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)

Laminin and fibronectin are glycoproteins that influence cell behavior and mediate cell/substratum adhesion. We have examined the interaction of these macromolecules with the serine protease plasminogen activator (PA) in two types of extracellular matrices; one produced by the murine Engelbreth-Holm-Swarm (EHS) tumor (Matrigel), and another by normal kidney epithelial cells in culture. Matrigel was found to contain significant quantities of tissue-type PA (tPA). Two of the major components of Matrigel, laminin and type IV collagen, were also examined. Tissue-type PA was associated with purified preparations of laminin; however, it was not found associated with type IV collagen. Normal kidney epithelial cells in culture secrete large amounts of urokinase (UK) and deposit a subepithelial matrix containing both laminin and fibronectin. These matrix macromolecules were isolated from the deposited matrix by immunoprecipitation, examined by zymography, and found to contain UK. The potential role of this interaction in the mechanisms of cell migration and matrix remodeling is discussed.
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PMID:The interaction of plasminogen activator with a reconstituted basement membrane matrix and extracellular macromolecules produced by cultured epithelial cells. 250 31

Mucoid effusions from 39 children with secretory otitis media, altogether 42 specimens, were analyzed for proteolytic activity using radial caseinolysis procedures, for fibronectin using a solid-phase enzyme immunoassay, and for fibronectin fragmentation using immunoblotting. All samples contained proteolytic activity, tentatively identified as plasmin on the basis of comigration with purified human plasmin in zymographic analysis. In 19 specimens the plasmin level exceeded 1 microgram/mg of protein; the highest value recorded was 18.7 micrograms/mg. Low levels of net plasminogen activator activity were found in 12 specimens and identified as urokinase according to comigration with the urokinase standard in zymography. Fibronectin was detected in all but one of the 42 specimens; in seven specimens the levels exceeded those in normal plasma, calculated per milligram of total protein. Extensive fragmentation of fibronectin was found in 19 specimens, correlating with high plasmin levels. The results are indicative of an ongoing proteolytic process in secretory otitis media and suggest that plasmin-caused degradation of the fibronectin-containing basement membrane and subsequent formation of granulation tissue may be involved in the development of adhesive middle ears.
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PMID:Plasmin and fibronectin degradation in chronic secretory otitis media. 252 Dec

The profile of blood coagulation and fibrinolysis was studied in detail in eight patients with acute thrombotic thrombocytopenic purpura (TTP). In the majority of the patients, fibrinogen, factor XIII, antithrombin III, alpha 2-plasmin inhibitor, plasminogen, and alpha 2-macroglobulin were normal, whereas FDP, plasmin-alpha 2-plasmin inhibitor complex, and tissue-type plasminogen activator antigen were marginally or moderately elevated. Low fibronectin values were observed in four patients. Protein C and C4b-binding protein were nearly normal, whereas total protein S and free protein S were reduced in five and six patients, respectively. A positive correlation was found between total protein S and C4 and between free protein S and C3. von Willebrand factor antigen (vWf:Ag) and ristocetin cofactor (RCof) were either normal or elevated, but RCof/vWf:Ag ratio was decreased in seven patients. Crossed immunoelectrophoresis and sodium dodecyl sulfate (SDS)-agarose gel electrophoresis revealed that the large vWf multimers were either absent from or relatively decreased in all patients except one. In addition, one patient had unusually large vWf multimers, and a low-molecular-weight vWf fragment was apparently observed in three patients. These findings indicate that the intravascular generation of thrombin and plasmin was minimal in TTP and suggest that the alterations of the vWf molecule were caused not only by consumption through its participation in platelet thrombus formation but also by accelerated proteolysis. Low protein S values would be related to the immunological abnormalities underlying TTP.
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PMID:Coagulation studies in thrombotic thrombocytopenic purpura, with special reference to von Willebrand factor and protein S. 252 Dec 76

Excess production of growth hormone (GH) in poorly controlled diabetes is believed to be a causal factor in the development of diabetic angiopathy, the mechanism(s) of which is unknown. The present study was undertaken to determine whether exogenous growth hormone would specifically change some quantities and functional parameters known to often be abnormal in long-standing diabetes and thought to result from the development of vascular lesions in general. The authors studied capillary resistance, factor VIII coagulant antigen (F VIII:Ag), von Willebrand factor (vWf:Ag), fibronectin, fibrinogen, and tissue-type plasminogen activator (t-PA) before, during, and after 1 week's subcutaneous GH administration (6 IU per day divided into two doses). Capillary resistance decreased insignificantly, but returned to higher levels (p less than 0.05) 1 week after withdrawal. F VIII:Ag, vWf:Ag, fibronectin, and fibrinogen all increased significantly during GH treatment. Except for F VIII:Ag, these quantities returned to pre-medication levels 7 days after termination of GH administration. The present results may contribute to the clarification of the role of GH hypersecretion in diabetic microangiopathy and macroangiopathy.
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PMID:Diabetes-like alterations in hemostatic parameters after growth hormone administration for one week in normal man. 252 35

An early event in malignant transformation is the increased expression of proteases, such as plasminogen activator, which can degrade surrounding extracellular matrices, thereby conferring an advantage for tumour cell invasion and metastasis. The present studies provide evidence that plasma fibronectin (Fn), which is a component of the extracellular matrix, is a direct substrate for the plasminogen activator urokinase (UK). Human plasma Fn was incubated with human UK under plasminogen-free conditions. Fn cleavage was both time- and dose-dependent and was evident within 30 min. The proteolytic digestion was limited and complete within 12 h at an enzyme/substrate ratio of 1:20. Analysis of the final proteolytic digestion products demonstrated the disappearance of the native dimeric 440 kDa structure of Fn with the concomitant appearance of three proteolytic fragments of 210, 200 and 25 kDa. Since two large fragments of similar size to the 220 kDa monomeric chains of Fn were obtained following proteolysis, it is proposed that UK cleaves Fn at two sites, one towards the N-terminal and one close to the C-terminal, but N-terminal to its interchain disulphide bonds. These studies suggest that the local proteolytic digestion and release of Fn from the extracellular matrix by tumour cells possessing high levels of UK may involve the direct proteolytic breakdown of Fn by UK.
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PMID:Human plasma fibronectin as a substrate for human urokinase. 252 51

Plasmin can degrade fibronectin and laminin, two important components of the extracellular matrix facilitating cell sliding and healing following a wound. In this study we investigated the relationship between the tear fluid level of plasmin and plasminogen activator and the healing of a corneal wound. Anterior keratectomy (AKE) was performed for seven rabbits (11 eyes). Eight eyes were rewounded after re-epithelialization. Tear fluid samples were collected with capillaries before wounding and during wound healing. Plasmin and plasminogen activator (PA) activities were determined using radial caseinolysis procedures. After AKE the plasmin concentrations increased rapidly, from a mean (+/- SEM) of 3.9 +/- 0.9 micrograms/ml to a mean of 37.9 +/- 7.8 micrograms/ml (p less than 0.01), and decreased during wound healing. Rewounding also resulted in an increase in plasmin concentration in the tear fluid (from a mean of 2.9 +/- 0.6 micrograms/ml to a mean of 5.0 +/- 1.1 micrograms/ml; p greater than 0.05). The PA activity showed an inverse trend as it decreased after AKE from a mean of 2.0 +/- 0.6 IU/ml to a mean of 0.3 +/- 0.1 IU/ml (p less than 0.001). During wound healing and re-epithelialization, the PA activity increased again, to 2.1 +/- 0.3 IU/ml (p less than 0.001). Abrasion of the newly grown epithelium in eight eyes caused a second elevation of PA activity which was not significant. This study demonstrates a close association between the healing of corneal wounds and changes in the plasmin and PA activities in tear fluid. Determination of the activity of these enzymes may therefore be useful for monitoring corneal wound healing.
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PMID:Plasmin and plasminogen activator activities in tear fluid during corneal wound healing after anterior keratectomy. 253 68

To assess the direct effects of Bacteroides gingivalis on periodontal cells, human gingival fibroblasts were cultured in the presence of B. gingivalis extracts or a trypsinlike enzyme partially purified from the bacteria by chromatography on benzamidine-Sepharose and Sephacryl S-200. Analysis of cell surface glycoproteins by the periodate-[3H]borohydride labeling technique combined with sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE)-fluorography demonstrated that fibronectin and some other high-molecular-weight cell surface glycoproteins were degraded by a 35,000-Mr(35K) B. gingivalis protease. Immunostaining of the fibroblast cultures showed degradation of intercellular matrix fibronectin by the 35K protease. The pattern of fibronectin degradation was monitored by examining the reaction products with the SDS-PAGE-immunoblotting technique. The protease degraded fibronectin rapidly and more extensively than did corresponding amounts of pancreatic trypsin. Collagenase secretion by the fibroblasts was assayed by incubating cell culture medium with soluble type I [3H]collagen at 25 degrees C followed by SDS-PAGE-fluorography analysis of the reaction products. The medium was also assayed for plasminogen activator activity by using a casein-agarose diffusion plate assay. The fibroblasts cultured with the 35K protease secreted increased amounts of collagenase and plasminogen activator into the medium. The results suggest that periodontal infection by B. gingivalis causes proteolytic damage of the host cell surface structures. Concomitantly, B. gingivalis may induce the cells to degrade their pericellular matrix.
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PMID:A protease of Bacteroides gingivalis degrades cell surface and matrix glycoproteins of cultured gingival fibroblasts and induces secretion of collagenase and plasminogen activator. 253 33

We investigated the effect of agents which raise intracellular levels of cyclic AMP (cAMP) on the secretion of tissue-type plasminogen activator (t-PA) and type 1 plasminogen activator inhibitor (PAI-1) by cultured human umbilical-vein endothelial cells. Significant inhibition of baseline (unstimulated) t-PA and PAI-1 secretion was observed in response to several agents which, when added exogenously, cause increased intracellular cAMP: cholera toxin, 1-methyl-3-isobutylxanthine (MIX), dibutyryl-cAMP, and prostaglandin E1. These agents also significantly reduced or abolished the previously reported stimulatory effects of thrombin and histamine on t-PA secretion, and, with the exception of MIX, significantly reduced the previously reported stimulatory effect of thrombin on PAI-1 secretion. MIX at a concentration (10 microM) below that required to inhibit t-PA and PAI-1 secretion when tested alone, significantly increased the inhibitory effects of cholera toxin, dibutyryl-cAMP, and prostaglandin E1 on both t-PA and PAI-1 secretion. The data suggest that elevated intracellular levels of cAMP inhibit both spontaneous endothelial secretion of t-PA and PAI-1, and secretion induced by agents (thrombin and histamine) which stimulate endothelial phosphoinositide metabolism, consistent with bidirectional regulation of endothelial fibrinolytic protein secretion by the adenylate cyclase and phosphoinositide signal transduction pathways. The inhibitory effects of cAMP do not appear to be specific for t-PA and PAI-1, since cholera toxin and MIX also inhibited endothelial secretion of the adhesive protein, fibronectin. Significant inhibition of baseline endothelial t-PA and PAI-1 secretion was also caused by the stable prostacyclin analogue iloprost (ZK 36 374) and by arachidonic acid, which is converted by endothelial cells to prostacyclin, suggesting that prostacyclin produced endogenously by endothelial cells may inhibit secretion of fibrinolytic proteins by increasing intracellular cAMP.
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PMID:Inhibition of endothelial secretion of tissue-type plasminogen activator and its rapid inhibitor by agents which increase intracellular cyclic AMP. 254 66

An epithelial cell line derived from the liver of a normal Buffalo rat (BRL) was transformed by Rous sarcoma virus (RSV). The RSV-transformed cells were separated into five clones (RSV-BRL1 through 5), which were morphologically different. RSV-BRL cells exhibited the following characteristics distinct from those of BRL cells: tumorigenicity, irregular cell arrangement, loose intercellular junction, growth in soft agar (anchorage-independent growth) except for RSV-BRL3 and 5, and loss of cell surface fibronectin. When BRL cells were cultured in the standard medium supplemented with the serum-free conditioned medium of RSV-BRL cells, the amount of the cell surface fibronectin decreased significantly. It was found that RSV-BRL cells secreted a proteinase capable of hydrolyzing the fibronectin, whereas BRL cells secreted hardly any of this proteinase. The fibronectin-hydrolyzing proteinase (FNase) could also hydrolyze plasma fibronectin added as an exogenous substrate. The hydrolysis of plasma fibronectin was inhibited by ethylenediamine tetraacetate, but stimulated by rho-chloromercuribenzoate and calcium ion. This indicates that FNase is a metallo-enzyme, but not a serine or thiol enzyme. In addition to the proteinase, RSV-BRL cells secreted plasminogen activator and a proteinase inhibitor which inhibited the activity of plasmin but not FNase.
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PMID:Transformation of rat liver cell line by Rous sarcoma virus causes loss of cell surface fibronectin, accompanied with secretion of metallo-proteinase that preferentially digests the fibronectin. 282 45

The effect of basement membrane components (laminin, fibronectin and type IV collagen) and lung fibroblasts on type IV collagenase and plasminogen activator activity was investigated in a primary HSV-2-induced hamster fibrosarcoma, and its in vivo derived sublines and in vitro derived clones of varying metastatic potential. Fibronectin and type IV collagen were ineffective at influencing the expression of either type IV collagenase or plasminogen activator activity. Laminin, however, at concentrations of 1-10 micrograms ml-1 added to the serum-free culture supernatants, increased the release of type IV collagenase by up to 100% for the parental cell line. Three highly metastatic sublines (two from in vivo origin and one from in vitro cloning) showed increases of up to 300%. Non-metastatic sublines (two from in vivo origin and one from in vitro cloning), however, showed no increase in type IV collagenase activity. Plasminogen activator release from either the parental line cell or its metastatic sublines and clones, was unaffected by the addition of laminin. Addition of tumour cells to lung fibroblast monolayers resulted in an increased expression of PA activity in the supernatant, whilst type IV collagenase activity was reduced.
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PMID:Modulation of type IV collagenase and plasminogen activator in a hamster fibrosarcoma by basement membrane components and lung fibroblasts. 284 Jan 8


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