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)

Tissue-type plasminogen activator (t-pa) is a serine protease comprising four different putative structural domains with homologies to fibronectin finger-like structures (finger), epidermal growth factor, kringle structures, and the active site of serine proteases. Only the finger and epidermal growth factor domain are each entirely encoded by unique single exons. We assessed the functional contribution of these two structural domains by making mutants precisely deleted for one or both of the relevant exons. The three mutant genes were expressed in monkey cells, and the variant proteins, purified from the culture medium, were characterized for their fibrinolytic activity, fibrinogenolytic potential, and affinity for fibrin. No significant difference in any biochemical property was observed among the variants. All three variants retained a catalytic dependence on cyanogen bromide fragments of fibrinogen which could not be distinguished from the wild-type enzyme. The activities of the variants were also very similar to that of wild-type t-pa, showing no detectable fibrinogenolytic potential in human plasma at activator concentrations of 500 IU/ml, or when their fibrinolytic activity was tested in human plasma using the 125I-labeled fibrin clot lysis assay at activator concentrations of 150 IU/ml or greater. However, the variants were markedly defective in fibrinolysis at low activator concentrations such that essentially no fibrinolysis was detected at 15 IU/ml. Measurement of fibrin binding showed that the variants lacked the high fibrin binding characteristic of wild-type t-pa. These results demonstrate that the fibrin specificity and fibrin-dependent activity of t-pa are independent of the protein's high affinity for fibrin. The implication of these results is that the t-pa variants would be ineffective activators at a physiological concentration of approximately 2 IU/ml but would be expected to behave similarly to wild-type t-pa at the steady-state plasma concentrations of 0.75-1.25 micrograms/ml (approximately 500 IU/ml) currently required for coronary reperfusion in patients receiving t-pa for acute myocardial infarction (Garabedian, H.D., Gold, H.K., Leinbach, R.C., Yasuda, T., Johns, J.A., and Collen, D. (1986) Am. J. Cardiol. 58, 673-679).
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PMID:Variants of human tissue-type plasminogen activator. Fibrin binding, fibrinolytic, and fibrinogenolytic characterization of genetic variants lacking the fibronectin finger-like and/or the epidermal growth factor domains. 312 18

It was previously demonstrated that substrata derived from well differentiated colon carcinoma cell lines induced a more benign program in a separate malignant colon cell line, MOSERsf. This study attempts to define a role for extracellular matrix components in the biological events of MOSERsf cells. Alterations in morphology, secreted carcinoembryonic antigen (CEA) and urokinase brought about by individual components were determined. Laminin induced similar changes to colon-derived substrata in that there was increased cell attachment and spreading, a 4-fold elevation in CEA and a 45% reduction in urokinase. Fibronectin stimulated cell attachment without altered morphology and reduced the amount of plasminogen activator. CEA values, however, remained unchanged. Growth of MOSERsf cells on all types of collagen failed to elicit any change in cell shape or CEA. However, type I/III collagen raised urokinase levels by 40%. Transforming growth factor beta (TGF-beta) induces cellular laminin and fibronectin, promotes cell attachment, and spreading, elevates CEA and diminishes urokinase. These data argue for a role for laminin and possibly fibronectin in the governing of biological events culminating in a more mature colon cell.
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PMID:Alteration in the behavior of a colon carcinoma cell line by extracellular matrix components. 316 44

Guanidinobenzoatase is a proteolytic enzyme capable of degrading fibronectin and is a tumour associated enzyme. Guanidinobenzoatase has been shown to be an arginine selective protease and is distinct from trypsin, plasminogen activator, plasmin, thrombin and a newly described tumour associated enzyme specific for guanidino phenylalanine residues. These conclusions have been derived from inhibition studies employing 4-methyl-p-guanidinobenzoate as substrate. Three active site titrants for trypsin have been shown to be good substrates for guanidinobenzoatase. A new active site titrant for trypsin, rhodamine bisguanidinobenzoate, can also be used to assay guanidinobenzoatase in a stoichiometric manner. This active site titrant can be employed to label guanidinobenzoate on the surface of leukaemia cells.
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PMID:Further inhibition studies on guanidinobenzoatase, a trypsin-like enzyme associated with tumour cells. 333 44

Fibrinolytic and other factors have been measured in 73 patients with systemic lupus erythematosus or related conditions to determine whether clinical thrombosis, a common feature of these disorders, is associated with defective fibrinolysis. Twenty five of 72 (35%) patients, compared with two of 22 (9%) controls, showed a low level of plasminogen activator activity in response to venous occlusion, suggesting decreased fibrinolytic potential. In addition, mean plasma levels of von Willebrand factor antigen and fibronectin were markedly raised in the patients (mean (SD) 384.5 (277)% and 727 (436) mg/l respectively) compared with healthy controls (100 (50)% and 306 (65) mg/l). These data suggest a degree of endothelial cell dysfunction. No clear correlation was found between a history of thrombosis and any plasma factor measured, except for prolongation of clotting tests suggestive of the 'lupus anticoagulant'.
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PMID:Indications of vascular endothelial cell dysfunction in systemic lupus erythematosus. 350 Jun 77

We succeeded for the first time in extracting and purifying a coagulation fibrinolysis factor in the placenta, that is, a placental plasminogen activator (PPA). Using the enzyme-labeled antibody technique (indirect method), we investigated the localization of PPA, fibrinogen (FBG) and fibronectin (FN) in the placenta. And we tried to elucidate the physiological significance of the above three. The F(ab')2 fragments of their antibodies were produced by pepsin digestion, because there were various Fc receptors in the placenta. The results are summarized as follows: PPA was produced in the trophoblast, and was secreted out of the microvilli. FBG was located in the plasma. But, in the placenta, it was not in the cells and the connective tissue of which chorionic villi was composed. FN was located in the ground substances of connective tissue in the chorionic villi, and was associated with the cell structure. Because PPA, FBG and FN showed the same distribution on the fibrinoid material, it is expected that coagulation fibrinolysis activity proceeds in that fibrinoid material.
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PMID:[Studies on the immunohistochemical localization of coagulation fibrinolysis factors in the placenta, especially of placental plasminogen activator (PPA)]. 351 41

An avian retrovirus containing only the v-mil oncogene (PA200-MH2) was analyzed for its ability to induce a transformed phenotype in chicken embryo fibroblasts. Infected cultures exhibited an altered morphology, disarranged actin cable filaments, and a decrease in the amount of cell surface fibronectin. In addition, these cells showed a high level of plasminogen activator protease activity and were also capable of growth in low serum concentrations. In contrast, PA200-MH2 was very inefficient at inducing foci under agar and colonies in semisolid medium relative to the Mill Hill 2 and Rous sarcoma viruses. This inefficiency was further reflected in vivo by the total inability of PA200-MH2 to induce wing tumors in young birds. However, 40% of the birds inoculated in the wing web with PA200-MH2-infected cells did develop slow-growing tumors at the site of injection, with no evidence of hematopoietic involvement. Our results indicate that the v-mil oncogene is transforming both in vitro and in vivo and that each of the oncogenes in the Mill Hill 2 virus, v-mil and v-myc, can independently transform fibroblasts. These data suggest that v-mil is functionally related to its homologous murine counterpart, v-raf, which also transforms fibroblasts.
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PMID:Fibroblast transformation parameters induced by the avian v-mil oncogene. 357 49

Cell lines derived from 3 different types of human tumor (e.g., squamous carcinomas, melanomas and gliomas) were examined for production of plasminogen activator activity and for attachment and spreading on various extracellular matrix components in the presence or absence of plasminogen. All of the squamous carcinoma and melanoma lines produced high levels of plasminogen activator activity. In contrast, 4 of 6 glioma lines had undetectable activity. Cells from all 3 tumor types attached and spread on fibrinogen-coated or fibrin-coated plastic dishes in the absence of plasminogen. In the presence of exogenous plasminogen, the attachment and spreading of the cells which produced high levels of plasminogen activator activity was inhibited. The plasminogen activator-deficient cells were much less sensitive to exogenous plasminogen. In the presence of plasminogen, attachment and spreading on fibronectin-coated dishes was also partially inhibited. In contrast, plasminogen had no effect on the attachment and spreading of the cells on type-I or -IV collagen, laminin or thrombospondin. Previous studies have shown that tumor-cell adhesion to the extracellular matrix depends on the synthesis of receptors for extracellular matrix components or on the synthesis of extracellular matrix components themselves. The present study shows that, in addition, the production of enzymes which are capable of degrading these components also influences tumor-cell adhesion to extracellular matrix moieties.
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PMID:Plasminogen activator production by human tumor cells: effect on tumor cell-extracellular matrix interactions. 369 23

We have examined the expression of the transformed phenotype in a series of clonal lines of NIH/3T3 cells transfected with the human c-Ha-rasVal 12 oncogene and the neomycin phosphotransferase gene. Cells from individual transformed foci were cloned and subjected to detailed analyses of the ras sequences. Three clones were found that expressed approximately one, 2-4, or 4-8 copies of the human c-ras oncogene, respectively. A fourth clone had multiple copies of the transfected sequences, and expressed abundant c-Ha-ras RNA. Analysis of the transformed phenotype of various clones indicated that cells expressing low levels of mutant c-Ha-ras had lost some of their extracellular fibronectin network, and were barely altered in their cytoskeleton. In contrast, cells expressing abundant c-Ha-ras had lost both their actin and fibronectin networks and showed an increase in plasminogen activator activity. Cells with amplified c-Ha-rasVal 12 grew better in low serum, formed large colonies in soft agar and showed enhanced activity of ornithine decarboxylase, the rate-controlling enzyme in polyamine biosynthesis. These results show that the dosage level of the mutant oncogene makes a significant contribution to the transformed phenotype of c-Ha-ras oncogene-transformed cells.
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PMID:Dose effects of transfected c-Ha-rasVal 12 oncogene in transformed cell clones. 380 52

A human liver cDNA library was screened by colony hybridization with two mixtures of synthetic oligodeoxyribonucleotides as probes. These oligonucleotides encoded regions of beta-factor XIIa as predicted from the amino acid sequence. Four positive clones were isolated that contained DNA coding for most of factor XII mRNA. DNA sequence analysis of these overlapping clones showed that they contained DNA coding for part of an amino-terminal extension, the complete amino acid sequence of plasma factor XII, a TGA stop codon, a 3' untranslated region of 150 nucleotides, and a poly(A)+ tail. The cDNA sequence predicts that plasma factor XII consists of 596 amino acid residues. Within the predicted amino acid sequence of factor XII, we have identified three peptide bonds that are cleaved by kallikrein during the formation of beta-factor XIIa. Comparison of the structure of factor XII with other proteins revealed extensive sequence identity with regions of tissue-type plasminogen activator (the epidermal growth factor-like region and the kringle region) and fibronectin (type I and type II homologies). As the type II region of fibronectin contains a collagen-binding site, the homologous region in factor XII may be responsible for the binding of factor XII to collagen. The carboxyl-terminal region of factor XII shares considerable amino acid sequence homology with other serine proteases including trypsin and many clotting factors. A preliminary structural model of beta-factor XIIa is proposed based on the known high resolution x-ray diffraction structures of trypsin, chymotrypsin, and elastase.
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PMID:Characterization of human blood coagulation factor XII cDNA. Prediction of the primary structure of factor XII and the tertiary structure of beta-factor XIIa. 387 53

Bone marrow-derived macrophages were prepared from human bone marrow mononuclear cells following cultivation in GCT-conditioned medium (GCT-CM) and purification by adherence to fibronectin-coated flasks. The growth of bone marrow mononuclear cells in GCT-CM was dependent on the shape of the culture vessels, being increased in round-bottomed versus flat-bottomed wells. Proliferation was confined to nonadherent cells; like blood monocytes, bone marrow-derived macrophages did not incorporate [3H]thymidine in response to GCT-CM or human serum. Purified macrophages from this source expressed nonspecific esterase and OKM1, OKla, FMC 17, 32, and 34 and 25F9 antigens but lacked Mo2. They expressed high levels of an inactivator of plasminogen activator, minactivin, and gave a substantial metabolic burst in response to phorbol myristate acetate or opsonized (but not unopsonized) zymosan. Bone marrow-derived macrophages acted as accessory cells in the response of T lymphocytes to phytohemagglutinin. The results suggest that liquid bone marrow cultures are useful in the study of the differentiation of human mononuclear phagocytes.
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PMID:Preparation and characterization of human bone marrow-derived macrophages. 392 88


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