanied by a dose- and time-dependent accumulation of HSP30 and HSP70. Celastrol-induced HSP accumulation was mediated by HSF1-DNA binding activity since this response was inhibited by the HSF1 activation inhibitor, KNK437. Simultaneous exposure of cells with celastrol plus either mild heat shock or the proteasome inhibitor, MG132, produced an enhanced accumulation of HSP30 that was greater than the sum of the individual stressors alone. Immunocytochemical analysis revealed that celastrol-induced HSP30 accumulation occurred in the cytoplasm in a granular pattern supplemented with larger circular HSP30 staining structures. HSP30 was also noted in the nucleus with less staining in the nucleolus. In some cells, celastrol induced the collapse of the actin cytoskeleton and conversion to a rounder morphology. In conclusion, this study has shown that celastrol inhibited proteasome activity and induced HSF1-mediated expression of hsp genes in amphibian cells.
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PMID:Celastrol can inhibit proteasome activity and upregulate the expression of heat shock protein genes, hsp30 and hsp70, in Xenopus laevis A6 cells. 2018 6


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PMID:In-depth exploration of Hevea brasiliensis latex proteome and "hidden allergens" via combinatorial peptide ligand libraries. 2022 88

BAG3, a member of the BAG family of heat shock protein (HSP) 70 cochaperones, is expressed in response to stressful stimuli in a number of normal cell types and constitutively in a variety of tumors, including pancreas carcinomas, lymphocytic and myeloblastic leukemias, and thyroid carcinomas. Down-regulation of BAG3 results in cell death, but the underlying molecular mechanisms are still elusive. Here, we investigated the molecular mechanism of BAG3-dependent survival in human osteosarcoma (SAOS-2) and melanoma (M14) cells. We show that bag3 overexpression in tumors promotes survival through the NF-kappaB pathway. Indeed, we demonstrate that BAG3 alters the interaction between HSP70 and IKKgamma, increasing availability of IKKgamma and protecting it from proteasome-dependent degradation; this, in turn, results in increased NF-kappaB activity and survival. These results identify bag3 as a potential target for anticancer therapies in those tumors in which this gene is constitutively expressed. As a proof of principle, we show that treatment of a mouse xenograft tumor model with bag3siRNA-adenovirus that down-regulates bag3 results in reduced tumor growth and increased animal survival.
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PMID:IKK{gamma} protein is a target of BAG3 regulatory activity in human tumor growth. 2036 14

Treatment-emergent peripheral neuropathy (PN) is an important dose-limiting toxicity during treatment of multiple myeloma (MM). Bortezomib-induced PN (BIPN) occurred in 37-44% of clinical trial patients with MM, with the cumulative treatment dose as its single most significant predictor. This review discusses the clinical profile of BIPN in the treatment of MM and guidelines for its management. Lower rates of BIPN observed during treatment of solid tumors compared with rates of hematologic cancers are also discussed. Several areas of research are reviewed that may improve the management of BIPN, including co-therapies with the novel heat shock protein inhibitor tanespimycin, which appears to reduce the incidence of BIPN, and recent studies with second-generation proteasome inhibitors such as carfilzomib and NPI-0052. Adherence to the National Cancer Institute dose-modification algorithm is the most effective method for mitigating BIPN. Reversal of BIPN after treatment cessation occurs in most cases, but recovery in some patients takes as long as 1.7 years, and some individuals fail to return to baseline neurologic function. BIPN can cause a significant reduction in quality of life, primarily due to severe treatment-emergent pain. Ongoing research may provide additional information about the mechanism of BIPN and strategies to reduce PN.
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PMID:Peripheral neuropathy during bortezomib treatment of multiple myeloma: a review of recent studies. 2049 1


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