Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.24.3 (collagenase)
18,340 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We report a novel 3-dimensional model for visualizing tumor cell migration across a nylon mesh-supported gelatin matrix. To visualize migration across these model barriers, cell proteolytic activity of the pericellular matrix was detected using Bodipy-BSA (fluorescent upon proteolysis) and DQ collagen (fluorescent upon collagenase activity). For 3-dimensional image reconstruction, multiple optical images at sequential z axis positions were deconvoluted by computer analysis. Specificity was indicated using well-known inhibitors. Using these fluorescent proteolysis markers and imaging methods, we have directly demonstrated proteolytic and collagenolytic activity during tumor cell invasion. Moreover, it is possible to visualize migratory pathways followed by tumor cells during matrix invasion. Using cells of differing invasive potentials (uPAR-negative T-47D wild-type and uPAR-positive T-47D A2--1 cells), we show that the presence of the T-47D-A2--1 cells facilitates the entry of T-47D wild-type cells into the matrix. In some cases, wild-type cells follow T-47D A2--1 cells into the matrix whereas other T-47D-wild-type cells appear to enter without the direct intervention of T-47D A2--1 cells. Thus, we have developed a new 3-dimensional model of tumor cell invasion, demonstrated protein and collagen disruption, mapped the pathways followed by tumor cells during migration through an extracellular matrix, and illustrated cross-talk among tumor cell populations during invasion.
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PMID:Tumor cell invasion of model 3-dimensional matrices: demonstration of migratory pathways, collagen disruption, and intercellular cooperation. 1129 53

Proteases of the plasminogen activator (PA) and matrix metalloproteinase (MMP) system play an important role in smooth muscle cell (SMC) migration and neointima formation after vascular injury. Inhibition of either PAs or MMPs has previously been shown to result in decreased neointima formation in vivo. To inhibit both protease systems simultaneously, a novel hybrid protein, TIMP-1.ATF, was constructed consisting of the tissue inhibitor of metalloproteinase-1 (TIMP-1) domain, as MMP inhibitor, linked to the receptor-binding amino terminal fragment (ATF) of urokinase. By binding to the u-PA receptor this protein will not only anchor the TIMP-1 moiety directly to the cell surface, it will also prevent the local activation of plasminogen by blocking the binding of urokinase-type plasminogen activator (u-PA) to its receptor. Adenoviral expression of TIMP-1.ATF was used to inhibit SMC migration and neointima formation in human saphenous vein segments in vitro. SMC migration was inhibited by 65% in Ad.TIMP-1.ATF-infected cells. Infection with adenoviral vectors encoding the individual domains, Ad.TIMP-1 and Ad.ATF, reduced migration by 32% and 52%, respectively. Neointima formation in saphenous vein organ cultures infected with Ad.TIMP-1.ATF was inhibited by 72% compared with 42% reduction after Ad.TIMP-1 infection and 34% after Ad.ATF infection. These data show that binding of TIMP-1.ATF hybrid protein to the u-PA receptor at the cell surface strongly enhances the inhibitory effect of TIMP-1 on neointima formation in human saphenous vein cultures.
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PMID:Gene transfer of the urokinase-type plasminogen activator receptor-targeted matrix metalloproteinase inhibitor TIMP-1.ATF suppresses neointima formation more efficiently than tissue inhibitor of metalloproteinase-1. 1243 29

Age-related macular degeneration (ARMD), proliferative vitreoretinopathy (PVR) and uveitis are characterized by RPE motility through the ECM of retinal lesions. The purpose of this study was to test the hypothesis that multiple proteolytic systems are functionally intact at the HRPE surface and peri-cellular region and that these activities are differentially modulated by IL-1beta. HRPE cells were evaluated: (1). as individual cells or cell extracts, (2). during migration across three-dimensional ECM-like layers and (3). in tissue sections. The urokirase plasminogen activator receptor (uPAR; CD87) was detected on HRPE cells as well as its functional activity. Although uPAR was associated with CD11b (CR3) on live resting cells, polarized migratory HRPE cells were found to dissociate uPAR from CR3; uPAR then translocated to anterior pole of the cell, where it enhanced PAI-1-inhibitable local proteolytic activity. The relative contribution of uPAR and collagenase in HRPE migration was evaluated using three-dimensional gelatin matrices. Interestingly, uPAR/uPA was found to play a key role in migration across these layers. IL-1 upregulated uPAR, collagenase, and elastase activities, suggesting that cytokines may affect the invasive program of HRPE cells in vivo. Immunohistochemistry for uPAR was performed in sections of human retina. Immunoreactive uPAR was present along the HRPE basolateral membrane in retinal sections and in sections of diseased retinal tissue at an enhanced level. Our results suggest that multiple proteolytic systems are present in association with HRPE and that the uPAR/uPA system may be particularly important.
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PMID:Human RPE cell lysis of extracellular matrix: functional urokinase plasminogen activator receptor (uPAR), collagenase and elastase. 1269 22

The aim of this study was to determine the expression of proteinases and inhibitors from the matrix metalloproteinase (MMP) (MMPs 1, 2, 3, 9, tissue inhibitors of metalloproteinases (TIMPs) 1, 2) and plasminogen activator ((PA) urokinase (uPA), tissue type (tPA), uPAR, plasminogen activator inhibitors (PAIs) 1, 2) systems in colorectal cancer pathology by gelatin zymography, enzyme-linked immunosorbent assays (ELISAs) and quenched fluorescent substrate hydrolysis. The levels of all studied MMPs, uPA, uPAR, TIMP-1 and PAIs were significantly greater in tumour tissues than normal tissues. However, tPA and TIMP-2 were greater in normal colon (P<0.05, Mann-Whitney) e.g. PAI-1: tumour, median 14.9 (range 0.2-80.2) ng/mg total protein; normal, 2.1 (0.1-65.0). Tumour levels of several factors, in particular MMP-1 and PAI-1, correlated with pathology, i.e. Dukes' stage, differentiation, lymphatic or vascular invasion and tumour depth. The interactions between proteinase systems in colorectal cancer are complex and the balance between active proteinases and their inhibitors is important for extracellular matrix (ECM) degradation/remodelling at each stage of the metastatic cascade.
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PMID:The plasminogen activator and matrix metalloproteinase systems in colorectal cancer: relationship to tumour pathology. 1270 68

Hepatocyte growth factor (HGF) was suggested to play an important role in the regulation of mitogenesis, motogenesis, angiogenesis, migration and invasion for various types of cells, and acts through a specific membrane receptor encoded by c-met proto-oncogene. However, the mechanism of the effect of HGF on tumor invasion of prostate cancer cells remains unclear. We investigated the effect of HGF on the invasion of PC-3 and DU-145 prostate cancer cells through a reconstituted basement membrane (Matrigel), the haptotactic migration to fibronectin substrate, the expression of protein and mRNA for matrix metalloproteinases (MMP)-1 and -9, membrane-type 1-MMP (MT1-MMP), urokinase-type plasminogen activator (u-PA) and its receptor (uPAR). HGF increased both Matrigel invasion and haptotactic migration of prostate cancer cells. Furthermore, HGF also increased the production of MMP-1 and -9, MT1-MMP, u-PA and uPAR of these cells. These results suggested that HGF increased the invasive potential of prostate cancer cells probably through enhancement of cell motility and the production of MMPs and u-PA.
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PMID:Effect of hepatocyte growth factor on invasion of prostate cancer cell lines. 1279 60

Matrix metalloproteinase (MMP) is critical for carcinoma progression. In our study, we evaluated the prognostic significance of the major MMP family such as MMP-3, MMP-9, MMP-11 and MT1-MMP at the mRNA in 44 esophageal squamous cell carcinoma (ESCC) that were previously characterized for MMP-7, MMP-1 and MMP-2, and their relation to urokinase system (uPA and uPAR). MT1-MMP, MMP-11 and MMP-2 expressions are closely associated with each other, while MMP-9 and uPAR expressions are inversely associated with the former group. There is no MMP related to clinicopathological factors; however, patients with high MT1-MMP could show worse prognosis, as compared to those with low MT1-MMP expression (p=0.01), as well as MMP-11 did (p=0.02). Both MMP showed clear expression of carcinoma cells by immunohistochemistry. In patients with high MT1-MMP, recurrence was more prominent (23/26: 88.5%) than those with low MT1-MMP (7/18: 38.9%) (p=0.0016). In the 20 cases who died within 3 years, all 15 cases with high MT1-MMP showed initial recurrence of distant metastasis, and the other 5 cases with low MT1-MMP showed locoregional recurrence (p=0.000064). These results could indicate that there is a relevant mechanism of associated expression of clinically significant MMP and that among them, MT1-MMP plays the most critical role in ESCC progression.
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PMID:Differential expression of MMP and uPA systems and prognostic relevance of their expression in esophageal squamous cell carcinoma. 1506 82

Cancer invasion and metastasis develop through a sequence of processes involving loss of cell-cell and cell-matrix adhesions, proteolysis and induction of angiogenesis. We reviewed the current literature on the molecules that have been shown to play a significant role in these three steps of metastatisation in bladder cancer (BC) cells and their host microenvironment. Particular emphasis was given to markers that are assessable through immunohistochemistry and for which an additional prognostic value over the TNM variables has been recognized, in order to identify a subset of tumour markers readily available for application in daily clinical practice. We conclude that markers such as E-cadherin, Sialosyl-LeX, laminin, collagen IV, TSP-1 and MVD are useful prognostic markers, alpha, beta, and gamma catenin, MMP-2 and -9, uPAR, PD-ECGF and Bfgf can be considered potentially useful, while research on CD44, MMP-1 and -3, uPA, cathepsin D and VEGF has proved inconclusive. Further research in this field should concentrate on the molecules listed in the first group.
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PMID:Metastasis markers in bladder cancer: a review of the literature and clinical considerations. 1530 99

Protease activity promotes the progression and rupture of atherosclerotic plaques. LDL has been described to become enzymatically modified within the vessel wall yielding an atherogenic moiety (E-LDL). We studied the effect of E-LDL on the activation of plasminogen and matrix metalloproteinases (MMPs) in monocytes and vascular smooth muscle cells (VSMCs) as well as on MMP activation during cellular interactions. Human monocytes, monocytic MonoMac6 cells and human VSMCs were incubated with human native LDL (n-LDL) or E-LDL for 24 hours. E-LDL in contrast to n-LDL induced substantial activation of the plasminogen activation system as well as of the MMP system in monocytic cells, as measured by enhanced cell surface expression of the urokinase receptor (uPAR),the extracellular matrix metalloproteinase Inducer (EMMPRIN) and the membrane type-1 MMPs (MT1-MMP,MMP-14), as well as by secretion of active uPA, and of MMP-9. Consistently, E-LDL-treated monocytes exhibited increased transmigration through "matrigel", which was specifically abrogated by the MMP inhibitor galardin or the plasmin inhibitor aprotinin. In VSMCs, E-LDL induced MMP-1 and MMP-2 secretion. Moreover, monocyte incubation with supernatants of E-LDL-treated (but not n-LDL-treated) VSMCs strongly induced MMP-9 in monoytes, which was inhibited by blocking mAb anti-TNF-alpha. Together, enzymatical modification of LDL allows a direct activation of MMP expression in monocytes and VSMCs, and indirectly promotes the induction of paracrine, cytokine-mediated intercellular activation processes. There by, E-LDL may contribute to atheroprogression, inflammation and plaque rupture.
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PMID:Plasminogen and matrix metalloproteinase activation by enzymatically modified low density lipoproteins in monocytes and smooth muscle cells. 1584 17

Chronic inflammatory diseases are associated with connective tissue turnover that involves a series of proteases, which include the plasminogen activation system and the family of matrix metalloproteinases (MMPs). Urokinase-type plasminogen activator (uPA) and plasmin, in addition to their role in fibrinolysis and activation of pro-MMPs, have been shown to transduce intracellular signals through specific receptors. The potential for uPA and plasmin to also contribute to connective tissue turnover by directly regulating MMP production was examined in human monocytes. Both catalytically active high m.w. uPA, which binds to the uPAR, and low m.w. uPA, which does not, significantly enhanced MMP-1 synthesis by activated human monocytes. In contrast, the N-terminal fragment of uPA, which binds to uPAR, but lacks the catalytic site, failed to induce MMP-1 production, indicating that uPA-stimulated MMP-1 synthesis was plasmin dependent. Endogenous plasmin generated by the action of uPA or exogenous plasmin increased MMP-1 synthesis by signaling through annexin A2, as demonstrated by inhibition of MMP-1 production with Abs against annexin A2 and S100A10, a dimeric protein associated with annexin A2. Interaction of plasmin with annexin A2 resulted in the stimulation of ERK1/2 and p38 MAPK, cyclooxygenase-2, and PGE(2), leading to increased MMP-1 production. Furthermore, binding of inactive plasmin to annexin A2 inhibited plasmin induction of MMP-1, suggesting that inactive plasmin may be useful in suppressing inflammation.
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PMID:Urokinase-type plasminogen activator stimulation of monocyte matrix metalloproteinase-1 production is mediated by plasmin-dependent signaling through annexin A2 and inhibited by inactive plasmin. 1770 46

The identification of high-risk patients with thyroid cancer and the preoperative differentiation between follicular adenoma and carcinoma remain clinically challenging. Our study was conducted to analyze whether the quantification of matrix metalloproteinases (MMPs) and urokinase-type plasminogen activator receptor (u-PAR) and transcription factor binding to the u-PAR promoter improve prognostic predictability and differential diagnosis of thyroid tumors. Tumor/normal tissue was collected from 69 prospectively followed patients with thyroid carcinomas (papillary, medullary, follicular and anaplastic, PTC, MTC, FTC and ATC) or follicular adenomas. U-PAR, MMP-1, MMP-7 and MMP-9 amounts were determined by ELISA, and transcription factor binding was determined by electrophoretic mobility shift assay. Binding of transcription factors to the u-PAR promoter was observed, but not associated with u-PAR expression. Carcinomas except MTC expressed significantly more u-PAR/MMPs than adenomas/normal tissues, this being associated with advanced pT- or M-stages. MMP-1 and MMP-9 were significantly higher in follicular carcinomas than in adenomas. In carcinomas, high u-PAR-gene expression correlated significantly with high MMP-9, the latter being associated with MMP-7 in normal tissues. Poor survival in differentiated tumors was associated in trend (p = 0.07); poor survival of all patients (p = 0.043) and especially of patients with carcinomas of follicular origin (including ATC), but not medullary carcinomas, were significantly associated with high u-PAR-protein (p = 0.015). Quantification of u-PAR is of prognostic relevance in thyroid carcinomas of non-c-cell origin, and u-PAR in part may be regulated nontranscriptionally in thyroid cancers. This is the first study to suggest MMP-1/-9 as significant differentiation markers between follicular adenoma and follicular carcinoma.
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PMID:Urokinase receptor, MMP-1 and MMP-9 are markers to differentiate prognosis, adenoma and carcinoma in thyroid malignancies. 1948 10


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