Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Proteases of the plasminogen activator (PA) and matrix metalloproteinase (MMP) system play an important role in smooth muscle cell (SMC) migration and neointima formation after vascular injury. Inhibition of either PAs or MMPs has previously been shown to result in decreased neointima formation in vivo. To inhibit both protease systems simultaneously, a novel hybrid protein, TIMP-1.ATF, was constructed consisting of the tissue inhibitor of metalloproteinase-1 (TIMP-1) domain, as MMP inhibitor, linked to the receptor-binding amino terminal fragment (ATF) of urokinase. By binding to the u-PA receptor this protein will not only anchor the TIMP-1 moiety directly to the cell surface, it will also prevent the local activation of plasminogen by blocking the binding of urokinase-type plasminogen activator (u-PA) to its receptor. Adenoviral expression of TIMP-1.ATF was used to inhibit SMC migration and neointima formation in human saphenous vein segments in vitro. SMC migration was inhibited by 65% in Ad.TIMP-1.ATF-infected cells. Infection with adenoviral vectors encoding the individual domains, Ad.TIMP-1 and Ad.ATF, reduced migration by 32% and 52%, respectively. Neointima formation in saphenous vein organ cultures infected with Ad.TIMP-1.ATF was inhibited by 72% compared with 42% reduction after Ad.TIMP-1 infection and 34% after Ad.ATF infection. These data show that binding of TIMP-1.ATF hybrid protein to the u-PA receptor at the cell surface strongly enhances the inhibitory effect of TIMP-1 on neointima formation in human saphenous vein cultures.
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PMID:Gene transfer of the urokinase-type plasminogen activator receptor-targeted matrix metalloproteinase inhibitor TIMP-1.ATF suppresses neointima formation more efficiently than tissue inhibitor of metalloproteinase-1. 1243 29

Age is an important factor in the development and spread of breast cancer. Stromal cells also contribute to breast cancer growth and metastasis through the production of extracellular matrix (ECM) modifiers such as urokinase type plasminogen activator (uPA), its receptor (uPAR), its inhibitors (PAI-1 and PAI-2), matrix metalloproteinases (MMPs), and growth factors, including the fibroblast and insulin-like growth factors (FGF's and IGF's). In the present study we have investigated whether breast fibroblasts aged in vitro through passage in culture display altered levels of the plasminogen activator system and growth factors that are known to modulate that system. With real-time RT-PCR we found that during passage human breast fibroblasts, whether derived from the tumour burden or from matched adjacent normal breast tissue, exhibited a consistent increase in PAI-1 and FGF-1 and a decrease in MMP-2 mRNA expression. In addition, in 5 out of 7 fibroblast strains we observed an induction of uPA expression in combination with a reduced IGF-1 expression. Interestingly, while during aging MMP-2 protein increased in all tumour-derived fibroblast strains, these protein levels were reduced in all normal tissue- derived fibroblasts. No other clear-cut age-dependent alterations were found in the all-together 25 factors investigated. We furthermore demonstrate in one tumour-derived fibroblast strain that the increases in uPA and PAI-1 mRNA and MMP-2 protein production are inversely related to the telomere length. Artificially increasing telomere length in this fibroblast strain by expressing human telomerase reverse transcriptase (hTERT) prevented senescence and resulted in late passage cultures with early passage uPA, PAI-1 and MMP-2 levels. Our results show that aging accompanied by telomere loss induces PAI-1 and FGF-1 mRNA expression in all breast fibroblast strains, increases uPA and decreases IGF-1 mRNA expression in a subset, and increases MMP-2 protein expression only in tumour-derived breast fibroblasts. These age-induced levels of PAI-1, FGF-1, uPA and MMP-2 in stromal breast fibroblast could contribute to breast cancer progression.
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PMID:Aging of stromal-derived human breast fibroblasts might contribute to breast cancer progression. 1257 21

Membrane type serine protease 1 (MT-SP1) is a representative member of a large family of related enzymes known as type II transmembrane serine proteases or membrane type serine proteases. MT-SP1 has been implicated in the selective proteolysis of key extracellular substrates but its physiological role is still not fully understood. MT-SP1 expression at the protein and RNA level has been previously examined by nonquantitative methods such as in situ hybridization, Northern blotting and immunohistochemistry. To establish an introductory understanding of the quantitative mRNA expression of MT-SP1 and to correlate these levels with urokinase-type plasminogen activator receptor (uPAR), a key component of extracellular proteolysis, quantitative RT-PCR was carried out. RNA expression was analyzed in 34 human cancer cell lines, 26 human tissues and 18 primary human breast cancer tissue samples. MT-SP1 mRNA is highly expressed in many breast, ovarian, prostate and colon cancer cell lines and normal human tissues of endodermal origin. At the transcript level, MT-SP1 shows a highly statistically significant correlation (Pearson's product moment correlation r = 0.784, p < 0.001) with uPAR in human breast cancer tissue. The exact role of MT-SP1 in concert with proteins such as uPAR and other members of the plasminogen activator cascade has yet to be ascertained. However, the significant correlation between MT-SP1 and uPAR transcript levels in this initial study suggests further work to establish the role of MT-SP1 as a possible prognostic, diagnostic or therapeutic target for breast cancer.
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PMID:Quantitation of membrane type serine protease 1 (MT-SP1) in transformed and normal cells. 1267 19

Pemphigus is an autoimmune blistering disease of the skin and mucous membranes. It is caused by autoantibodies directed against desmosomes, which are the principal adhesion structures between epidermal keratinocytes. Binding of autoantibodies leads to the destruction of desmosomes resulting in the loss of cell-cell adhesion (acantholysis) and epidermal blisters. The plasminogen activator system has been implicated as a proteolytic effector in pemphigus. We have tested inhibitors of the plasminogen activator system with regard to their potential to prevent pemphigus-induced cutaneous pathology. In a human split skin culture system, IgG preparations of sera from pemphigus vulgaris patients caused histopathologic changes (acantholysis) similar to those observed in the original pemphigus disease. All inhibitors that were tested (active site inhibitors directed against uPA, tPA, and/or plasmin; antibodies neutralizing the enzymatic activity of uPA or tPA; substances interfering with the binding of uPA to its specific cell surface receptor uPAR) failed to prevent pemphigus vulgaris IgG-mediated acantholysis. Plasminogen-mediated acantholysis, however, was effectively antagonized by the synthetic active site serine protease inhibitor WX-UK1 or by p-aminomethylbenzoic acid. Our data argue against applying anti-plasminogen activator/anti-plasmin strategies in the management of pemphigus.
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PMID:Protease inhibitors prevent plasminogen-mediated, but not pemphigus vulgaris-induced, acantholysis in human epidermis. 1267 25

Age-related macular degeneration (ARMD), proliferative vitreoretinopathy (PVR) and uveitis are characterized by RPE motility through the ECM of retinal lesions. The purpose of this study was to test the hypothesis that multiple proteolytic systems are functionally intact at the HRPE surface and peri-cellular region and that these activities are differentially modulated by IL-1beta. HRPE cells were evaluated: (1). as individual cells or cell extracts, (2). during migration across three-dimensional ECM-like layers and (3). in tissue sections. The urokirase plasminogen activator receptor (uPAR; CD87) was detected on HRPE cells as well as its functional activity. Although uPAR was associated with CD11b (CR3) on live resting cells, polarized migratory HRPE cells were found to dissociate uPAR from CR3; uPAR then translocated to anterior pole of the cell, where it enhanced PAI-1-inhibitable local proteolytic activity. The relative contribution of uPAR and collagenase in HRPE migration was evaluated using three-dimensional gelatin matrices. Interestingly, uPAR/uPA was found to play a key role in migration across these layers. IL-1 upregulated uPAR, collagenase, and elastase activities, suggesting that cytokines may affect the invasive program of HRPE cells in vivo. Immunohistochemistry for uPAR was performed in sections of human retina. Immunoreactive uPAR was present along the HRPE basolateral membrane in retinal sections and in sections of diseased retinal tissue at an enhanced level. Our results suggest that multiple proteolytic systems are present in association with HRPE and that the uPAR/uPA system may be particularly important.
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PMID:Human RPE cell lysis of extracellular matrix: functional urokinase plasminogen activator receptor (uPAR), collagenase and elastase. 1269 22

The aim of this study was to determine the expression of proteinases and inhibitors from the matrix metalloproteinase (MMP) (MMPs 1, 2, 3, 9, tissue inhibitors of metalloproteinases (TIMPs) 1, 2) and plasminogen activator ((PA) urokinase (uPA), tissue type (tPA), uPAR, plasminogen activator inhibitors (PAIs) 1, 2) systems in colorectal cancer pathology by gelatin zymography, enzyme-linked immunosorbent assays (ELISAs) and quenched fluorescent substrate hydrolysis. The levels of all studied MMPs, uPA, uPAR, TIMP-1 and PAIs were significantly greater in tumour tissues than normal tissues. However, tPA and TIMP-2 were greater in normal colon (P<0.05, Mann-Whitney) e.g. PAI-1: tumour, median 14.9 (range 0.2-80.2) ng/mg total protein; normal, 2.1 (0.1-65.0). Tumour levels of several factors, in particular MMP-1 and PAI-1, correlated with pathology, i.e. Dukes' stage, differentiation, lymphatic or vascular invasion and tumour depth. The interactions between proteinase systems in colorectal cancer are complex and the balance between active proteinases and their inhibitors is important for extracellular matrix (ECM) degradation/remodelling at each stage of the metastatic cascade.
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PMID:The plasminogen activator and matrix metalloproteinase systems in colorectal cancer: relationship to tumour pathology. 1270 68

The fibrinolytic system is known to play an important role in the inflammatory response to bacterial infections. In the present study, relationships between protein components of the fibrinolytic system and infectivity by Mycobacterium avium were analyzed. Infections were initiated through noninvasive intratracheal administration of M. avium 724 in mice individually deficient for plasminogen, tissue-type plasminogen activator, urokinase-type plasminogen activator, and urokinase-type plasminogen activator receptor, along with wild-type control mice. There were no differences in lung colony counts among all mouse genotypes throughout a 10-week infection. However, in tissue-type plasminogen activator and plasminogen-deficient mice an earlier dissemination of M. avium to other organs was observed. Nevertheless, the M. avium growth rates in the liver, spleen, and lung did not differ between the various mouse populations throughout a 10-week infection. Histochemical and immunohistochemical analyses at 5 and 10 weeks after infection demonstrated that plasminogen-deficient mice, compared to wild-type mice, had enhanced fibrin and fibronectin deposition, as well as increased neutrophil infiltration within liver granulomas. These results suggest that plasmin(ogen) plays a role in the turnover of extracellular matrix proteins within granulomas and has a limited effect in the early dissemination of M. avium from lungs. Thus, plasmin(ogen) functions in limiting progressive fibrosis in the granuloma during a chronic mycobacterial infection.
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PMID:The fibrinolytic system in dissemination and matrix protein deposition during a mycobacterium infection. 1287 72

Malignancy is characterized by the occurrence of components of coagulation reaction pathways in situ within tumor tissues detectable immunohistochemically. However, tumors vary in the details of this coagulation-cancer interaction. We have previously described tumor cell-associated tissue factor (TF), factor (F) VII, and F X in laryngeal carcinoma tissues. Fibrinogen and F XIIIa were found in the tumor connective tissue. Tissue factor pathway inhibitor (TFPI) occurred in the tumor connective tissue and on microvascular endothelial cells and normal squamous epithelial cells but not in the tumor cells. Fibrin (thrombin-cleaved fibrinogen) existed at the host-tumor interface and the margins of tumor nodules consistent with an active tumor cell-associated clotting pathway in this tumor type. Studies were extended here to detect components of fibrinolytic pathways. Plasminogen and tissue plasminogen activator (t-PA) were detected on laryngeal tumor cells, particularly in more well-differentiated cases. Low-molecular-weight urokinase plasminogen activator (LMW u-PA) was primarily a feature of more undifferentiated laryngeal carcinoma cells. Staining to a lesser extent was found for high-molecular-weight u-PA (HMW u-PA) on tumor cells and various normal cell types in the tumor tissue. Relatively weak and variable tumor cell staining was found for plasminogen activator inhibitors (PAI) 1, 2, and 3. Trace staining was found for u-PA receptor (u-PAR) in differentiated tumor cells. The significance of coagulation and fibrinolytic pathways present in situ to the economy of laryngeal carcinoma remains to be determined.
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PMID:Occurrence of components of fibrinolytic pathways in situ in laryngeal cancer. 1288 36

Fibrin is a temporary matrix which not only covers a wound, but also provides a structure for invading cells during healing. Changes in the polymerization conditions before gelation of the clot affect the structure of fibrin and thus might influence the interaction with invading cells. Therefore we tested whether changes in the fibrin structure influence the formation of capillary-like tubular structures by human microvascular endothelial cells (hMVEC) in an in vitro angiogenesis model. Opaque [125I]fibrin structures prepared at pH 7.0, fibrin matrices at pH 7.4 and transparent [125I]fibrin structures prepared at pH 7.8 were neutralized (pH 7.4) before seeding hMVEC on top of them in confluent density. Endothelial cells were stimulated with a growth factor [basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF)165] and a cytokine [tumor necrosis factor (TNF)-alpha] to induce the u-PA/u-PA receptor-dependent formation of capillary-like tubular structures. The formation of these structures was quantified by determining the length of the invasive structures by image analysis and by measuring the accompanying [125I]fibrin degradation. Ingrowth of tubular structures proceeded at a faster rate in opaque matrices consisting of thick fibrin fibers as compared to transparent gels with fine fibrin fibers. The more rapid ingrowth of tubular structures in opaque fibrin gels induced by bFGF/TNF-alpha or VEGF165/TNF-alpha was accompanied by a larger extent of fibrin degradation. Both processes were inhibited by aprotinin and epsilon-aminocaproic acid indicating the involvement of plasmin. They were also inhibited by anti-u-PA or anti-u-PA receptor IgG, but not by anti-t-PA IgG, suggesting the involvement of cell-bound u-PA activity. However, in the opaque fibrin gels, the tubular structures dissolved upon prolonged incubation due to excessive fibrin degradation. Simulation of hMVEC with bFGF alone did not induce tubular structures, but ca used a high degree of t-PA- and plasmin-dependent fibrin lysis, and, after several days, a partial detachment of sheets of cells. Gradual inhibition of the excessive fibrin degradation by a series of aprotinin concentrations did not lead to tube formation in bFGF-treated cells. These data indicate that the formation and stability of tubular structures by hMVEC in fibrin is accompanied by controlled fibrinolysis and depends critically not only on cell-bound u-PA-dependent plasminogen activation, but also on the fibrin structure. Because the fibrin structure is largely influenced by the conditions in which fibrin has been polymerized, these conditions may have considerable impact on angiogenesis during wound healing and vascularization of tumour stroma.
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PMID:Influence of fibrin structure on the formation and maintenance of capillary-like tubules by human microvascular endothelial cells. 1451 71

Urokinase plasminogen activator (uPA), its cell-bound receptor (uPAR) and its main inhibitor plasminogen activator type 1 (PAI-1) are present primarily in stromal cells in invasive breast carcinoma. The purpose of this study was to investigate the regulation by 1,25 dihydroxyvitamin-D3 (VD3) of these invasion-associated markers expressed in breast cancer tumors under organ culture, which preserves the interacting network of tumor and stromal cells. Breast carcinoma slices (30 cases), obtained using the Krumdieck tissue slicer, cultured for 48 h in the presence or absence of 100 nM vitamin D3, were embedded in formalin-fixed paraffin. uPA, uPAR, PAI-1 and VD3 receptor (VDR) were analyzed by immunohistochemistry, and their expression, detected in tumor cells and fibroblasts of the specimens, was not statistically changed by culture conditions. The proportion of cases expressing uPA, uPAR and PAI-1 was not affected by VD3 in epithelial cells, but the fraction of cases displaying strong PAI-1 reactivity in fibroblasts was reduced ( P=0.016) compared with control slices. Fibroblasts isolated from invasive ductal carcinomas and from normal breast tissues expressed higher VDR mRNA levels than epithelial cells. In cultured tumor fibroblasts, PAI-1 immunostaining and mRNA levels were reduced by VD3-limiting fibroblast contribution to invasion.
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PMID:Vitamin D3 modulation of plasminogen activator inhibitor type-1 in human breast carcinomas under organ culture. 1465 54


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