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)

Recent studies indicate that highly selective proteasome inhibitors can be useful in prevention of some cardiovascular events. Here we demonstrate that proteasome inhibitor, Z-Ile-Glu (Ot-Bu) Ala-Leucinal (PSI), is active in the prevention of platelet-dependent arterial thrombosis induced in renovascular hypertensive rats (two-kidney, one clip Goldblatt model, and 2K1C, n=5). The administration of PSI intravenously at a single dose of 0.3 mg/kg before induction of arterial thrombosis markedly increased carotid final flow rate, as compared to control (vehicle) group (10.36 +/- 1.8 ml/min and 1.2 +/- 1.2 ml/min, respectively), significantly decreased the wet (1.23 +/- 0.23 mg and 4.1 +/- 0.94 mg, respectively), and dry (0.46 +/- 0.145 mg and 1.46 +/- 0.39, respectively) thrombus weight, and completely prevented arterial occlusion. Moreover, platelets from PSI - treated thrombotic 2K1C rats, showed in response to collagen a significant inhibition of aggregation in the whole blood (10.26 +/- 0.6 ohms vs. 15.51 +/- 0.91 ohms in the control group). In contrast, collagen-induced platelet aggregation was not inhibited in vitro, after pre-treatment of the blood with PSI at the concentration of 10 microM that effectively inhibited the 20S proteasome activity in platelets, indicating that ex vivo anti-aggregatory effect of PSI proceeds through an indirect mechanism not associated with suppression of 20S proteasome activity in platelets. In conclusion, our in vivo findings demonstrate that proteasome inhibitor, Z-Ile-Glu(Ot-Bu)Ala-Leucinal, prevents the development of arterial thrombosis in renovascular hypertensive rats and effectively suppresses platelet aggregation by an indirect mechanism. Thus the data provide a new insight into the potential role for the proteasome-dependent pathway in cardiovascular events.
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PMID:Proteasome inhibitor prevents experimental arterial thrombosis in renovascular hypertensive rats. 1521 58

Myocardial remodeling is an adaptive response of the myocardium to several forms of stress culminating in cardiac fibrosis, left ventricular dilation, and loss of contractility. The remodeling processes of the extracellular matrix are controlled by matrix metalloproteinases, which are in turn regulated by growth factors and inflammatory cytokines. The inflammatory transcription factor nuclear factor kappaB has been implicated in the transcriptional regulation of several matrix metalloproteinases. Because activation of nuclear factor kappaB in turn is essentially controlled by the ubiquitin-proteasome system, we investigated the hypothesis that inhibition of the proteasome may prevent activation of matrix metalloproteinases. We demonstrate here that inhibition of the proteasome in rat cardiac fibroblasts suppressed not only expression of matrix metalloproteinases 2 and 9, but also expression of collagen Ialpha1, Ialpha2, and IIIalpha1 as determined by in-gel zymography and real-time reverse transcription-polymerase chain reaction. Moreover, myocardial expression of matrix metalloproteinases and collagens was effectively suppressed by systemic treatment of spontaneously hypertensive rats over 12 weeks with the proteasome inhibitor MG132, which resulted in a marked reduction of cardiac fibrosis (-38%) compared with control animals. We conclude that inhibition of the ubiquitin-proteasome system may provide a new and attractive tool to interfere with collagen and matrix metalloproteinase expression, and therefore might be of possible use in the therapy of myocardial remodeling.
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PMID:Downregulation of matrix metalloproteinases and collagens and suppression of cardiac fibrosis by inhibition of the proteasome. 1533 35

Glycoprotein (GP) V is noncovalently linked to GPIbalpha, GPIbbeta and GPIX within the platelet GPIb-V-IX complex, a receptor for von Willebrand factor and thrombin. Two functions have been ascribed to GPV, namely, the modulation of thrombin- and collagen-dependent platelet responses. The biosynthesis of this molecule was investigated in pulse-chase metabolic labelling experiments performed in CHO cell lines transfected with GPV, alone or in the presence of GPIb-IX. GPV could not be detected at the surface of cells expressing the single subunit but was found instead as a soluble form in the culture medium. In pulse-chase studies, an immature 70 kDa protein was detected in cell lysates, whereas a fully processed 80-82 kDa form was only observed in the culture supernatants at later chase times. Immature GPV was N-glycosylated and retained before the medial Golgi while the secreted molecule contained complex sialylated sugars. The mature soluble form of GPV was produced by an enzymatic cleavage which was not affected by inhibitors of proteasome, calpain or metalloproteinases. When GPV was cotransfected with GPIb-IX, the former was no longer found in the culture supernatant but was retained in the cell membrane as shown by fluorescence-activated cell sorting and confocal microscopy analyses. Surface expressed GPV was processed from an immature 70 kDa form to produce a mature 80 kDa protein, processing similar to the intracellular trafficking of GPIbalpha. These results indicate that correct biosynthesis and surface expression of GPV in platelets requires the presence of the other subunits of the GPIb-V-IX complex.
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PMID:Biosynthesis of platelet glycoprotein V expressed as a single subunit or in association with GPIb-IX. 1535 44

The medicinal plant Withania somnifera is widely researched for its anti-inflammatory, cardioactive and central nervous system effects. In Ayurveda , the major Traditional Indian medicine system, extracts from W. somnifera are distinctively employed for the treatment of arthritis and menstrual disorders. Because these conditions involve angiogenic processes we hypothesized that the W. somnifera extracts might contain angiogenesis inhibitors. We employed an endothelial cell-sprouting assay to monitor the purification of substances from W. somnifera root extracts and isolated as the active principle the previously known natural product withaferin A. We show that withaferin A inhibits human umbilical vein endothelial cell (HUVEC) sprouting in three-dimensional collagen-I matrix at doses which are relevant to NF-kappa B-inhibitory activity. Withaferin A inhibits cell proliferation in HUVECs (IC50 =12 nM) at doses that are significantly lower than those required for tumor cell lines through a process associated with inhibition of cyclin D1 expression. We propose that the inhibition of NF-kappa B by withaferin A in HUVECs occurs by interference with the ubiquitin-mediated proteasome pathway as suggested by the increased levels of poly-ubiquitinated proteins. Finally, withaferin A is shown to exert potent anti-angiogenic activity in vivo at doses that are 500-fold lower than those previously reported to exert anti-tumor activity in vivo. In conclusion, our findings identify a novel mode of action of withaferin A, which highlights the potential use of this natural product for cancer treatment or prevention.
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PMID:Withaferin A is a potent inhibitor of angiogenesis. 1551 32

Cyclooxygenase-2 (COX-2), a key enzyme in prostaglandin synthesis, is highly expressed during inflammation and cellular transformation and promotes tumor progression and angiogenesis. We have previously demonstrated that endothelial cell COX-2 is required for integrin alphaVbeta3-dependent activation of Rac-1 and Cdc-42 and for endothelial cell spreading, migration, and angiogenesis (Dormond, O., Foletti, A., Paroz, C., and Ruegg, C. (2001) Nat. Med. 7, 1041-1047; Dormond, O., Bezzi, M., Mariotti, A., and Ruegg, C. (2002) J. Biol. Chem. 277, 45838-45846). In this study, we addressed the question of whether integrin-mediated cell adhesion may regulate COX-2 expression in endothelial cells. We report that cell detachment from the substrate caused rapid degradation of COX-2 protein in human umbilical vein endothelial cells (HUVEC) independent of serum stimulation. This effect was prevented by broad inhibition of cellular proteinases and by neutralizing lysosomal activity but not by inhibiting the proteasome. HUVEC adhesion to laminin, collagen I, fibronectin, or vitronectin induced rapid COX-2 protein expression with peak levels reached within 2 h and increased COX-2-dependent prostaglandin E2 production. In contrast, nonspecific adhesion to poly-L-lysine was ineffective in inducing COX-2 expression. Furthermore, the addition of matrix proteins in solution promoted COX-2 protein expression in suspended or poly-L-lysine-attached HUVEC. Adhesion-induced COX-2 expression was strongly suppressed by pharmacological inhibition of c-Src, phosphatidylinositol 3-kinase, p38, extracellular-regulated kinase 1/2, and, to a lesser extent, protein kinase C and by the inhibition of mRNA or protein synthesis. In conclusion, this work demonstrates that integrin-mediated cell adhesion and soluble integrin ligands contribute to maintaining COX-2 steady-state levels in endothelial cells by the combined prevention of lysosomal-dependent degradation and the stimulation of mRNA synthesis involving multiple signaling pathways.
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PMID:Integrin-mediated adhesion and soluble ligand binding stabilize COX-2 protein levels in endothelial cells by inducing expression and preventing degradation. 1552 53

Mastin is a tryptic peptidase secreted by canine mast cells. This work reveals that mastin is composed of catalytic domain singlets and disulfide-linked dimers. Monomers unite non-covalently to form tryptase-like tetramers, whereas dimers aggregate with monomers into larger clusters stabilized by hydrophobic contacts. Unlike tryptases, mastin resists inactivation by leech-derived tryptase inhibitor, indicating a smaller central cavity, as confirmed by structural models. Nonetheless, mastin is strongly gelatinolytic while not cleaving native collagen or casein, suggesting a preference for denatured proteins threaded into its central cavity. Phylogenetic analysis suggests that mammalian mastins shared more recent ancestors with soluble alpha/beta/delta tryptases than with membrane-anchored gamma-tryptases, and diverged more rapidly. We hypothesize that gelatinase activity and formation of inhibitor-resistant oligomers are ancestral characteristics shared by soluble tryptases and mastins, and that secreted mastin is a mini-proteasome-like complex that breaks down partially degraded proteins without causing bystander damage to intact, native proteins.
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PMID:Mastin is a gelatinolytic mast cell peptidase resembling a mini-proteasome. 1570 74

Interleukin (IL)-15, a cytokine expressed in skeletal muscle, has been shown to have muscle anabolic effects in vitro and to slow muscle wasting in rats with cancer cachexia. Whether IL-15 has therapeutic potential for diseases such as Duchenne muscular dystrophy (DMD) is unknown. We examined whether IL-15 administration could ameliorate the dystrophic pathology in the diaphragm muscle of the mdx mouse, an animal model for DMD. Four weeks of IL-15 treatment improved diaphragm strength, a highly significant finding because respiratory function is a mortality predictor in DMD. Enhanced diaphragm function was associated with increased muscle fiber cross-sectional area and decreased collagen infiltration. IL-15 administration was not associated with changes in T-cell populations or alterations in specific components of the ubiquitin proteasome pathway. To determine the effects of IL-15 on myofiber regeneration, muscles of IL-15-treated and untreated wild-type mice were injured myotoxically, and their functional recovery was assessed. IL-15 had a mild anabolic effect, increasing fiber cross-sectional area after 2 and 6 days but not after 10 days. Our findings demonstrate that IL-15 administration improves the pathophysiology of dystrophic muscle and highlight a possible therapeutic role for IL-15 in the treatment of neuromuscular disorders especially in which muscle wasting is indicated.
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PMID:Interleukin-15 administration improves diaphragm muscle pathology and function in dystrophic mdx mice. 1579 93

BRCA2 is a tumor suppressor gene that when mutated confers an increased susceptibility to developing breast and prostate carcinoma. Besides its role in mediating DNA repair, new evidence suggests that BRCA2 may also play a role in suppressing cancer cell growth. Because altered interactions between neoplastic cells and the surrounding extracellular matrix (ECM) play a pivotal role in unchecked cancer cell proliferation and metastatic progression, we hypothesized that the ECM may have an effect in BRCA2 expression. By using normal and prostate carcinoma cell lines, we demonstrated that although normal cells transiently increase BRCA2 protein levels when adhering to the ECM protein collagen type I (COL1), carcinoma cells exhibit a significant reduction in BRCA2 protein. This aberrant effect is independent from de novo protein synthesis and results from COL1-beta(1) integrin signaling through phosphatidylinositol (PI) 3-kinase leading to BRCA2 ubiquitination and degradation in the proteasome. BRCA2 protein depletion after cancer cell adhesion to COL1 or in small RNA interference assays triggers new DNA synthesis, a trophic effect that is abrogated by recombinant BRCA2 expression. Blocking or inhibiting beta(1) integrin, PI 3-kinase, or proteasome activity all have a negative effect on COL1-mediated DNA synthesis in cancer cells. In normal cells, the transient increase in BRCA2 expression is independent from beta(1) integrin or PI 3-kinase and has no effect in cell proliferation. In summary, these results unravel a novel mechanism whereby prostate carcinoma cell proliferation is enhanced by the down-regulation of BRCA2 expression when interacting with COL1, a major component of the ECM at osseous metastatic sites.
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PMID:Down-regulation of BRCA2 expression by collagen type I promotes prostate cancer cell proliferation. 2495 45

Two proteins, ColQ and PRiMA, organize tetramers of acetylcholinesterase (AChE) and of butyrylcholinesterase (BChE) through peptide interactions. A short proline rich sequence in the N-terminal domain of ColQ or PRiMA associates four C-terminal extension of AChE or BChE. ColQ targets the enzymes in the basal lamina, PRiMA targets the enzymes at the plasma membrane. These complexes represent the mature proteins. The unassembled C-terminal extention of AChE is the key determinant recognized during the "quality control" of protein synthesis. Unassembled catalytic subunits are then degraded by the proteasome pathway. At the neuromuscular junction, ColQ/AChE represents the concentrated enzyme. The clusterisation of AChE depends upon ColQ through three sites of interactions: two different heparin binding domains in the collagen domain interact with heparan sulfate proteoglycan particularly the perlecan and the C-terminal non collagenic domain interacts with MuSK, the tyrosine kinase receptor organiser of the neuromuscular junction. The absence of ColQ and AChE has revealed that the excess of Ach stimulates more nicotinic receptors but probably not until their desensitization. Several morphological modifications may help the clearance of Ach. Conversely the synapse transmission fails during high frequency nerve stimulation.
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PMID:[Cholinesterases: anchored enzymes in membranes and basal laminae]. 1611 64

Tissue fibrosis results when dysregulation of extracellular matrix (ECM) turnover favors deposition of collagen and other ECM proteins over degradation. Fibrosis may then lead to organ dysfunction and pathology as observed in systemic sclerosis (SSc). In the present study, we investigated the antifibrotic properties of proteasome blockade. A dose- and time-dependent reduction in type-I collagen and tissue inhibitor of metalloproteinase-1 (TIMP-1) production was observed in normal fibroblasts exposed to proteasome inhibitors (PI). In the same culture conditions, metalloproteinase-1 (MMP-1) protein and the collagenolytic activity on type I collagen was increased. The steady-state mRNA levels of COL1A1, TIMP-1, and MMP-1 paralleled protein levels. These effects were dominant over the profibrotic properties of TGF-beta and were observed with fibroblasts generated from normal and SSc skin. PI decreased type I collagen mRNA levels with kinetics similar to those observed with DRB, a specific RNA polymerase II inhibitor, thus indicating transcriptional inhibition. Of interest, PI induced c-Jun phosphorylation and c-Jun nuclear accumulation. The specific N-terminal Jun-kinase inhibitor SP-600125 selectively abrogated c-Jun phosphorylation and, in a dose-dependent fashion, the up-regulated synthesis of MMP-1 induced by PI. Finally, PI did not affect fibroblast viability. Thus, the coordinated down-regulation of collagen and TIMP-1 and up-regulation of MMP-1 renders proteasome blockade an attractive strategy for treating conditions as SSc, characterized by excessive fibrosis.
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PMID:Proteasome blockade exerts an antifibrotic activity by coordinately down-regulating type I collagen and tissue inhibitor of metalloproteinase-1 and up-regulating metalloproteinase-1 production in human dermal fibroblasts. 1641 Mar 44


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