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:3.4.21.7 (plasmin)
9,023 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human tissue factor pathway inhibitor-2 (TFPI-2), also known as placental protein (PP5) and matrix-associated serine protease inhibitor (MSPI), is a 32-kDa extracellular matrix (ECM) protein consisting of three tandomly arranged Kunitz-type domains that inhibits plasmin, trypsin, chymotrypsin, cathepsin G and plasma kallikrein but not urokinase and tissue-type plasminogen activators or thrombin. Earlier studies in our laboratory revealed that the production of TFPI-2 is reduced or absent during the tumor progression of human gliomas. In the present study, we investigated the role of TFPI-2 in the invasiveness of the amelanotic melanoma cell line C-32. We stably transfected C-32 cells with a vector capable of expressing TFPI-2 in a sense orientation (0.7 kb). TFPI-2 protein production was then determined by western blotting and the mRNA level by northern blotting in parental and stably transfected (vector and sense) clones. The levels of TFPI-2 protein and mRNA were significantly higher in the sense clones, but neither was detected in parental and vector control clones. In addition, in vitro Matrigel invasion/migration assays revealed that the invasive behavior of sense clones was inhibited compared with the behavior of parental and vector clones. This is the first study to show that the upregulation of TFPI-2 plays a significant role in reducing the invasive behavior of human amelanotic melanomas.
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PMID:Role of tissue factor pathway inhibitor-2 (TFPI-2) in amelanotic melanoma (C-32) invasion. 1144 60

Protease nexin-1 (PN-1) is a serine protease inhibitor (serpin) that inactivates several proteases, including thrombin, urokinase, plasminogen activators (PA), and plasmin. It also plays a role in regulating proteolytic activity generated by PA system. PN-1 is known to be involved in tissue remodeling, cellular invasiveness, matrix degradation, and tumor growth. However, the role of PN-1 in female reproductive tracts, such as the uterus, ovary, and oviduct, during pregnancy is not known. The present study was designed to investigate the changes of PN-1 mRNA level and localization in the tracts during implantation and early pregnancy by using reverse transcription (RT)-polymerase chain reaction (PCR) and in situ hybridization. We found that PN-1 mRNA levels were coordinately regulated during early pregnancy in a stage- and tissue-specific manner, such that an increased expression of PN-1 gene appeared at the time of the implantation period in the uterus and ovary. Both the uterus and ovary synthesized PN-1 mRNA and their maximal PN-1 expression occurred on Day 6.5 postcoitum (p.c.). On 13.5 days of pregnancy, PN-1 level was low in the uterus and ovary. On the other hand, PN-1 mRNA in the oviduct did not show after 6.5 days of pregnancy. It appears that PN-1 mRNA in the uterus and ovary was highly regulated during early pregnancy, which might have an important role in implantation of rat blastocysts. PN-1 was localized in endometrial stromal cells of the uterus and in granulosa cells of the unstimulated primary follicles in the ovary during periimplantation period. Also, PN-1 mRNA expression was higher at implantation period than that at nonimplantation period of pregnancy. In conclusion, PN-1 is expressed in female reproductive tracts and highly regulated during implantation and early pregnancy.
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PMID:Increased expression and localization of a serine protease inhibitor, protease nexin-1 (PN-1), in the ovary and uterus during implantation in rat. 1145 71

Tissue factor pathway inhibitor-2 (TFPI-2) is a 32 kDa serine protease inhibitor found at high levels in extracellular matrix. Recombinant human TFPI-2 has recently been shown to be a strong inhibitor of trypsin, plasmin, plasma kallikrein, and factor XIa amidolytic activity. Earlier studies in our laboratory showed that the expression of TFPI-2 is lost during tumor progression in human gliomas. We stably transfected this protease inhibitor in multiform glioblastoma cell line (SNB-19) and in low-grade glioma cell line (Hs683) in sense and antisense orientation respectively. This confirmed that the upregulation/down-regulation of TFPI-2 plays a significant role in the invasive behavior of human gliomas both in vitro and in vivo models. Collectively, these results suggested an idea to determine whether TFPI-2 is necessary for cell survival and inhibition of tumor formation in nude mice, due to apoptosis of intracerebrally injected SNB-19 cells. In the present study we determined p-ERK levels and found that they are decreased in TFPI-2 over-expressed clones (SNB-19) and increased in TFPI-2 down-regulated clones (Hs683). We also checked the levels of BAX/BCl-2, caspases (for e.g., 9, 7, 3, 8), PARP, cytochrome-c and Apaf-1. Moreover, the increase of apoptosis in vitro is associated with increased and decreased expression of apoptotic protein BAX in sense clones (SNB-19) and antisense clones (Hs683) respectively, when compared to controls and vice versa with Bcl-2 the anti-apoptotic protein. Caspases (9, 7 and 3), cytochrome-c, Apaf-1 and PARP levels are increased in SNB-19 and decreased in Hs683. Caspase 8 was not expressed in either cell line. Caspases 9 and 3 activity assay revealed higher activity in sense clones (SNB-19) but lesser in antisense clones (Hs683) compared to controls. This is the first report of TFPI-2 playing a novel role in cell survival in human gliomas.
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PMID:A novel role of tissue factor pathway inhibitor-2 in apoptosis of malignant human gliomas. 1149 41

The new serine protease inhibitor, ONO-3403 is an analog of FOY-305 (Foypan). The IC50s values of ONO-3403 toward serine proteases, such as trypsin, plasmin, kallikrein and thrombin are much lower than that of FOY-305. To investigate the growth-suppressing effect of ONO-3403 on 3-methylcholanthrene-induced autochthonous solid tumors in mice, ONO-3403 was intraperitoneally administered to mice at a dose of 4 mg/kg twice a day for 5 weeks. All seven mice receiving the drug had a solitary tumor and showed potent growth suppression (p<0.001) without any apparent side effects such as hair loss and body weight loss. The results suggest that ONO-3403 may be useful for the treatment of squamous cell carcinoma.
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PMID:Growth inhibition of mouse skin tumor by serine protease inhibitor ONO-3403. 1149 62

Previously, we demonstrated that amorphous calcium phosphate (ACP), chemical precursor to apatite, strongly interacted with fibrin and facilitated binding of matrix metalloproteinase (MMP)-9, a type IV collagenase. Plasmin-dependent fibrinolysis resulted in coordinate MMP-9 activation. Here we report on the effect(s) of ACP on fibrin degradation and binding of endogenous plasma proteases. Electrophoresis (8.5% SDS-PAGE) revealed that fibrin formed in the presence of ACP demonstrated characteristic gamma-gamma dimers (90-kDa) and beta-monomers (55-kDa), but resisted spontaneous fibrinolysis (72 h, 37 degrees C) or degradation by plasminogen activators (uPA, tPA). Casein zymography revealed an ACP-dependent decrease in fibrin binding of a low molecular weight (Mw) protease triplet (47-, 43-, 42-kDa) and increased fibrin binding of two high Mw proteases (94- and 84-kDa). The low Mw triplet also possessed gelatinolytic activity, but was not an MMP since 1,10-phenanthroline was ineffective as an inhibitor. Fibrin-binding proteases were inhibited to some degree by the serine protease inhibitor aprotinin. Competition/dissociation experiments with epsilon-aminocaproic acid revealed that the low Mw triplet lacked kringle regions whereas the 94- and 84-kDa proteases were tentatively identified and glu-/lys-plasmin(ogen)s. The triplet may, however, represent one or more kringle deficient mini-plasminogen(s), since electrophoretic mobility and substrate specificity was similar to elastase-generated mini-plasminogen. To explore these findings in a clinically relevant setting, a series of plasma samples was collected from a patient with unstable angina prior to, during, and post coronary artery bypass graft (CABG) surgery. Fibrin formed from plasma collected during and immediately post CABG was associated with increased fibrinolytic capacity and enhanced binding of a) MMP-9, b) the low Mw protease triplet (described above), and c) PA (as putative 110-kDa tPA:PAI-1 complex). The relevance of these findings to pathologic calcification of atherosclerotic plaques is discussed.
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PMID:Interaction of amorphous calcium phosphate with fibrin in vitro causes decreased fibrinolysis and altered protease profiles: implications for atherosclerotic disease. 1182 Apr 59

Tissue factor pathway inhibitor-2 (TFPI-2) is a Kunitz-type, serine protease inhibitor with inhibitory activity toward activated factor XI, plasma kallikrein, plasmin, certain matrix metalloproteinases, and the tissue factor:activated factor VII complex. In this study, we investigated TFPI-2 expression and localization in normal and atherosclerotic human arteries by using in situ hybridization and immunohistochemical techniques. In healthy human blood vessels, TFPI-2 was detected in the vascular endothelium alone. In human atherosclerotic tissues, TFPI-2 expression was assigned to macrophages, T cells, endothelial cells, and smooth muscle cells. Western blot analysis for TFPI-2 confirmed its production by cultured human aortic smooth muscle cells, U937 cells (monocytes), and Jurkat (T cell) cell lines. Reverse transcription-polymerase chain reaction revealed similar TFPI-2 expression levels in both monocytes and macrophages in culture. Electron microscopic study with immunogold labeling revealed the association of TFPI-2 antigen with both the extracellular matrix and plasma membranes. TFPI-2 antigen was detected in some areas of atheroma that also stained positively for both tissue factor and factor VII. Moreover, detection of TFPI-2 in close spatial proximity to plasmin/plasminogen on macrophages, on endothelial cells, and in matrix-rich areas highlighted its possible functional significance in the regulation of plasmin activity and downstream proteolytic mechanisms that occur in the atherosclerotic lesion.
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PMID:Expression and localization of tissue factor pathway inhibitor-2 in normal and atherosclerotic human vessels. 1183 19

Mesangial cells maintain normal glomerular function by mediating ECM remodeling and immune complex disposal. We have recently identified megsin, a novel member of the serine protease inhibitor (serpin) superfamily predominantly expressed in the mesangium. While our previous studies suggested a role for megsin in the pathogenesis of human glomerular diseases, its exact biological significance remained unknown. Here we produced two lines of megsin transgenic mice. Overexpression of megsin led to progressive mesangial matrix expansion and an increase in the number of mesangial cells. These glomerular lesions were accompanied by an augmented immune complex deposition, together with Ig's and complement. Binding and functional assays in vitro identified plasmin as one biological substrate of megsin and confirmed its activity as a proteinase inhibitor. Transgenic animals exhibiting nephritis as a result of treatment with anti--glomerular basement membrane antiserum showed significantly more persistent expansion of the mesangial ECM than was seen in parental mice. Megsin therefore exerts a biologically relevant influence on mesangial function, and on the mesangial microenvironment, such that simple overexpression of this endogenous serpin engenders elementary mesangial lesions.
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PMID:Overexpression of the serpin megsin induces progressive mesangial cell proliferation and expansion. 1187 66

Angiostatin, a plasminogen fragment containing 3-4 N-terminal kringle domains, is a potent inhibitor of tumor-induced angiogenesis, but its mechanism of action is unclear. Angiostatin is a ligand for integrin alphavbeta(3) but does not induce stress fiber formation upon integrin binding, suggesting that angiostatin is a potential integrin antagonist. Plasmin, the parent molecule of angiostatin and a major extracellular protease, induces platelet aggregation, migration of peripheral blood monocytes, and release of arachidonate and leukotriene from several cell types. In the current study, we found that plasmin specifically bound to alphavbeta(3) through the kringle domains and induced migration of endothelial cells. In contrast, angiostatin did not induce cell migration. Notably, angiostatin, anti-alphavbeta(3) antibodies, RGD-peptide, and a serine protease inhibitor effectively blocked plasmin-induced cell migration. These results suggest that plasmin-induced migration of endothelial cells requires alphavbeta(3) and the catalytic activity of plasmin and that this process is a potential target for the inhibitory activity of angiostatin.
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PMID:Plasmin-induced migration of endothelial cells. A potential target for the anti-angiogenic action of angiostatin. 1208 8

This work describes the purification, gene cloning and expression of infestin, a thrombin inhibitor from midguts of Triatoma infestans. Infestin is located in the midgut and its purification was performed by anion-exchange and affinity chromatographies. The N-terminal sequence and the sequence of tryptic peptides were determined. Using RT-PCR, total RNA and infestin cDNA information, a DNA fragment was cloned which encodes a multi non-classical Kazal-type serine protease inhibitor. Isolated native infestin has two non-classical Kazal-type domains and shows an apparent molecular mass of 13 kDa, while its gene codes for a protein with four non-classical Kazal-type domains corresponding to an apparent molecular mass of 22 kDa. Two recombinant infestins, r-infestin 1-2 and r-infestin 1-4, were constructed using the vector pVT102U/alpha and expressed in S. cerevisiae. Native and r-infestin 1-2 showed very similar inhibitory activities towards thrombin and trypsin with dissociation constants of 43.5 and 25 pM for thrombin and 2.0 and 3.1 nM for trypsin, respectively. No other serine protease of the blood coagulation cascade was inhibited by the r-infestin 1-2. Surprisingly, r-infestin 1-4 inhibited not only thrombin and trypsin (K(i) of 0.8 and 5.2 nM, respectively), but also factor XIIa, factor Xa and plasmin (K(i) of 78 pM, 59.2 and 1.1 nM, respectively).
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PMID:Infestin, a thrombin inhibitor presents in Triatoma infestans midgut, a Chagas' disease vector: gene cloning, expression and characterization of the inhibitor. 1221 35

Aqueous extracts of Schistosoma mansoni eggs have been shown to have fibrinolytic activity inhibitable by a serine protease inhibitor. Fibrinolytic activity was not present in extracts of either adult worms or cercariae. A 27 kDa enzyme that was proteolytically active on fibrinogen in zymography and that degraded fibrinogen in a pattern similar to that of plasmin, is presumed to be responsible for the schistosome egg fibrinolytic activity. Anti-human fibrinogen antisera were shown to have antibodies that cross-reacted with mouse fibrinogen in Western immunoblots. Electroblotted sera from S. mansoni-infected and control uninfected mice displayed different antigenic profiles when probed with the cross-reactive anti-human fibrinogen antibodies, suggesting an alteration in mouse host fibrinogen metabolism as a result of the parasitic infection. We discuss the possibility that modulation of fibrinogen metabolism is a factor in a recently discovered anti-atherogenic effect exerted by schistosomes.
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PMID:Identification of a fibrinolytic enzyme in Schistosoma mansoni eggs and modulated blood fibrinogen metabolism in S. mansoni-infected mice. 1266 81


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