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 plasminogen activator (uPA) and metalloproteinases (MMP) play key roles in invasion and metastasis, degrading extracellular matrix compounds and modulating tumor cell motility. Their regulation is an attractive therapeutic target for controlling tumor metastasis. Previously we have demonstrated that urokinase overexpression in murine mammary tumor cells is regulated by a Ca2+-dependent pathway and that blockage of Ca2+ channels by verapamil partially inhibited their invasive and metastatic ability. Moreover, the catalytic inhibition of uPA by a synthetic uPA inhibitor B428 reduced local tumor invasiveness but not tumor cell dissemination. We evaluated the effect of a combined treatment with verapamil and B428 on the murine mammary carcinoma F3II behavior in vivo and in vitro. In vivo administration of the combined treatment was not associated to an overt toxicity. Only the daily combined treatment, beginning after tumor take, reduced the incidence and the number of spontaneous lung metastasis, while no differences were found in the subcutaneous growth of the primary tumor. Interestingly, a remarkable reduction in plasma MMP-9 activity was found associated to metastasis impairment. In addition, the number of experimental lung metastases was also significantly diminished, with respect to the control group, only when both compounds were co-administered daily, beginning three days after i.v. tumor cell injection. In vitro, both compounds, either separately or combined, could inhibit secreted uPA activity. F3II cell migration was significantly inhibited by incubation with 50 microM verapamil, 15 microM B428 or the co-treatment with 7.5 microM B428 + 25 microM verapamil. The cell spread was also significantly reduced when F3II cells were exposed to the compounds, with an additive effect when B428 + verapamil combination was used. The combination of two compounds acting through different molecular targets may be useful to improve the control of metastatic dissemination.
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PMID:Combined treatment with verapamil, a calcium channel blocker, and B428, a synthetic uPA inhibitor, impairs the metastatic ability of a murine mammary carcinoma. 1268 50

Extracellular proteolytic enzymes of the urokinase-type plasminogen activator (uPA) system and the family of metalloproteinases (MMPs) catalyse the matrix degradation and remodelling processes characteristic of invasive malignant disorders. In a cohort of 50 patients with chronic myeloproliferative disorders (MPD) serum markers for collagen metabolism were compared to plasma levels of enzymes of the uPA and MMP system. Serum aminoterminal propeptide of type III procollagen (S-PIIINP) (P < 0.0001) concentration was significantly higher in the patients (median 3.7 micro g/L vs. 2.5 micro g/L) compared with controls. In a subgroup analysis comprising patients with myelofibrosis (MF), polycythaemia vera (PV) and essential thrombocythaemia (ET), respectively, S-PIIINP levels differed significantly with the highest values found in patients with MF (MF vs. PV vs. ET; P = 0.0027). Serum concentration of carboxyterminal telopeptide of type I collagen (S-ICTP) (P = 0.0006), reflecting type I collagen degradation, was significantly higher in patients compared with controls (median 4.0 micro g/L vs. 2.7 micro g/L). When comparing S-ICTP measurements between patient subgroups and controls there were only significantly higher values among MF and PV patients (MF vs. controls; P < 0.0001, PV vs. controls; P = 0.0016). A significant correlation between the marker for collagen synthesis (S-PIIINP) and degradation (S-ICTP) (r = 0.59; P < 0.0001) was demonstrated. A correlation analysis between serum markers for bone marrow remodelling processes (S-PIIINP, S-ICTP and S-hyaluronan) and plasma-soluble urokinase plasminogen receptor (suPAR) disclosed a significant relationship between suPAR and S-PIIINP (r = 0.48; P = 0.0009), S-hyaluronan (r = 0.56; P < 0.0001) and S-ICTP (r = 0.47; P = 0.0013), respectively. Plasma levels of MMP-2 and -9 were not correlated to serum markers for collagen metabolism. These findings suggest that enzymes of the uPA system might participate in the bone marrow remodelling processes characteristic of MPD.
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PMID:Collagen metabolism and enzymes of the urokinase plasminogen activator system in chronic myeloproliferative disorders: correlation between plasma-soluble urokinase plasminogen activator receptor and serum markers for collagen metabolism. 1295 Feb 37

Human macrophages found in juxtaposition to fragmented elastin in vivo express the elastolytic matrix metalloproteinases (MMPs) progelatinase B, prometalloelastase, and promatrilysin. Though MMPs can degrade a range of extracellular matrix components, increasing evidence suggests that preferred targets in vivo include nonmatrix substrates such as chemokines and growth factors. Hence, the means by which MMPs participate in elastin turnover remain undefined as does the identity of the elastolysins. Herein, human macrophage cultures have been established that express a complement of elastolytic proteinases similar, if not identical, to that found in vivo. Under plasminogen-free conditions, macrophages preferentially use metalloelastase to mediate elastolysis via a process that deposits active enzyme on elastin surfaces. By contrast, in the presence of plasminogen, human macrophages up-regulate proteolysis 10-fold by processing promatrilysin to an active elastolysin via a urokinase-type plasminogen activator-dependent pathway. Matrilysin-deficient human macrophages fail to mediate an elastolytic response despite the continued expression of gelatinase B and metalloelastase. Thus, acting in concert with cosecreted cysteine proteinases whose activities are constrained to sites of macrophage-elastin contact (Punturieri, A., S. Filippov, E. Allen, I. Caras, R. Murray, V. Reddy, and S.J. Weiss. 2000. J. Exp. Med. 192:789-799), matrilysin confers macrophages with their most potent MMP-dependent elastolytic system.
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PMID:Matrilysin-dependent elastolysis by human macrophages. 1296 95

Infection with Helicobacter pylori (H. pylori) is considered a risk factor for gastric carcinoma. The purpose of this study was to clarify whether H. pylori infection plays a role in progression of gastric carcinoma. We examined the expression of genes encoding angiogenic factors and proteases by human gastric carcinoma cell lines (MKN-1 and TMK-1) co-cultured with or without H. pylori by cDNA microarray analysis. Co-culture with H. pylori increased expression of mRNAs encoding interleukin (IL)-8, vascular endothelial growth factor (VEGF), angiogenin, urokinase-type plasminogen activator (uPA), and metalloproteinase (MMP)-9 by gastric carcinoma cells. Up-regulation of these genes at the mRNA and protein levels was confirmed by Northern blot analysis, semi-quantitative RT-PCR analysis, and ELISA. In vitro angiogenic and collagenase activities of conditioned medium from the gastric carcinoma cells were also stimulated by co-culture with H. pylori. These results indicate that H. pylori infection may regulate angiogenesis and invasion of human gastric carcinoma.
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PMID:Helicobacter pylori infection influences expression of genes related to angiogenesis and invasion in human gastric carcinoma cells. 1462 53

Chronic myeloproliferative disorders (MPD) are characterized by progressive remodelling of bone marrow stroma as evidenced by increased deposition of extracellular matrix proteins, neoangiogenesis and displacement of normal haematopoietic cells by fibrotic tissue. The family of metalloproteinases (MMPs) and tissue inhibitors of metalloproteinase (TIMPs) serve to facilitate and inhibit matrix degradation processes, respectively. In an attempt to investigate potential markers for bone marrow remodelling processes, we investigated plasma levels of total-, free- and complexed TIMP-1, TIMP-2, MMP-2 and MMP-9 in a patient cohort comprising 17 with myelofibrosis (MF), 17 with polycythaemia vera (PV), 15 with essential thrombocythaemia (ET), 1 with a transitional MPD and 30 controls. Compared with controls, total- (P < 0.0001) (median: 132.6 microg/L vs. 80.8 microg/L), free- (P < 0.0001) (median: 126.4 microg/L vs. 65.8 microg/L) and complexed TIMP-1 (P = 0.0009) (median: 17.7 microg/L vs. 10.7 microg/L) concentration was significantly higher in the patients. TIMP-1 was significantly correlated with plasma soluble urokinase plasminogen activator receptor (P = 0.003) and urokinase plasminogen activator (P < 0.0001), respectively, suggesting a common cellular origin. No statistical significant difference between TIMP-2 and MMP-2 levels was observed between patients and controls. Furthermore, a significant correlation between free TIMP-1 and TIMP-2 levels was detected (r = 0.56; P < 0.0001). Median MMP-9 concentration was significantly higher among PV patients compared with controls (P = 0.0015), and 41% of patients with PV (7/17) had MMP-9 values that were above the mean + 2SD of plasma MMP-9 levels found in controls. The ratio of total TIMP-1/MMP-9 was significantly higher in patients with MF compared with controls (P = 0.0004). These findings suggest that a disturbed TIMP-1/MMP ratio may reflect an imbalance of the extracellular homeostasis towards an increased matrix deposition promoting fibrosis.
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PMID:Elevated plasma levels of TIMP-1 correlate with plasma suPAR/uPA in patients with chronic myeloproliferative disorders. 1466 1

Extracellular proteolytic enzymes of the urokinase-type plasminogen activator (uPA) and metalloproteinase (MMP) family play a crucial role in the matrix degradation and tissue remodeling process characteristic of malignant disorders. The receptor for urokinase plasminogen activator (uPAR) serves to localize and intensify the action of UPA and is expressed on the surface of malignant cells. Although the biological significance of MMP-9 and soluble urokinase receptor in growth and progression of lymphoid neoplasm is understood, its clinical significance in acute myeloid leukemia (AML) has not been fully elucidated. In this study, we determined the levels of soluble urokinase-type plasminogen activator receptor (suPAR), cellular uPAR and sMMP-9 in 43 newly diagnosed AML patients at diagnosis, before chemotherapy, and also studied 10 normal subjects served as a control group. After chemotherapy suPAR and MMP-9 were determined at remission and relapse. The levels of suPAR, cellular PAR were significantly higher (P= 0.001, 0.001) and MMP-9 was significantly lower (P=0.001) in AML patients at diagnosis as compared to controls. suPAR and MMP-9 levels were significantly lower in AML patients who achieved complete remission (CR) as compared to those who did not (P= 0.001 for both). Levels of suPAR and MMP-9 were significantly correlated to peripheral blood blast cells (r= 0.88, P= 0.001; r= 0.65, P= 0.001, respectively) and blast cell distribution ratio (BCDR, r= 0.84, P= 0.001; r=65, P= 0.001, respectively). suPAR, cellular PAR and MMP-9 were significantly higher in patients with extramedullary infiltration as compared with those without (P= 0.001, 0.001, <0.05). The suPAR, cellular uPAR, and MMP-9 levels were uneven in AML FAB subtypes being highest in M5(P<0.05 for all). MMP-9 and suPAR levels were correlated with the disease status. In AML survivors, MMP-9, cellular uPAR and suPAR were significantly lower as compared to non-survivors (P= 0.001 for all). In conclusion, MMP-9 and su PAR levels might be used as a marker for disease activity and may contribute to blast cell dissemination. MMP-9 and suPAR may be target molecules in the strategy of treatment of AML.
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PMID:Urokinase plasminogen activator receptor and soluble matrix metalloproteinase-9 in acute myeloid leukemia patients: a possible relation to disease invasion. 1466 33

Urokinase-type plasminogen activator receptor (uPAR) and epidermal growth factor receptor (EGFR) are ubiquitous receptors involved in the control of a variety of cellular processes frequently found altered in cancer cells. The EGFR has been recently described to play a transduction role of uPAR stimuli, mediating uPA-induced proliferation in highly malignant cells that overexpress uPAR. In the present work, we found for the first time that uPAR stimulation with the amino-terminal fragment (ATF) of urokinase devoid of proteolytic activity transactivates the EGFR in mammary MCF-7 cells through a mechanism involving Src and a metalloproteinase, as indicated by its sensitivity to selected inhibitors. In these cells, which express low levels of uPAR and malignancy, both ATF and EGF stimuli induced an interaction of the EGFR with uPAR and ERK activation. However, EGFR activation by uPAR stimuli mediated cellular invasion rather than proliferation, while EGFR activation by EGF led to a proliferative response. These results revealed a complex modulation of EGFR function toward different cellular responses according to the status of uPAR activity. On the other hand, we also found that MMP-mediated activation of EGFR can occur in an autocrine manner in cells which secrete uPA. All this reveals novel regulatory systems operating through autocrine loops involving uPAR stimuli, Src, MMP and EGFR activation which could mediate fine control of physiological processes as well as contribute to the expression of proliferative and invasive phenotypes of cancerous cells.
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PMID:EGF receptor transactivation by urokinase receptor stimulus through a mechanism involving Src and matrix metalloproteinases. 1472 May 19

C18 unsaturated fatty acids were here found to inhibit proMMP (matrix metalloproteinase)-3 activation by plasmin. This effect was suppressed by lysine ligand competitors, indicating that it was mediated by binding to kringle domains. Surface plasmon resonance analysis demonstrated that oleic acid interacted to a similar extent with plasmin and kringle 5 (KD values of 3.4 x 10(-8) and 5.9 x 10(-8)M) while interaction with kringles 1-2-3 was 10-fold lower. Furthermore, oleic acid stimulated the amidolytic activity of plasmin and mini-plasmin, but not micro-plasmin. Oleic acid also enhanced u-PA (urokinase-type plasminogen activator)-mediated plasminogen activation over 50-fold. Taken together, these data indicate that inhibition of plasmin-induced proMMP-3 activation by unsaturated fatty acids was mediated through their preferential binding to kringle 5. The influence of elaidic acid on the plasmin/MMP-3/MMP-1 proteolytic cascade was assessed ex vivo. Exogenous addition of plasmin to dermal fibroblasts or supplementation of gingival fibroblast culture medium with plasminogen triggered this cascade. In both instances, elaidic acid totally abolished proMMP-3 and proMMP-1 activation. Additionally, a significant decrease in lattice retraction and collagen degradation in a range similar to that obtained with Batimastat was observed when human gingival fibroblasts were cultured in plasminogen-containing type I collagen gels, indicative of the dual influence of unsaturated fatty acids on MMP activation and activity. In conclusion, unsaturated fatty acids or molecules with similar structures could be attractive target for the development of natural pharmacological inhibitors directed against plasmin and/or MMPs in different pathological contexts such, skin UV irradiation, vascular diseases and tumour growth and invasion.
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PMID:Inhibition of plasmin-mediated prostromelysin-1 activation by interaction of long chain unsaturated fatty acids with kringle 5. 1475 64

The target extracellular matrix (ECM) degradation generated by plasminogen activator (PA) and regulated by plasminogen activator inhibitor (PAI) is an event that affects a wide variety of physiological and pathological processes in the ovary. Studies carried out over the past 25 years in a number of laboratories have elucidated some of the biochemical events related to the function and regulation of the PA system in the ovary. Hormone-induced coordinated expression of tissue-type PA (tPA) produced mainly by granulosa cells and its inhibitor PAI-1 secreted by theca cells in the preovulatory follicles is responsible for a controlled and directed proteolysis leading to the rupture of selected follicles in the rat, monkey and other mammals. Increase in tPA and PAI-1 expression in corpus luteum (CL) of rat and monkey at a later stage is well correlated with a sharp decrease in CL progesterone production, indicating its important role in the initiation of luteal regression. In contrast, the urokinase-type PA (uPA) may play an essential role in the early growing follicles during cell proliferation and migration, and in the early CL formation related to ECM degradation and angiogenesis. Ovarian function is also modulated by endogenously-produced local factors that regulate expression of the PA activator and inhibitor, and the MMP system. Thus, the next challenge is to identify the interrelationship between multiple paracrine and autocrine factors and the PA system, and to know how they regulate the protease and the protease inhibitor in the ovary.
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PMID:Plasminogen activator/plasminogen activator inhibitors in ovarian physiology. 1535 63

In mammalian females, follicular units arise from the fragmentation of ovigerous cords, which spread over the first three postnatal days in the rat. The mechanisms underlying such a process of epithelial remodeling involve a specific balance between basal membrane (BM) deposition and degradation that has as yet not been precisely described. We have investigated the contribution of proteases in BM remodeling by localization of transcripts, protein, or enzymatic activity. In addition, we have analyzed BM deposition at the ultrastructural level and by immunofluorescence detection of BM components. At birth, when fragmentation occurred, epithelial cells displayed an upregulation of membrane type 1-matrix metalloproteinase (MT1-MMP) and urokinase-type plasminogen activator (uPA), as well as laminin alpha1 mRNAs. Although MMP2 expression was restricted to mesenchymal cells throughout development, in situ zymography showed that gelatinase-MMP2 activity colocalized with BM deposition inside deepening clefts in the areas of ovigerous cord fragmentation. In the days following birth, gelatin and plasminogen-casein zymography showed an increased enzymatic activity of MMP2 and uPA, respectively. In organotypic cultures of 21-day postconception ovaries, serine protease inhibitors like aprotinin could efficiently block follicle histogenesis. In addition, our results show that the well described and great wave of oocyte attrition characteristic of the days following birth closely correlates with BM remodeling. Altogether, our data show that during follicle histogenesis, ovigerous cord fragmentation results from an acute BM component deposition in deepening clefts and that BM homeostasy involves proteinases of the MMP2/MT1-MMP/TIMP3 and plasminogen/uPA families.
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PMID:Basal membrane remodeling during follicle histogenesis in the rat ovary: contribution of proteinases of the MMP and PA families. 1561 83


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