Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.73 (urokinase-type plasminogen activator)
 10,685 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:The role of the urokinase receptor in extracellular matrix degradation by HT29 human colon carcinoma cells. 838 94

We investigated the interactive regulation of the plasminogen activators (PAs) and their inhibitors (PAIs) by all-trans-retinoic acid (RA) in the presence and absence of the phorbol ester, phorbol myristate acetate (PMA), in four developmentally distinct human myeloid leukemic cell lines. Treatment of HL-60, K562, THP-1, and U937 cells with PMA resulted in an induction of urokinase-type PA (u-PA), the u-PA receptor (u-PAR), and PAI types 1 and 2 (PAI-1 and PAI-2). The addition of RA alone failed to alter gene expression or antigen production of PAI-1, PAI-2, or u-PAR. However, RA potentiated PMA-mediated induction of PAI-2 mRNA in HL-60 and U937 cells and PAI-2 antigen in all four cell lines. The effect of PMA on u-PA mRNA was also potentiated by RA in HL-60 and U937 cells. A similar, but transient, effect was seen on u-PA antigen levels. Run-on transcription analysis confirmed that these effects were due at least in part to changes in gene template activity. Furthermore, RA did not potentiate the effects of PMA on either u-PAR or PAI-1. In fact, in U937 cells, RA inhibited PMA-induced PAI-1 antigen secretion by approximately 60%. It would seem that interactive regulation of these genes allows for greater diversity of control, which may, in turn, be required for localized control of plasminogen-dependent extracellular proteolysis generated by monocytes/macrophage during cell migration and tissue remodeling.
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PMID:Retinoic acid potentiates phorbol ester-mediated induction of urokinase and plasminogen activator inhibitor type 2 in human myeloid leukemic cell lines. 840 15

We have previously demonstrated that collateral development takes place in a swine model of coronary artery occlusion. In this report we have examined the effect of coronary artery occlusion on urokinase and tissue plasminogen activator activity in the myocardium. Urokinase activity was increased four-fold in the ischemic heart compared to sham and unoperated controls. In contrast, the level of tissue plasminogen activator activity remained relatively constant. The increase in urokinase activity was associated with an upregulation of urokinase RNA levels and of the RNAs corresponding to the plasminogen activator inhibitors, PAI I and II. Urokinase has been shown to be an important angiogenic protease both in vivo and in cultured cells. Its increase during collateral development suggests that urokinase may play a role in angiogenesis in the ischemic heart.
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PMID:Urokinase plasminogen activator activity is increased in the myocardium during coronary artery occlusion. 853 Dec 14

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.
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PMID:Induction of plasminogen activator inhibitor type 1 in murine lupus-like glomerulonephritis. 854 2

Mice with combined homozygous deficiency of tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA) (T-U-), of t-PA and plasminogen activator inhibitor-1 (PAI-1) (T-P-), of u-PA and PAI-1 (U-P-) or of t-PA, u-PA, and PAI-1 (T-U-P-) were generated by inbreeding of mice with the respective deficiencies. Homologous recombination at the t-PA, u-PA and PAI-1 locus was verified by Southern blot analysis of genomic tail tip DNA, and confirmed by measurement of antigen levels in plasma or urine. T-P- and U-P- mice were apparently healthy and fertile. T-U- mice showed extensive fibrin deposition with calcification in the liver, whereas T-U-P- mice were significantly (p < 0.001) less affected. Spontaneous in vivo clot lysis measured 4 h after injection of a 125I-fibrin-labeled clot prepared from plasma of wild-type (WT) mice into the jugular vein, was (mean +/- SEM of n experiments) 2 +/- 1% (n = 8) for T-P-, 49 +/- 6% (n = 9) for U-P-, 1 +/- 1% (n = 4) for T-U- and 3 +/- 3% (n = 3) for T-U-P- mice, as compared to 32 +/- 4% (n = 10) for WT, 1 +/- 0% (n = 7) for T-, 30 +/- 5% (n = 5) for U- and 58 +/- 10% (n = 6) for P- mice. Plasminogen-dependent lysis of 125I-fibrin-labeled matrix and of 3H-proline-labeled subendothelial matrix (mean +/- SEM; n = 4 to 6) was lower with thioglycollate-stimulated macrophages obtained from U-P- mice (22 +/- 7% and 5 +/- 1%, respectively), as compared to WT mice (57 +/- 14% and 18 +/- 5%, respectively) and T-P- mice (87 +/- 6% and 27 +/- 4%, respectively). A similar decrease was previously observed with U- mice, but not with T- or P- mice. Thus, the phenotype of mice with combined deficiency of t-PA and PAI-1 or of u-PA and PAI-1 is similar to the phenotype observed in mice with single deficiency of the plasminogen activator. Additional deletion of PAI-1 does not affect viability, fertility, macrophage function or thrombolytic potential of the single deficient mice. Additional deletion of PAI in mice with combined deficiency of t-PA and u-PA does not restore the deficient in vivo fibrinolytic capacity, but significantly reduces the thrombotic phenotype, as revealed by fewer, smaller and less calcified fibrin deposits in the liver.
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PMID:Biological effects of combined inactivation of plasminogen activator and plasminogen activator inhibitor-1 gene function in mice. 856 Apr 24

The involution of the prostate gland after castration is an active process which requires the induction of new proteins. The plasminogen activator urokinase has been proposed to be a gene repressed by androgen which is activated upon castration and thus participating in the atrophy of the gland. However, urokinase is secreted by the ventral lobe of the rat prostate and this should be positively affected by androgens. The purpose of this study was to examine further the effects of castration upon plasminogen activator (PA) activities in the rat prostate and to determine possible explanations to this apparent dilemma. Castration of young sexually mature adult rats resulted in a substantial increase in PA activities at 4 days after castration in the ventral prostate, but then the activities returned to within the range of untreated animals with a longer duration of castration. Urokinase was the predominant molecular form of PA in the normal ventral prostate and it was the molecular form increased after castration; based upon its sensitivity to amiloride and its molecular size determined in zymograms. In contrast to the effect of castration, there was no increase in PA activities in the ventral prostate with treatment of rats with the antiandrogen flutamide, but rather a decrease when specific activity was expressed per unit DNA. In addition, the effect of castration was specific for the ventral lobe for there was no change in the PA activity in the dorsolateral prostate after androgen ablation. The diminished PA activities in the ventral prostates of rats castrated for 7 days or longer appeared to be due at least in part to an increase in plasminogen activator inhibitor type-1 (PAI-1). Immunoreactive PAI-1 was found predominantly in high molecular weight forms which indicates that the inhibitor was complexed with PA. Daily treatment of rats upon castration with agents known to retard the rate of regression of the involuting prostate gave dichotomous results. Hydrocortisone prevented the increase in PA activity, whereas treatment with actinomycin D, an inhibitor of RNA synthesis, not only did not prevent an increase in PA activity, but actually produced a superinduction in PA activity at 4 days orchiectomy. These data may be interpreted to mean that hydrocortisone stimulated PAI activity and that actinomycin D treatment blocked its induction. However, the actinomycin D data may also indicate that an increase in urokinase protein and mRNA after castration may result from some mechanism to conserve these molecules suggesting that this inhibitor of RNA synthesis prevented the transcription of messages for proteins involved in the degradation of urokinase message.
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PMID:Effects of castration on plasminogen activator activities and plasminogen activator inhibitor type 1 in the rat ventral prostate. 860

Proteolytic joint destruction in inflammatory and non-inflammatory arthropathy is believed to be mediated, at least in part, by the plasminogen activation (PA) system. To further investigate possible involvement of the PA system, we quantified immunoreactive urokinase-type plasminogen activator (u-PA), tissue-type plasminogen activator (t-PA), both plasminogen activator inhibitors (PAI-1 and PAI-2) and u-PA-receptor (u-PAR) in synovial tissue extracts of 14 patients with rheumatoid arthritis (RA) and 12 with osteoarthritis (OA). u-PA, PAI-1, PAI-2 and u-PAR concentrations were significantly higher in RA than in OA patients. t-PA antigen levels were significantly lower in RA than in OA synovial tissue extracts. Immunohistochemistry was performed to compare the distribution and staining intensity of these components in samples of RA and OA synovial tissue. Intense immunostaining of u-PA, u-PAR, PAI-1 and, to a lesser degree, PAI-2 was observed predominantly in the synovial lining of RA patients. In OA patients, u-PA, PAI-1, PAI-2 and u-PAR were barely detectable. t-PA immunostaining was restricted to the endothelial side of vascular walls in both groups. We conclude that the observed increase of u-PA, u-PAR and PAI expression, distributed mainly in the synovial lining area of proliferative and invasively growing synovial tissue in RA patients, supports a pathogenic role for the PA system in destructive arthritis. Depressed t-PA-mediated plasminogen activation might contribute to delayed intra-articular fibrin removal.
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PMID:Difference in expression of the plasminogen activation system in synovial tissue of patients with rheumatoid arthritis and osteoarthritis. 864 30

We studied exercise-induced changes in coagulation and fibrinolytic factors and activation products in different age categories. Thirty-eight sedentary males, divided in three age categories (cats I-III; 20-30, 35-45 and 50-60 y) were subjected to a standardized exercise test. Pre-exercise levels (cats I-III resp) of FVII:c (105 +/- 5, 121 +/- 6 and 123 +/- 7% NP), fibrinogen (2.35 +/- 0.12, 2.55 +/- 0.10 and 2.66 +/- 0.09 mg/ml), prothrombin activation fragment F1 + 2 (0.80 +/- 0.10, 0.80 +/- 0.11 and 1.22 +/- 0.16 nM), t-PA (5.2 +/- 0.6, 9.2 +/- 1.0, 8.6 +/- 1.2 ng/ml) and PAI-I (42.8 +/- 7.5, 67.6 +/- 7.6, 62.2 +/- 10.9 ng/ml) showed differences that seemed related to age. Regression analysis revealed associations with anthropometry (FVII:c, fibrinogen, F1+2, t-PA, PAI-1) rather than with age. Exercise-induced changes in coagulation (increase in von Willebrand factor and FVIII:c and a shortening of APTT) and fibrinolytic potential (increase in t-PA and u-PA) were of comparable magnitude for the three age categories. Hardly any change in F1 + 2 (6%) was observed, while thrombin-antithrombin complexes (93%), plasmin-antiplasmin complexes (79%) and D-dimer (77%) almost doubled during maximal exercise. We conclude that anthropometric differences play a more significant role than age on constitutive levels of haemostatic factors in participants up to 60 years of age. The magnitude of exercise-induced changes is comparable in the age categories under study, and simply super-imposed on constitutive (pre-exercise) levels. Clear evidence for prothrombin activation is lacking, but plasmin formation is enhanced during exercise.
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PMID:Changes in haemostatic factors and activation products after exercise in healthy subjects with different ages. 877 20

Cultured human mesangial cells (HMC) derived from normal kidneys have been shown to synthesize tissue-type plasminogen activator (t-PA) and excess amounts of PA inhibitor type 1 (PAI-1). Conflicting results have been obtained concerning the production of urokinase-type PA (u-PA) and efforts to show PA inhibitor 2 (PAI-2) met with failure. We evaluated the fibrinolytic profile of cultured HMC lines obtained from 12 patients with renal carcinoma and one cadaveric kidney donor. Subconfluent cells (third passage) were incubated overnight in serum-free medium. t-PA, u-PA, PAI-1 and PAI-2 antigens were assayed by ELISA methods and PA and PAI activities by amidolytic methods both in conditioned medium (CM) and cell extracts (CE). Besides PAI-1, PAI-2 antigen was detected in all but one HMC lines. At variance with the former, which was largely released in the culture medium, PAI-2 was mainly cell-associated. t-PA antigen was found in all but two cell lines while u-PA antigen was detected in relatively high concentrations in 8 cell lines. PA activity, identified as u-PA by functional and immunological criteria, was measured in CM of six of the eight u-PA producing cell lines, whereas PAI activity was undetectable or very low in CM of all cell lines, suggesting that PAI-1 was largely inactive. Functional assays of cell extracts demonstrated the presence of PA activity, again identified as u-PA, only in samples (five lines) containing u-PA antigen in excess over PAI-2. PAI activity was found instead in the extracts in which the inhibitor was higher than the activator (six lines) and was identified as PAI-2, as it inhibited u-PA but not single-chain t-PA and was neutralized by a polyclonal anti-PAI-2 antibody. The heterogeneous fibrinolytic pattern of HMC lines was confirmed by mRNA analysis of three representative lines. Results were similar when HMC lines at passage five were used, except that the u-PA content was significantly reduced both in CM and CE. These findings indicate that the fibrinolytic profile of cultured HMC is more complex than previously reported. The production of large amounts of PAI-2 may represent an additional control mechanism of proteinase activity.
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PMID:Cultured human mesangial cells produce both type 1 and type 2 plasminogen activator inhibitors. 877 30

Since thromboembolic complications in transplanted patients are generally attributed to combined abnormalities in platelets and coagulo-lytic system, some hemostatic parameters tPA (tissue plasmogin activator):Ag and activity, its inhibitor-PAIAg and activity, tPA/PAI, thrombin-antithrombin (TAT) and plasmin-antiplasmin complexes (PAP), urokinase-uPA, euglobulin clot lysis time-ECLT, fibrinogen, plasminogen, protein C activity, D-dimer, prothrombin fragments1+2 (F1+2), fibrin monomers, fibronectin, lipoprotein-a, and von Willebrand factor(vWF), were evaluated using commercially available kits. The studies were performed on kidney transplant recipients treated with CsA, azathioprine and prednisone (n=21), and healthy volunteers (n=21). ECLT was significantly prolonged in kidney transplant recipients together with a rise in F1+2,lipoprotein-a, fibrinogen, fibronectin, and vWF when compared with controls. The TPA level was lower, whereas the PAI level was higher in kidney transplant recipients when compared with controls. In conclusion, CsA-treated kidney transplant recipients show evidence of pronounced impairment in fibrinolysis and endothelial damage in comparison with healthy volunteers.
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PMID:The coagulo-lytic system and endothelial function in cyclosporine-treated kidney allograft recipients. 882 84


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