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 pathogenesis of severe acute respiratory syndrome coronavirus (SARS CoV) is an important issue for treatment and prevention of SARS. Previously, SARS CoV 3C-like protease (3CLpro) has been demonstrated to induce apoptosis via the activation of caspase-3 and caspase-9 (Lin, C. W., Lin, K. H., Hsieh, T. H., Shiu, S. Y. et al., FEMS Immunol. Med. Microbiol. 2006, 46, 375-380). In this study, proteome analysis of the human promonocyte HL-CZ cells expressing SARS CoV 3CLpro was performed using 2-DE and nanoscale capillary LC/ESI quadrupole-TOF MS. Functional classification of identified up-regulated proteins indicated that protein metabolism and modification, particularly in the ubiquitin proteasome pathway, was the main biological process occurring in SARS CoV 3CLpro-expressing cells. Thirty-six percent of identified up-regulated proteins were located in the mitochondria, including apoptosis-inducing factor, ATP synthase beta chain and cytochrome c oxidase. Interestingly, heat shock cognate 71-kDa protein (HSP70), which antagonizes apoptosis-inducing factor was shown to down-regulate and had a 5.29-fold decrease. In addition, confocal image analysis has shown release of mitochondrial apoptogenic apoptosis-inducing factor and cytochrome c into the cytosol. Our results revealed that SARS CoV 3CLpro could be considered to induce mitochondrial-mediated apoptosis. The study provides system-level insights into the interaction of SARS CoV 3CLpro with host cells, which will be helpful in elucidating the molecular basis of SARS CoV pathogenesis.
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PMID:Proteomic analysis of up-regulated proteins in human promonocyte cells expressing severe acute respiratory syndrome coronavirus 3C-like protease. 1740 83

We studied the ability of heat shock, DnaJ-like-1 (HSJ1) proteins (which contain DnaJ and ubiquitin-interacting motifs) to reduce polyglutamine-mediated inclusion formation. The experiments demonstrated that expression of heat shock protein 70 (hsp70), hsp40, HSJ1a, and HSJ1b significantly reduced protein inclusion formation in a model of spinal and bulbar muscular atrophy (SBMA). HSJ1a also mediated a significant decrease in the number of inclusions formed in a primary neuronal model of protein aggregation. Studies to elucidate the mechanisms underlying these reductions showed that hsp70 and hsp40 increased chaperone-mediated refolding. In contrast, expression of HSJ1 proteins did not promote chaperone activity but caused an increase in ubiquitylation. Furthermore, HSJ1a was associated with a ubiquitylated luciferase complex, and in the presence of HSJ1a but not an HSJ1a UIM mutant (HSJ1a-deltaUIM) there was a reduction in luciferase protein levels. Together these results show that HSJ1 proteins mediated an increase in target protein degradation via the ubiquitin-proteasome system (UPS). We also found that the expression of HSJ1a significantly decreased the number of neurons containing inclusions in an in vivo model of polyglutamine disease. These findings indicate that targeted modification of the UPS to facilitate degradation of misfolded proteins may represent a highly effective therapeutic avenue for the treatment of polyglutamine disease.
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PMID:Hsp40 molecules that target to the ubiquitin-proteasome system decrease inclusion formation in models of polyglutamine disease. 1742 12

It has been proposed that chemotherapy enhances tumor antigen (TA)-specific immunity. The molecular form of TA from ovarian tumor that activates cellular immunity is unknown. We report here identification of a novel molecular form of immunogenic TA for CD8(+) cells named self-immune stimulatory multimolecular complexes (ISMMC). ISMMC consist of a molecular complex of polyosome/ribosome-bound ubiquitinated nascent HER-2 polypeptides. This complex is chaperoned by heat shock protein Gp96, which mediates ISMMC uptake by antigen-presenting cells through the scavenger receptor CD91. RNAs in ISMMC stimulate immature dendritic cells to secrete interleukin 12 and induce IFN-gamma in peripheral blood mononuclear cells. ISMMC dissociate, retrotranslocate from the lysosome to cytoplasm, and are processed to peptides by the proteasome. At subpharmacologic doses, Taxol increased the amount of ISMMC by three to four times and modified their composition by inducing the attachment of cochaperones of HSP70, such as the mitotic-phase phosphoprotein 11J. On a total protein basis, Taxol induced ISMMC, expanded more CD8(+) cells, activated more CD56(+) NKG2D(+) cells to produce IFN-gamma, and were more potent inducers of high T-cell receptor density Perforin(+) cells than native ISMMC and peptide E75. Elucidation of the composition of ISMMC and identification of adducts formed by Taxol should be important for developing molecular cancer vaccines.
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PMID:Taxol increases the amount and T cell activating ability of self-immune stimulatory multimolecular complexes found in ovarian cancer cells. 1780 54

Germination of barley is accompanied by changes in water-soluble seed proteins. 2-DE was used to describe spatio-temporal proteome differences in dissected seed tissues associated with germination and the subsequent radicle elongation. Protein identification by MS enabled assignment of proteins and functions to the seed embryo, aleurone, and endosperm. Abundance in 2-DE patterns was monitored for 48 different proteins appearing in 79 gel spots at 8 time-points up to 72 h post imbibition (PI). In embryo, a beta-type proteasome subunit and a heat shock protein 70 fragment were among the earliest proteins to appear (at 4 h PI). Other early changes were observed that affected spots containing desiccation stress-associated late embryogenesis abundant and abscisic acid (ABA)-induced proteins. From 12 h PI proteins characteristic for desiccation stress disappeared rapidly, as did a putative embryonic protein and an ABA-induced protein, suggesting that these proteins are also involved in desiccation stress. Several redox-related proteins differed in spatio-temporal patterns at the end of germination and onset of radicle elongation. Notably, ascorbate peroxidase that was observed only in the embryo, increased in abundance at 36 h PI. The surprisingly early changes seen in the protein profiles already 4 h after imbibition indicate that germination is programmed during seed maturation.
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PMID:Spatio-temporal changes in germination and radical elongation of barley seeds tracked by proteome analysis of dissected embryo, aleurone layer, and endosperm tissues. 1802 42

The proteasome inhibitor bortezomib, which induces cell death in various cancer cell lines including lymphatic neoplasias, has recently been approved for the treatment of relapsed multiple myeloma. Important mechanisms of proteasome inhibitor-mediated tumor cell death are the inhibition of NF-kappaB activation and induction of the terminal unfolded protein response (UPR). However, little is known about effects of bortezomib on developing and mature lymphocytes. Therefore, Balb/C mice were injected with bortezomib and lymphocyte subsets were analyzed. This treatment resulted in dramatically decreased numbers of T and B lymphocyte precursors, while mature lymphocytes were only partially affected. Thymocytes were almost depleted 3 days after a single bortezomib injection, pro-B and pre-B cells already after 2 days. Thymocytes and B cell precursors recovered within 2 weeks. The decreased numbers of developing lymphocytes were due to apoptotic cell death accompanied by strongly increased caspase 3/7 activity. Within 8 h after bortezomib injection, there was a strong induction of heat shock protein 70 and C/EBP homologous protein in bone marrow B cells, indicating endoplasmic reticulum stress and activation of the terminal UPR, respectively. Hence, induction of apoptosis by proteasome inhibition can dramatically affect lymphocyte development, a fact which has important implications for the clinical use of bortezomib, especially in situations with ongoing lymphopoiesis.
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PMID:Proteasome inhibition drastically but reversibly impairs murine lymphocyte development. 1818 68

Arrhythmia-prone epicardial border zone (EBZ) tissues demonstrate decreased G protein-coupled receptor kinase-2 (GRK2) activity and increased sensitivity to isoproterenol 6-24 h after coronary artery ligation in the dog. We previously demonstrated that the ischemia-mediated decrease in GRK2 in cardiac ischemic tissue was largely blocked by proteasome blockade initiated 1 h before the onset of ischemia, and this was associated with significant cardioprotection against malignant ventricular tachyarrhythmias. For application to clinical circumstances, it is desirable to determine whether a clinical window exists following the onset of ischemia for such a protective effect. The treatment of six dogs with the selective proteasome inhibitor bortezomib 1 h after the surgical induction of left coronary artery ischemia provided 80% (EBZ) and 42% (infarct) protection (by immunoblot) against the loss of GRK2 at 24 h. There was no significant increase of heat shock protein 70(72) in the EBZ of bortezomib-treated animals compared with control. There was a striking absence of rapid (>300 beats/min) and very rapid (>360 beats/min) ventricular triplets that is highly predictive of sudden cardiac deaths (SCDs) during electrocardiogram monitoring of the first 24 h in the bortezomib-treated animals in contrast with nontreated infarcted animals. There were no SCDs in the 6 treated animals (0%) and five SCDs in the 14 control animals (36%). Assay of whole blood proteasome activity demonstrated the expected decrease over the 24-h observation period. These data support the concept that proteasome inhibition within a window of time following myocardial infarction may be of use in suppressing malignant tachyarrhythmias and SCD.
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PMID:Proteasome inhibition 1 h following ischemia protects GRK2 and prevents malignant ventricular tachyarrhythmias and SCD in a model of myocardial infarction. 1819 26

We previously observed that in yeast cisplatin activates different pathways accounting for stress response. Here, we investigated whether genes involved in yeast drug response were modulated by cisplatin in human tumor cell lines (A2780, IGROV-1, A431, U2-OS) including cisplatin-resistant sublines (A2780/BBR, IGROV-1/Pt1, A431/Pt and U2-OS/Pt). Factors and pathways involved in stress response (glutathione-S-transferase, proteasome, checkpoint control and recombinational repair) were increased by cisplatin in human tumor sensitive and resistant cells. Moreover, sensitization to cisplatin by pharmacologically targeting glutathione or proteasome was observed in sensitive and resistant cells. Interestingly, only in IGROV-1/Pt1 cells, in which cisplatin up-regulated HSP70 and HSP90, targeting of HSP90 resulted in sensitization of resistant cells, suggesting a protective role of stress response. In conclusion, the present findings support the potential relevance of interfering with heat shock protein response to increase cisplatin cytotoxicity in resistant cells. Overall, pathways activated by cisplatin in human tumor cells appear cell-type specific, at least in part reflecting the stress response observed in yeast.
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PMID:Defining targets of modulation of human tumor cell response to cisplatin. 1827 62

Repeated mild heat shock treatment has been shown to have anti-aging effects on cellular mechanisms in vitro. Among these, the age-associated accumulation of advanced glycation end products (AGEs), such as N(epsilon)-(carboxymethyl)lysine (CML), has been demonstrated to be effectively prevented in glyoxal-exposed human skin fibroblasts following mild heat shock treatment. The biochemical mechanism responsible for this inhibition is not yet known. However, the involvement of heat shock proteins (HSPs) and the misfolded proteins degrading the ubiquitin-proteasome system have been hypothesized. As AGE-modified proteins are likely to be conformationally modified, we investigated whether treatment of human intestinal cells with casein-linked CML or nonprotein-linked CML affects the expression of HSPs and the ubiquitin-proteasome system by using matrix-assisted laser desorption/ionization-time-of-flight tandem mass spectroscopy (after protein separation by two-dimensional gel electrophoresis) and by Western blotting. Compared to nontreated control cells, expression of HSP90, HSP60, HSP70 chaperones, and the proteasome S26 ATPase subunit 2 were significantly upregulated in casein-CML and in CML-treated cells. Exposure of Caco-2 cells to beta-amyloid, a nonglycation product, revealed similar results. In conclusion, the results indicate that CML and casein-linked CML activate the expression of HSPs as well as the proteasome system, which are involved in the degradation of misfolded and possibly glycated proteins. Whether this mechanism is based on binding to cell surface receptors, such as the receptor for AGE, has to be clarified in future studies.
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PMID:Induction of heat shock proteins and the proteasome system by casein-N epsilon-(carboxymethyl)lysine and N epsilon-(carboxymethyl)lysine in Caco-2 cells. 1844 26

In several pathologic conditions, like cardiac ischemia/reperfusion, the sustained elevation of plasma and interstitial catecholamine levels, namely adrenaline (ADR), and the generation of reactive oxygen species (ROS) are hallmarks. The present work aimed to investigate in cardiomyocytes which intracellular signalling pathways are altered by ADR redox ability. To mimic pathologic conditions, freshly isolated calcium tolerant cardiomyocytes from adult rat were incubated with ADR alone or in the presence of a system capable of generating ROS [(xanthine with xanthine oxidase) (X/XO)]. ADR elicited a pro-oxidant signal with generation of reactive species, which was largely magnified by the ROS generating system. However, no change in cardiomyocytes viability was observed. The pro-oxidant signal promoted the translocation to the nucleus of the transcription factors, Heat shock factor-1 (HSF-1) and Nuclear factor-kappaB (NF-kappaB). In addition, proteasome activity was compromised in the experimental groups where the generation of reactive species occurred. The decrease in the proteasome activity of the ADR group resulted from its redox sensitivity, since the activity was recovered by adding the ROS scavenger, tiron. Proteasome inhibition seemed to elicit an increase in HSP70 levels. Furthermore, retention of mitochondrial cytochrome c and inhibition of caspase 3 activity were observed by X/XO incubation in presence or absence of ADR. In conclusion, in spite of all the insults inflicted to the cardiomyocytes, they were capable to activate intracellular responses that enabled their survival. These mechanisms, namely the pathways altered by catecholamine proteasome inhibition, should be further characterized, as they could be of relevance in the ischemia preconditioning and the reperfusion injury.
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PMID:Adrenaline in pro-oxidant conditions elicits intracellular survival pathways in isolated rat cardiomyocytes. 1913 23

HSP70 family members are highly conserved proteins that function as molecular chaperones. Their principle role is to aid protein folding and promote the correct cellular localizations of their respective substrates. The function of HSP70 isoforms can be exhibited independently or with the HSP90 chaperone system in which HSP70 is important for substrate recruitment. In addition to their chaperone role, HSP70 isoforms promote cell survival by inhibiting apoptosis at multiple points within both the intrinsic and extrinsic cell death pathways. Consistent with this cytoprotective function, increased expression of HSP70 isoforms is commonly associated with the malignant phenotype. We recently reported that dual silencing of the major constitutive (HSC70) and inducible (HSP72) isoforms of HSP70 in cancer cells could phenocopy the effects of a pharmacologic HSP90 inhibitor to induce proteasome-dependent degradation of HSP90 client proteins CRAF, CDK4 and ERBB2. This was accompanied by a G(1) cell cycle arrest and extensive apoptosis which was not seen in non-tumorigenic human cell lines. Here we discuss the possible implications of our research for the development of HSP70 family modulators which offer not only the possibility of inhibiting HSP70 activity but also the simultaneous inhibition of HSP90, resulting in extensive tumor-specific apoptosis.
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PMID:Death by chaperone: HSP90, HSP70 or both? 1919 60


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