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:3.4.21.73 (urokinase-type plasminogen activator)
10,685 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mammalian bladder epithelium functions as an effective permeability barrier. We demonstrate here that this epithelium can also function as a secretory tissue directly involved in modifying urinary protein composition. Our data indicate that normal bovine urothelium synthesizes, as its major differentiation products, two well-known proteases: tissue-type plasminogen activator and urokinase, as well as a serine protease inhibitor, PP5. Moreover, we demonstrate that the urothelium secretes these proteins in a polarized fashion into the urine via a cAMP- and calcium-regulated pathway. Urinary plasminogen activators of ruminants are therefore urothelium derived rather then kidney derived as in some other species; this heterogeneity may have evolved in response to different physiological or dietary factors. In conjunction with our recent finding that transgenic mouse urothelium can secrete ectopically expressed human growth hormone into the urine, our data establish that normal mammalian urothelium can function not only as a permeability barrier but also as a secretor of urinary proteins that can play physiological or pathological roles in the urinary tract.
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PMID:Urothelial function reconsidered: a role in urinary protein secretion. 1113 52

Sepimostat mesilate (FUT-187: 6-amidino-2-naphthyl 4-[(4,5-dihydro-1H-imidazol-2-yl) amino] benzoate dimethane sulfonate) is a newly synthesized serine protease inhibitor. In the present study, the oral administration of FUT-187 inhibited stasis-induced venous thrombosis in rats. We supposed that such effect of this compound was caused by its inhibitory effect on coagulation. However, the dose of FUT-187 that was effective at inhibiting thrombosis (10 and 30 mg/kg, po) had no effect on the plasma recalcification time (PRCT), activated partial thromboplastin time (APTT) and prothrombin time (PT) in rats. Therefore, we investigated the fibrinolytic activity of FUT-187 in rat plasma. The results revealed that rat plasma after FUT-187 administration exhibited increased amidolytic activity for a plasmin-, tissue-type plasminogen activator (t-PA)-, urokinase-type plasminogen activator (u-PA)-, factor Xa-, factor XIa- and factor XIIa-sensitive synthetic peptide substrate. On the other hand, the inhibitory effect of FUT-187 in the thrombosis model was not affected by additional treatment with epsilon-amino-n-caproic acid (EACA), a plasmin-mediated fibrinolysis inhibitor. These results suggest that even if FUT-187 enhanced fibrinolysis, it would be independent of a plasmin-mediated fibrinolytic pathway. To characterize the fibrinolytic activity, which might reduce the thrombus weight in the thrombosis model administered FUT-187, we carried out fibrinogen zymography, and clarified that FUT-187 enhanced the formation of a 20-kDa fibrinolytic fragment. Interestingly, this fragment was not affected by t-PA. Consequently, we consider that the inhibitory effect of FUT-187 on venous thrombosis model is caused by fibrinolysis, which is attributable to the 20-kDa fragment, rather than by inhibition of thrombus formation.
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PMID:Effect of sepimostat mesilate on experimental venous thrombosis in rats. 1122 42

Plasminogen activator inhibitor type 2 (PAI-2) is a serine protease inhibitor that inhibits urokinase. Constitutive and regulated PAI-2 gene expression involves post-transcriptional events, and an AU-rich mRNA instability motif within the 3'-untranslated region of PAI-2 mRNA is required for this process (Maurer, F., Tierney, M., and Medcalf, R. L. (1999) Nucleic Acids Res. 27, 1664-1673). Here we show that instability determinants are present within various exons of the PAI-2 coding region, most notably within exon 4. Deletion of exon 4 from the full-length PAI-2 cDNA results in a doubling in the half-life of PAI-2 mRNA, whereas a 28-nucleotide region within exon 4 contains binding sites for cytoplasmic proteins. Inducible stabilization of PAI-2 mRNA in HT-1080 cells treated with phorbol ester and tumor necrosis factor does not alter the binding of proteins to the exon 4 instability determinant, but resulted in a transient increase in the binding of factors to the AU-rich RNA instability element. Hence, PAI-2 mRNA stability is influenced by elements located within both the coding region and the 3'-untranslated region and that cytoplasmic mRNA binding factors may influence steady state and inducible PAI-2 mRNA expression. Finally a 10-nucleotide region flanking the exon 4 protein-binding site is homologous to instability elements within five other transcripts, suggesting that a common coding region determinant may exist.
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PMID:Plasminogen activator inhibitor type 2 contains mRNA instability elements within exon 4 of the coding region. Sequence homology to coding region instability determinants in other mRNAs. 1127 13

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

Plasminogen activator inhibitor-1 (PAI-1) is a serine protease inhibitor (SERPIN) specific for tissue-type and urokinase-like plasminogen activators. High plasma PAI-1 activity is a risk factor for thrombotic diseases. Due to the short half-life of PAI-1, regulation of PAI-1 gene expression and secretion of active PAI-1 into the blood stream is important for hemostatic balance. We have investigated transcriptional control of PAI-1 gene expression in bovine aortic endothelial cells (BAECs) and human cell lines using PAI-1 5' promoter-luciferase reporter assays. Contrary to the cytokine-induced up-regulation of PAI-1 mRNA and protein levels, we found that only transforming growth factor-beta (TGF-beta) was efficient in inducing PAI-1 promoter activation. Tissue necrosis factor-alpha (TNF-alpha) induced a small luciferase activity with the 2.5 kb PAI-1 promoter, but not with the PAI-800/4G/5G and p3TP-lux promoters. Next we investigated whether a lack of response to TNF-alpha was due to deficient signaling pathways. BAECs responded to TNF-alpha with robust NFkappaB promoter activation. TGF-beta activated the p38 MAP kinase, while TNF-alpha activated both the SAPK/JNK and p38 MAP kinases. The ERK1/2 MAP kinases were constitutively activated in BAECs. BAEC therefore responded to TNF-alpha stimulation with activation of the MAP kinases and the NFkappaB transcriptional factors. We further measured the messenger RNA stability under the influence by TGF-beta and TNF-alpha and found no difference. PAI-1 gene activation by TNF-alpha apparently is yet to be defined for the location of the response element and/or the signaling pathway, while TGF-beta is the most important cytokine for PAI-1 transcriptional activation through its 5' proximal promoter.
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PMID:Differential mechanisms of plasminogen activator inhibitor-1 gene activation by transforming growth factor-beta and tumor necrosis factor-alpha in endothelial cells. 1177 28

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

Plasminogen activator inhibitor-1 (PAI-1) is a serine protease inhibitor that was isolated 20 years ago. First recognized as an inhibitor of intravascular fibrinolysis, it is now evident that PAI-1 is a multifunctional protein with actions that may be dependent on or independent of its protease inhibitory effects. The latter often involve interactions between PAI-1 and vitronectin or the urokinase receptor. The protease-inhibitory actions of PAI-1 extend beyond fibrinolysis and include extracellular matrix turnover and activation of several proenzymes and latent growth factors. PAI-1 has been implicated in several renal pathogenetic processes, including thrombotic microangiopathies and proliferative and/or crescentic glomerulopathies. Most recently, it has become clear that PAI-1 also plays a pivotal role in progressive renal disease, both glomerulosclerosis and tubulointerstitial fibrosis. An active area of present research interest, untold stories are likely to be uncovered soon.
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PMID:Plasminogen activator inhibitor-1 and the kidney. 1211 May 4

Plasminogen activator inhibitor-1 (PAI-1), an inhibitor of urokinase plasminogen activator, is paradoxically associated with a poor prognosis in breast cancer. PAI-1 is linked to several processes in the metastatic cascade. However, the role of PAI-1 in metastatic processes, which may be independent of protease inhibitory activity, is not fully understood. We report herein that PAI-1, when added exogenously to or stably transfected in human MDA-MB-435 breast carcinoma cells, had disparate effects on adhesion to extracellular matrix proteins and motility in vitro. Specifically, exogenously added PAI-1 inhibited cell adhesion to vitronectin but not fibronectin, in agreement with the literature. By contrast, stably transfected PAI-1 stimulated adhesion to both proteins. Wild-type PAI-1 was required for this stimulation, because expression of a non-protease inhibitory P14 (T333R) PAI-1 mutant failed to enhance adhesion. Compared with non-inhibitory PAI-1, wild-type PAI-1 also increased cell motility in chemotaxic assays. Furthermore, stable transfection of a related serine protease inhibitor, plasminogen activator inhibitor-3 (PAI-3, or protein C inhibitor) gave results similar to wild-type PAI-1. The stimulatory activity of PAI-3 was not seen with a non-protease inhibitory P14 PAI-3 mutant (T341R). We show that a downstream effect of endogenous wild-type PAI-1 and PAI-3 overexpression, but not their non-inhibitory counterparts, was the altered expression of alpha(2), alpha(3), alpha(4), alpha(5), and beta(1) integrin subunits. Additionally, blocking antibodies to beta(1) integrin inhibited PAI-1-induced adhesion. Our data provide experimental support for the stimulatory and inhibitory effects of PAI-1 in metastasis and introduce PAI-3 as another serpin potentially important in malignant disease.
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PMID:Plasminogen activator inhibitor-1 and -3 increase cell adhesion and motility of MDA-MB-435 breast cancer cells. 1217 77

Muscle cell migration plays an important role in the incorporation of transplanted myoblasts in muscle fibers. Understanding the mechanisms underlying the high migration capacity of the C(2)C(12) myoblast cell line may help to develop approaches to improve the migration of normal myoblasts and consequently to increase their participation to the host myofiber regeneration. We have previously shown that matrix metalloproteinases are implicated in the in vivo migration of C(2)C(12). Here, we studied the role of urokinase plasminogen activator (uPA) in this process. The expression of uPA mRNA and the enzymatic activity of uPA were studied in both normal myoblasts and the C(2)C(12) myoblast cell line. Reverse transcriptase polymerase chain reaction analysis showed that uPA mRNA was more strongly expressed in C(2)C(12) cells than in normal myoblasts. The enzymatic activity of secreted uPA analyzed by casein zymography is higher in medium conditioned by C(2)C(12) cells than in medium conditioned by normal myoblasts. Using our previously described microtube technique to assess in vivo cell migration, we showed that uPA is implicated in the in vivo migration of C(2)C(12) cells since this migration was abrogated in the presence of aprotinin (a general serine protease inhibitor) or amiloride (a uPA-specific inhibitor). We, therefore, hypothesized that increasing endogenous uPA expression by normal myoblasts may improve their migration capacity. Since an accumulating body of evidence has shown that growth factors regulate expression of uPA in a wide range of cells, we treated normal myoblasts with several growth factors alone or in combination with components of the extracellular matrix (ECM). All stimulants tested showed a minimal to strong effect on uPA enzymatic activity as assayed by zymography analysis. The positive effect of basic fibroblast growth factor (bFGF) on uPA enzymatic activity was slightly potentiated in the presence of fibronectin. Moreover, the pretreatment and coinjection of mouse myoblasts with bFGF alone or in combination with fibronectin improved significantly their in vivo migration throughout the tibialis anterior muscle of mdx mice. These results suggest that increasing uPA expression by an appropriate combination of growth factors and ECM components constitutes a possible approach to improving the migration of myogenic cells after transplantation.
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PMID:The urokinase plasminogen activator: an interesting way to improve myoblast migration following their transplantation. 1241 83


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