Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.35 (matrix metalloproteinase 9)
 2,207 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Membrane vesicles are shed by tumor cells both in vivo and in vitro. Although their functions are not well understood, it has been proposed that they may play multiple roles in tumor progression. We characterized membrane vesicles from human HT1080 fibrosarcoma cell cultures for the presence of proteinases involved in tumor invasion. By gelatin zymography and Western blotting, these vesicles showed major bands corresponding to the zymogen and active forms of gelatinase B (MMP-9) and gelatinase A (MMP-2) and to the MMP-9. tissue inhibitor of metalloproteinase 1 complex. Both gelatinases appeared to be associated with the vesicle membrane. HT1080 cell vesicles also showed a strong, plasminogen-dependent fibrinolytic activity in 125I fibrin assays; this activity was associated with urokinase plasminogen activator, as shown by casein zymography and Western blotting. Urokinase was bound to its high affinity receptor on the vesicle membrane. Addition of plasminogen resulted in activation of the progelatinases associated with the vesicles, indicating a role of the urokinase-plasmin system in MMP-2 and MMP-9 activation. We propose that vesicles shed by tumor cells may provide a large membrane surface for the activation of membrane-associated proteinases involved in extracellular matrix degradation and tissue invasion.
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PMID:Urokinase plasminogen activator and gelatinases are associated with membrane vesicles shed by human HT1080 fibrosarcoma cells. 920 45

The expression of matrix metalloproteinase-2 (MMP-2; 72 kDa type IV collagenase/gelatinase A) and MMP-9 (92 kDa type IV collagenase/gelatinase B) was immunohistochemically investigated in 79 T1 adenocarcinomas of the lung using non-commercial polyclonal anti-MMP-2 and -9 antibodies. Thirty-two (41%) and 22 (28%) among the 79 cases were positive in the tumor cells for MMP-2 and -9, respectively. The incidences of MMP-2 and -9 immunoreactivities were higher (64 and 45%, respectively) in poorly differentiated tumors than in well differentiated tumors (36 and 25%, respectively), and lower in bronchioloalveolar carcinoma (22 and 10%, respectively) compared with other subtypes of adenocarcinoma. The prognosis for patients with MMP-2 and/or -9 positive immunoreactivities was significantly poorer than for those with a MMP-negative tumor (P < 0.05). The degree of collagenization was divided into four grades, and tumors with a small to abundant amount of collagen (grade 2 and grade 3 fibrosis) had a higher incidence of immunoreactivity to both types of MMP. It is estimated that these expressions might be responsible for tumor invasion, metastasis, and for grade 2 and grade 3 fibrosis in T1 adenocarcinoma of the lung.
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PMID:Expression of matrix metalloproteinase (gelatinase) in T1 adenocarcinoma of the lung. 923 85

Connective tissues synthesise and secrete a family of matrix metalloproteinases (MMPs) which are capable of degrading most components of the extracellular matrix. Animal studies suggest that the MMPs play a role in bone turnover. Using specific polyclonal antisera, immunohistochemistry was used to determine the patterns of synthesis and distribution of collagenase (MMP-1), stromelysin (MMP-3), gelatinase A (MMP-2) and gelatinase B (MMP-9) and of the tissue inhibitor of metalloproteinases-1 (TIMP-1) within developing human osteophytic bone. The different MMPs and TIMP showed distinct patterns of localisation. Collagenase expression was seen at sites of vascular invasion, in osteoblasts synthesising new matrix and in some osteoclasts at sites of resorption. Chondrocytes demonstrated variable levels of collagenase and stromelysin expression throughout the proliferative and hypertrophic regions, stromelysin showing both cell-associated and strong matrix staining. Intense gelatinase B expression was observed at sites of bone resorption in osteoclasts and mononuclear cells. Gelatinase A was only weakly expressed in the fibrocartilage adjacent to areas of endochondral ossification. There was widespread but variable expression of TIMP-1 throughout the fibrous tissue, cartilage and bone. These results indicate that MMPs play a role in the development of human bone from cartilage and fibrous tissue and are likely to have multiple functions.
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PMID:Distribution of matrix metalloproteinases and their inhibitor, TIMP-1, in developing human osteophytic bone. 927 57

Physical disruption of an atheromatous lesion often underlies acute coronary syndromes. Matrix-degrading enzymes, eg, matrix metalloproteinases (MMPs), may cause loss in mechanical integrity of plaque tissue that favors rupture. T lymphocytes accumulate at sites where atheromata rupture, but the mechanisms by which these immune cells may contribute to plaque destabilization are unknown. This study tested the hypothesis that the T-lymphocyte surface molecule CD40 ligand (CD40L), recently localized in atherosclerotic plaques, regulates the expression of MMPs in human vascular smooth muscle cells (SMCs), the most numerous cell type in arteries. We report here that stimulated human T lymphocytes induced the expression of the matrix-degrading enzymes, ie, interstitial collagenase (MMP-1), stromelysin (MMP-3), gelatinase B (MMP-9), and activated gelatinase A (MMP-2), in human vascular SMCs by cell contact via CD40 ligation, as demonstrated by Western blot analysis, zymography, and antibody neutralization. Recombinant human CD40L (rCD40L) induced de novo synthesis of MMP-1, MMP-3, and MMP-9 on vascular SMCs and stimulated the expression of these enzymes to a greater extent than did maximally effective concentrations of tumor necrosis factor-alpha or interleukin-1beta, established agonists of MMP expression. Interferon gamma, another T-lymphocyte- derived cytokine, inhibited the induction of MMPs by rCD40L. Immunohistochemical analysis of human coronary atheromata colocalized MMP-1 and MMP-3 with CD40-positive SMCs. These results demonstrated that CD40 ligand, expressed on T lymphocytes, promoted the expression of matrix-degrading enzymes in vascular SMCs and thus established a new pathway of immune-modulated destabilization in human atheromata.
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PMID:Regulation of matrix metalloproteinase expression in human vascular smooth muscle cells by T lymphocytes: a role for CD40 signaling in plaque rupture? 928 47

The attachment of the blastocyst to the uterine luminal epithelium and the subsequent invasion by trophoblast cells through the stroma and deciduum occur in a highly regulated manner by remodeling of the extracellular matrix. We investigated the temporal and spatial expression of mRNAs for four matrix metalloproteinases (MMPs; MMP-2 [gelatinase A], MMP-3 [stromelysin 1], MMPs; MMP-2 [gelatinase B], and MMP-13 [collagenase 3]) and tissue inhibitors of metalloproteinases (TIMPs; TIMP-1, TIMP-2, and TIMP-3) in the mouse uterus from days 1 to 8 of pregnancy. Northern blot analyses showed the transcripts for MMP-2, MMP-3, RNA on these days. However, MMP-13 mRNA was not detected in the uterus, and only weak signals for MMP-3 mRNA were detected in the myometrium. Striking expression was observed with MMP-2 mRNA in the subepithelial stroma on days 3-5. With the progression of decidualization on day 6, signals were primarily in the secondary decidual zone. On day 8, MMP-2 mRNA was localized at the site of placenta formation in the mesometrial pole. Signals for MMP-9 mRNA were first detected in a small population of stromal cells exclusively at the site of implantation on day 5 at the antimesometrial pole. However, the most pronounced expressed was noted in trophoblast giant cells on day 8. TIMP-1 mRNA was present in the myometrium on day 1. On days 2-5, modest signals were detected in the stroma, and on days 6 and 8, they were in the secondary decidual zone. Localization of TIMP-2 mRNA was similar to that of TIMP-1 except it was restricted to the stroma on day 1. The regulation of TIMP-3 was more pronounced. While a gradual increase in signals was observed in stromal cells from days 1 to 4, strong signals were detected in antimesometrial stromal cells at the sites of blastocyst attachment on day 5. On days 6 and 7, even stronger signals were present in the primary decidual zone surrounding the embryo, and on day 8 signals were localized primarily in the mesometrial decidual bed. These results suggest that MMP-2 may participate in the early phase of decidualization and neovascularization required for placentation. The restricted MMP-9 expression in stromal cells on day 5 and in trophoblast giant cells on day 8, coupled with the expression of TIMP-3 in the stroma surrounding the embryo, suggests that a fine balance between MMP-9 and TIMP-3 may regulate trophoblast invasion in the uterus.
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PMID:Expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases in the mouse uterus during the peri-implantation period. 929 79

The obese Zucker rat represents a model of obesity combined with insulin resistance and hyperlipidaemia, which over a period of several months develops spontaneous glomerulosclerosis. The present study addressed the question as to whether glomerular sclerosis was associated with alterations in the degradation of matrix components. In the early phase (up to 6 months) glomeruli from obese rats displayed increased total collagen content (+64%) and decreased gelatinolytic activity (-34%) as compared to lean control animals. This decline in glomerular gelatinolytic activity was due to a reduction in gelatinase B [matrix metalloproteinase (MMP)-9]. Glomerular MMP-9 mRNA was reduced 4.6 +/- 0.6-fold (n = 3; p < 0.05), MMP-9 protein was not detectable by Western blotting and MMP-9 activity was considerably suppressed in gelatin zymograms. MMP-2, in terms of mRNA expression and activity, was unchanged. Tissue inhibitor of metalloproteinases (TIMP)-1 mRNA expression, TIMP-1 protein (immunohistochemistry) and TIMP-1 activity (reverse zymography) were enhanced in glomeruli from obese rats, while TIMP-2 mRNA remained unchanged. Moreover, mRNA for the alpha 1 IV collagen chain was 2.1 +/- 0.8-fold higher in glomeruli isolated from obese animals (n = 3; p < 0.05). These findings indicate that matrix expansion in glomeruli from obese Zucker rats is due to both enhanced synthesis of matrix components as well as reduced degradation by matrix metalloproteinases. Apparently the latter effect is based on a reduction in MMP-9 and up-regulation of its inhibitor TIMP-1.
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PMID:Differential regulation of glomerular gelatinase B (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) in obese Zucker rats. 930 Feb 40

Expression of interleukin-8 (IL-8) by human melanoma cells correlates with their metastatic potential. Moreover, UV-B irradiation of primary cutaneous melanoma cells induces IL-8 mRNA and protein production and increases both tumor growth and metastasis in nude mice. Although IL-8 has been shown to be an angiogenic factor, the biological consequences of increased IL-8 production by melanoma cells and the role of IL-8 in the metastatic process remains unclear. The purpose of this study was to determine the role of IL-8 in tumor growth and metastasis of human melanoma cells. Nonmetastatic SB-2 melanoma cells with negligible levels of IL-8 were transfected with IL-8 cDNA and subsequently analyzed for changes in their tumorigenic and metastatic potential. Enforced expression of IL-8 rendered the melanoma cells highly tumorigenic and increased their metastatic potential as compared with parental and control transfected cells. The IL-8-transfected cells displayed up-regulation in M(r) 72,000 collagenase type IV (MMP-2) mRNA and collagenase activity and increased invasiveness through Matrigel-coated filters. Moreover, when the MMP-2 promoter was linked upstream of the chloramphenicol acetyltransferase (CAT) reporter gene, CAT activity was up-regulated in IL-8 but not in control transfected cells, suggesting that IL-8 is involved in MMP-2 gene transcription. Activation of type IV collagenase by IL-8 can enhance the invasion of host stroma by the tumor cells and increase angiogenesis and, hence, metastasis.
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PMID:Expression of interleukin-8 by human melanoma cells up-regulates MMP-2 activity and increases tumor growth and metastasis. 932 44

The temporal relationship of matrix metalloproteinases (MMPs) and a specific tissue inhibitor (TIMP-1) has been examined by reverse transcription-polymerase chain reaction and substrate zymography, after balloon catheter angioplasty of the rat carotid artery. The contralateral uninjured carotid artery was used as a comparative control. Of the MMPs examined, only MMP-2 (72-kDa gelatinase) was produced constitutively by normal uninjured arteries. After injury, MMP-2 mRNA levels fell compared with the uninjured arteries; by 24 hours, levels had increased 2-fold. Zymography showed that the inactive form of MMP-2 predominated in uninjured vessels, but after injury, the level of the active form was increased. MMP-9 (92-kDa gelatinase) mRNA levels and activity peaked at 6 hours after injury and were still detectable at 7 days. MMP-3 (stromelysin) expression was detectable at low levels as early as 2 hours after injury and showed an approximate 2-fold increase of expression at 7 days. The presence of the active protein paralleled the mRNA expression. The inhibitor TIMP-1 mRNA was first detected 6 hours after injury and showed a marked peak of expression at 24 hours; however, no expression was detected by 7 days. The presence of a constitutively expressed, low molecular weight caseinolytic enzyme (27 kDa) was observed, and the induction of a caseinolytic enzyme (30 kDa) was noted that was induced as early as 2 hours after injury, peaked at 6 hours, and was barely detectable by 7 days. These results demonstrate that the process of extracellular matrix breakdown by MMPs after balloon catheter-induced injury is controlled by a tightly regulated temporal response by the genes responsible for the production of these enzymes and their inhibitor and by post-translational activation of the proenzymes.
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PMID:Expression of matrix metalloproteinases and their inhibitor TIMP-1 in the rat carotid artery after balloon injury. 932 85

The ATF/CREB family of eukaryotic transcription factors contain the bZIP structural motif and mediate their transcriptional activities via heterodimerization with ATF and AP-1 family members. Quenching of CREB-associated proteins by a dominant-negative CREB (KCREB) that is mutated within its DNA-binding domain decreases radiation resistance of human melanoma cells. The purpose of this study was to determine the role of CREB in tumor growth and metastasis of human melanoma using KCREB. Highly metastatic MeWo human melanoma cells were transfected with the KCREB expression vector and subsequently analysed for changes in their tumorigenic and metastatic potential. Expression of KCREB in MeWo human cells decreased their tumorigenic and metastatic potential in nude mice compared with parental and control transfected cells. The KCREB-transfected cells displayed downregulation of 72 kDa collagenase type IV (MMP-2) mRNA expression and activity and decreased invasiveness through Matrigel-coated filters. Moreover, transcriptional activities mediated by the CAT gene driven by the MMP-2 promoter were decreased by 14-45-fold in KCREB-transfected cells. In addition, the cell-surface adhesion molecule MCAM/MUC18 that is involved in metastasis of human melanoma was downregulated in the KCREB-transfected cells. These data indicate that, through their transcriptional activities, CREB and its associated proteins play an important role in the acquisition of the metastatic phenotype of human melanoma cells.
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PMID:Dominant-negative CREB inhibits tumor growth and metastasis of human melanoma cells. 936 24

Phospholipase C (PLC) is a putative virulence factor of several pathogenic bacteria. We studied if exogenous PLC would perturb epithelial behavior in infected tissues. Gelatin and casein zymography of cell culture medium indicated that the broad-spectrum PLC of Bacillus cereus induced matrix metalloproteinase (MMP) production in epithelial cells of human skin (NHEK), human gingiva (HGE), and porcine periodontal ligament (PLE). In all three cell types, the strongest increase (ninefold) at 0.1 U/ml was seen in the MMP-9 (92-kDa gelatinase) activity, and the effect was dose dependent in the range of 0.1 to 1.0 U/ml. A relatively weaker increase (twofold) in MMP-2 (72-kDa gelatinase) was also observed in each cell type. PLC induction of MMP-3 (48-kDa stromelysin) was also seen in NHEK and HGE on gelatin and more sensitively for PLE by casein zymography (fivefold). Total gelatinolytic activity as measured by degradation of 14C-labeled denatured type I collagen increased by about 18-fold (NHEK), 12-fold (HGE), and 14-fold (PLE). Northern analysis showed a clear increase in the MMP-9, and a minor increase in MMP-3 mRNA levels but no significant increase in MMP-2 mRNA levels. Further studies with PLE revealed that MMP-9 induction by PLC progressively increased with the length of cell culture time in the absence of serum. PLC induction of MMPs was polar, with MMP-9 and MMP-3 secreted primarily in the apical direction and MMP-2 secreted mainly in the basal direction. The PLC effect was blocked by neomycin, an inhibitor of the phosphoinositol signal pathway. No significant effects were observed in MMP expression with the calcium ionophore A23187 or phospholipase A2. Morphologically, PLC treatment resulted in reduced contacts between the cultured cells and loss of the cell surface microvilli. These results suggest that PLC secreted by bacterial pathogens may disrupt epithelium of infected tissue and increase the subepithelial tissue destruction through induction of MMPs.
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PMID:Bacterial phospholipase C upregulates matrix metalloproteinase expression by cultured epithelial cells. 939 78


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