Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.7 (plasmin)
 9,023 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Degradation of the extracellular matrix plays a crucial role in cancer invasion. This degradation is accomplished by the concerted action of several enzyme systems, including generation of the serine protease plasmin by the urokinase pathway of plasminogen activation, different types of collagenases and other metalloproteinases, and other extracellular enzymes. The degradative enzymes are involved also in tissue remodelling under non-malignant conditions, and the main difference appears to be that mechanisms which regulates these processes under normal conditions are defective in cancer. Specific inhibitors have been identified for most of the proteolytic enzymes, e.g. plasminogen activator inhibitors (PAI's) and tissue inhibitors of metalloproteinases (TIMP's). It has been contemplated that these inhibitors counteracted the proteolytic activity of the enzymes, thereby inhibiting extracellular tissue degradation which in turn should prevent tumor cell invasion. This review focuses on plasminogen inhibitor type 1 (PAI-1). It is described that PAI-1 is not produced by the epithelial cancer cell but by the stromal cells in the tumors, suggesting a concerted action between stroma and tumor cells in the processes controlling proteolysis in cancer. The specific localization of PAI-1 to the tumor stroma and in many cases to areas surrounding the tumor vessels has lead us to suggest that PAI-1 serves to protect the tumor stroma from the ongoing uPA-mediated proteolysis. This hypothesis is supported by recent clinical data showing increased levels of PAI-1 in metastases as compared to the primary tumor as well as data demonstrating that high levels of PAI-1 in tumor extracts from breast, lung, gastric and ovarian cancer is associated with a shorter overall survival.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Plasminogen activator inhibitor type 1 in cancer: therapeutic and prognostic implications. 766 68

Plasminogen activator inhibitor-1 (PAI-1) is the major inhibitor for plasmin formation promoted by tissue and urokinase plasminogen activators. The present study demonstrates that thrombin increase PAI-1 antigen, biological activity, and gene expression in cultured baboon aortic smooth muscle cells (BASMC). Thrombin elevates PAI-1 antigen in conditioned medium of BASMC within 10 min of the treatment, with the peak increase after 30 min of the treatment. Overexpression of PAI-1 gene was detected in the cultures exposed to thrombin for at least 60 min. PAI activity in conditioned medium increased in the cultures treated with thrombin for at least 4 h. The thrombin-induced early increase of PAI-1 antigen (up to 30 min of the stimulation) was blocked by hirudin (a specific inhibitor of thrombin), mimicked by trypsin and not suppressed by cycloheximide (a protein synthesis inhibitor). The majority of metabolically labeled PAI-1 associated with BASMC was present in extracellular matrix. The level of extracellular matrix-associated PAI-1 was reduced 40% by 30 min of thrombin treatment. Our results suggest that thrombin not only increases PAI-1 transcription but also proteolytically cleaves PAI-1 from the extracellular matrix of vascular SMC. PAI-1 released by thrombin from the extracellular matrix may not alter PAI activity in extracellular fluid but may reduce the storage of PAI-1 in the extracellular matrix of vascular smooth muscle cells.
 ...
PMID:Effect of thrombin on release of plasminogen activator inhibitor-1 from cultured primate arterial smooth muscle cells. 774 May 4

The plasminogen activator (PA)/plasmin system is thought to be involved in processes such as tumor invasion and wound healing, during which epithelial and mesenchymal cells come close together. However, information on regulation of the PA/plasmin system during epithelial-mesenchymal interactions is scarce. Therefore, we examined the in vitro modulation of the production and activity of the components of the PA/plasmin system in squamous carcinoma cells (SCC-4) and normal human keratinocytes in relation to cell density and the presence or absence of fibroblasts (3T3 cells). There was an inverse relation between cell density and mRNA expression for urokinase-type plasminogen activator (u-PA) and u-PA receptor in both SCC-4 cells and keratinocytes. In addition, such a relation was found for plasminogen activator inhibitor types 1 (PAI-1) and 2 (PAI-2) in SCC-4 monocultures, but not in keratinocyte monocultures. In contrast to monocultures, variation of cell density did not affect the mRNA expression of the components of the PA/plasmin system in cocultures of SCC-4 cells or keratinocytes with 3T3 cells. However, the relative expression of mRNAs in co-cultures was clearly different from that in monocultures, especially at low cell density. For most of the components of the PA/plasmin system, a decrease in mRNA expression and u-PA receptor protein was observed at most cell densities, whereas for PAI-1 only in keratinocytes a marked increase was documented. Zymography of supernatants revealed that the levels of both free u-PA and PA-PAI were increased in SCC-4/3T3 co-cultures, whereas in keratinocytes/3T3 co-cultures, only levels of the PA-PAI complex were increased, while the amount of free u-PA activity decreased. This occurred despite the increase u-PA immunoreactivity and was probably caused by the markedly elevated levels of immunoreactive PAI-1. The results of the present study reveal that the production and synthesis of various components of the PA/plasmin system in keratinocytes and SCC-4 cells depend on the density of epithelial cells and are modulated by fibroblasts, probably through a direct cell-cell or cell-matrix contact. Fibroblast-induced modulations are similar in keratinocytes and SCC-4 cells except for the regulation of PAI-1, which is markedly enhanced only in keratinocytes. This suggests that the modulation of PA activity in the direct microenvironment may be different under physiologic and pathologic conditions.
 ...
PMID:Differential regulation of plasminogen activation in normal keratinocytes and SCC-4 cells by fibroblasts. 786 Oct 5

The effects of coronary thrombolytic therapy with urokinase on the intrinsic hemostatic and fibrinolytic states were investigated by determining several markers for hemostatic and fibrinolytic activities in 6 patients with acute myocardial infarction who underwent coronary thrombolysis with urokinase. The markers for hemostasis and fibrinolysis were: markers for plasmin generation [alpha 2-plasmin inhibitor (alpha 2-PI), plasminogen, plasmin alpha 2-PI complex (PIC)]; markers for fibrinolysis [fibrin/fibrinogen degradation products-E fragment (FDP-E), FDP D-D dimer (D dimer), fibrinogen]; markers for hemostatic activity (prothrombin time (PT), antithrombin III (AT-III), protein C); markers for thrombin generation [thrombin antithrombin III complex (TAT)]; markers for intrinsic fibrinolytic activity [tissue plasminogen activator plasminogen activator inhibitor complex (TPA PAI complex)]. These markers were measured before, at 1 to 2 hours intervals during first 6 hours, daily during the next 3 days, and subsequently on the 7th and the 14th day after urokinase therapy. Fibrinolysis (determined by increased D dimer) occurred only when alpha 2-PI became unmeasurable with 96 x 10(4) or more units of urokinase administration, then persisted for more than 2 hours. TAT increased from 13.1 +/- 15.4 to 70.8 +/- 65.8 ng/ml soon after fibrinolysis occurred, indicating that thrombin generation occurred at the same time as fibrinolysis. The TPA PAI complex level before urokinase administration (26.4 +/- 6.4 ng/ml) was greater than the normal upper limit, indicating increased intrinsic fibrinolytic activity, then decreased after urokinase administration. These findings suggested that urokinase administration might affect the intrinsic fibrinolytic activity.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:[Serial changes in hemostatic and fibrinolytic states induced by coronary thrombolytic therapy]. 806 82

Plasma levels of tissue-type plasminogen activator antigen (t-PA:Ag), plasminogen activator inhibitor-1 antigen (PAI-1:Ag), the active form of PAI-1 (active PAI) and t-PA.PAI-1 complex (PAI-C) were analyzed in 7 patients with disseminated intravascular coagulation (DIC) syndrome. The levels of t-PA:Ag and PAI-C decreased after amelioration of DIC in 6 patients whose underlying disease improved, but their PAI-1:Ag and active PAI showed various fluctuations. The levels of t-PA:Ag and PAI-C showed a good correlation of r = 0.885. The levels of t-PA:Ag or PAI-C showed an inversed correlation with platelet counts, and correlations with the levels of plasmin.alpha 2PI complex, D dimer and E fragments of FDP. It was considered that plasma levels of PAI-C reflected levels of t-PA released from the endothelial cells, which was related to acceleration of fibrinolysis in DIC patients with improved underlying disease. On the other hand, these levels remained high in a patient whose underlying disease did not improve after recovering from DIC. It was considered that the stimulation of endothelial cells by cancer cells continued to exert an effect.
 ...
PMID:[Fluctuations of tissue-type plasminogen activator.plasminogen activator inhibitor-1 complex in patients with DIC]. 806 36

The fibrinolytic response to a venous occlusion test was evaluated in 116 consecutive patients who had each had early recurrent miscarriages of unknown origin. A normal response to venous occlusion was defined from the statistical analysis of data obtained in a matched group of 90 women with no past abortion. Seventy-four patients had at least one abnormal fibrinolysis-related test, whereas no member of the control group had any (p < 10(-6)). Fifty-six of the patients had a stasis-induced shortening of the euglobulin clot lysis time that was less than normal (median decrement 3.5% [normal > or = 28%] [p < 10(-6)]). In this subgroup, 17 women also had a poor tissue-type plasminogen activator (tPA) response (median increment 18% [normal > or = 34%] [p < 0.001]). Twenty-one of the 56 had high plasma levels of type 1 plasminogen activator inactivator (PAI-1) as well as a high PAI activity level (p < 0.001 for comparison with normal controls). Sixteen patients had both abnormalities (tPA response blunted and high PAI values). When retested in the same patients, the patterns persisted over time. Nine other habitual aborters had abnormally high type 2 plasminogen activator inhibitor plasma levels (> 4.2 ng/ml). Six other patients had a poor urokinase-type plasminogen activator reactivity to venous occlusion (post-stasis levels lower than 0.18 ng/ml). Thus activators and inhibitors of the fibrinolytic system are frequently abnormal in primary habitual aborters. The current pathogeneses of high PAI-1 concentrations and of impaired tPA reactivity to venous occlusion were not found in these patients. The role of the fibrinolytic components in trophoblast invasiveness has been suspected in animals, and an impaired plasmin-dependent proteolysis in women might favor recurrent abortion by promoting fibrin deposition in early placental circulation or by limiting trophoblast development, or both.
 ...
PMID:Plasma fibrinolytic activators and their inhibitors in women suffering from early recurrent abortion of unknown etiology. 822 80

We found that patients with thrombotic thrombocytopenic purpura (TTP) have significantly elevated plasma thrombin antithrombin III complex (TAT) and FDP-D-dimer levels, while the plasmin-alpha 2 plasmin inhibitor complex (PIC) level was only slightly increased. The tissue-type plasminogen activator (t-PA) level was increased, but it was well correlated with the plasminogen activator inhibitor-I (PAI-I) level. These findings suggest that hypercoagulable and hypofibrinolytic states coexist in these patients, in contrast to patients with disseminated intravascular coagulation, who exhibit coexisting hypercoagulable and hyperfibrinolytic states. Levels of vascular endothelial cell markers, such as PAI-I, thrombomodulin (TM), and t-PA, were increased at the onset of TTP, but the level of von Willebrand factor (vWF) antigen was not increased. The outcome in TTP patients was correlated with plasma t-PA and TM levels but not with TAT or PIC. These results suggest that vascular endothelial cell markers, such as TM and t-PA, are released from injured or stimulated endothelial cells, reflecting the degree of vascular endothelial damage, and that the main factor in the pathogenesis of TTP is vascular endothelial cell injury.
 ...
PMID:Increased levels of vascular endothelial cell markers in thrombotic thrombocytopenic purpura. 826 13

We examined vascular endothelial cell markers, thrombomodulin (TM), plasminogen activator inhibitor-I (PAI-I), tissue plasminogen activator (t-PA), and von Willebrand factor, in 80 patients with disseminated intravascular coagulation (DIC). The levels of thrombin-antithrombin III complex (TAT), plasmin-alpha 2 plasmin inhibitor complex (PIC) and FDP-D-dimer were significantly increased both before and after the onset of DIC, but were not correlated with organ failure or prognosis. However, the PIC/TAT ratio was lower in patients with poor prognosis than in those with good prognosis, and it was also lower in those with organ failure than in those without. Plasma TM, PAI-I, and t-PA levels were increased in DIC patients with organ failure or poor outcome, but were not significantly increased before the onset of DIC. We consider that the prognosis of patients with DIC might be related to organ failure or endothelial cell damage and that plasma levels of TM, PAI-I, and t-PA might be useful in the detection of these disorders and in assessing prognosis. A hypofibrinolytic state might enhance organ failure in patients with DIC.
 ...
PMID:Increased vascular endothelial cell markers in patients with disseminated intravascular coagulation. 826 24

Urokinase (u-PA) and the urokinase receptor (u-PAR), are thought to play a critical role in the invasive and metastatic properties of cancer cells. The HT29 human colon-carcinoma cell line was selected to evaluate these aspects. HT29 cells express u-PA receptors (100,000 sites/cell, KD = 1.5 nM), but no PA activity and therefore are unable to generate plasmin in the presence of plasminogen. These cells have been transfected with a human u-PA cDNA to investigate whether secreted u-PA would enhance in vitro extracellular matrix degradation, and whether the binding of u-PA to the cell surface is determinant. Five clones were selected for stable expression of high PA activity. These clones were capable of marked plasminogen-dependent degradation of R22 smooth-muscle-cell-derived extracellular matrix, whereas the parental cell line contributed to an insignificant breakdown only. Aprotinin, polyclonal anti-u-PA IgG, recombinant PAI-2, and co-culture with human PAI-I-producing mouse L cells significantly inhibited this degradation. Furthermore, a peptide displacing u-PA from its receptor as well as 2 different polyclonal anti-u-PA receptor IgGs decreased the breakdown after 24 hr by as much as 70% and 81%, respectively. These results show that the binding of u-PA to its receptor plays an important role in in vitro matrix breakdown by HT29 u-PA transfectants.
 ...
PMID:The role of the urokinase receptor in extracellular matrix degradation by HT29 human colon carcinoma cells. 838 94

Three major components of the plasminogen activators (PA)/plasmin system are synthesized physiologically in glomeruli, and can be involved in glomerular proteolysis and extracellular matrix metabolism: tissue-type PA (tPA), urokinase (uPA) and PA inhibitor type 1 (PAI-1). To explore the possible role of a dysregulation of the plasmin protease system in the development and progression of lupus-like glomerulonephritis, we studied the expression of the renal plasmin protease components during the course of the disease, either acute, induced by IgG3 monoclonal cryoglobulins, or chronic, occurring spontaneously in three different lupus-prone mice: (NZBxNZW)F1, BXSB and MRL-lpr/lpr. RNase protection assays and in situ hybridizations revealed a marked glomerular induction of PAI-1 mRNA abundance without any significant changes in renal tPA and uPA mRNA levels in the two different types of lupus-like glomerulonephritis. The overexpression of PAI-1 mRNA occurred in parallel with a significant decrease in glomerular tPA-catalyzed enzymatic activity as determined by zymographic analysis. In addition, a concomitant increase in glomerular expression of transforming growth factor beta 1 (TGF-beta 1) mRNA was observed. The demonstration of a close correlation between the PAI-1 and TGF-beta 1 mRNA levels and the severity of lupus-like glomerular lesions suggests that a pertubation of the glomerular PA/PAI balance, resulting from a marked TGF-beta 1-mediated induction of PAI-1 gene expression, plays an important role in the progression of lupus-like glomerular lesions, leading to glomerulosclerosis.
 ...
PMID:Induction of plasminogen activator inhibitor type 1 in murine lupus-like glomerulonephritis. 854 2


<< Previous 1 2 3 4 5 6 7 8 Next >>