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:3.4.24.23 (MMP)
4,246 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The chondrocytes of articular cartilage synthesize a number of proteinases which are capable of degrading the component molecules of this specialized extracellular matrix. The use of class-specific proteinase inhibitors indicates that major activities responsible for catabolism of proteoglycan (aggrecan) and collagen are attributable to zinc-dependent metalloproteinases. In this study, we have compared the mRNA expression profiles of two matrix metalloproteinases (MMP-3 and MMP-13) and five disintegrin-metalloproteinases (ADAM-10, ADAM-9, ADAM-15, TNF-alpha-converting enzyme and decysin) by chondrocytes (human, porcine and bovine) from fresh cartilage and in cartilage explant cultures and isolated cells cultured in monolayer or in agarose gels. Such cultures were maintained in the presence or absence of interleukin-1 (IL-1) or all-trans-retinoic acid, two agents which promote cartilage matrix degradation in vitro. Whereas transcripts for all metalloproteinases examined were detected in chondrocytes from human osteoarthritic cartilage in monolayer cultures, mRNAs for ADAM-15 and decysin were not present in fresh osteoarthritic human cartilage or explant cultures. Similarly, expression of porcine and bovine metalloproteinase mRNAs varied with different culture conditions. Novel cDNA sequences obtained for porcine and bovine MMP-3 and MMP-13, porcine ADAM-10, porcine and bovine ADAM-9 and porcine TACE confirmed expression of mRNAs for these molecules by articular chondrocytes. Quantitative RT-PCR analysis was used to determine the effects of IL-1 and retinoic acid on metalloproteinase mRNA levels in human chondrocytes cultured in monolayer and in porcine chondrocytes cultured in agarose. For the MMPs, IL-1 treatment resulted in an approximately two to threefold increase in human and porcine MMP-3 and MMP-13 mRNAs, while retinoic acid treatment caused a statistically significant increase in human MMP-3 mRNA levels, but no significant change in transcript levels for porcine MMP-3 nor human or porcine MMP-13. The mRNA levels for ADAM-15 were elevated in human monolayer chondrocytes exposed to IL-1 or retinoic acid, while transcripts levels for TNF-alpha converting enzyme were increased in response to retinoic acid. In contrast, ADAM-9 mRNA levels were decreased in human monolayer chondrocytes exposed to IL-1 or retinoic acid. The results demonstrate that chondrocyte metalloproteinase expression can vary dependent on cell environment in situ and in vitro, and information on chondrocyte MMP and ADAM gene expression following cytokine (IL-1) or retinoid stimulation.
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PMID:Effects of culture conditions and exposure to catabolic stimulators (IL-1 and retinoic acid) on the expression of matrix metalloproteinases (MMPs) and disintegrin metalloproteinases (ADAMs) by articular cartilage chondrocytes. 1042 42

Along with degradation of type IV collagen in basement membrane, destruction of the stromal collagens, types I and III, is an essential step in the invasive/metastatic behavior of tumor cells, and it is mediated, at least in part, by interstitial collagenase 1 (matrix metalloproteinase 1 (MMP-1)). Because A2058 melanoma cells produce substantial quantities of MMP-1, we used these cells as models for studying invasion of type I collagen. With a sensitive and quantitative in vitro invasion assay, we monitored the ability of these cells to invade a matrix of type I collagen and the ability of a serine proteinase inhibitor and all-trans-retinoic acid to block invasion. Although these cells produce copious amounts of MMP-1, they do not invade collagen unless they are co-cultured with fibroblasts or with conditioned medium derived from fibroblasts. Our studies indicate that a proteolytic cascade that depends on stromal/tumor cell interactions facilitates the ability of A2058 melanoma cells to invade a matrix of type I collagen. This cascade activates latent MMP-1 and involves both serine proteinases and MMPs, particularly stromelysin 1 (MMP-3). All-trans-retinoic acid (10(-6) M) suppresses the invasion of tumor cells by several mechanisms that include suppression of MMP synthesis and an increase in levels of tissue inhibitor of metalloproteinases 1 and 2. We conclude that invasion of stromal collagen by A2058 melanoma cells is mediated by a novel host/tumor cell interaction in which a proteolytic cascade culminates in the activation of pro-MMP-1 and tumor cell invasion.
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PMID:A novel host/tumor cell interaction activates matrix metalloproteinase 1 and mediates invasion through type I collagen. 1046 64

Proteolysis occurs when proteinase activity exceeds inhibitor activity. Proteolysis is normally tightly regulated and is involved in cancer invasion and metastasis. The aim of this study was to compare proteolysis in breast and colorectal cancer. Proteinase and inhibitor expression were analysed in paired tumour and normal tissue samples from 43 breast and 24 colorectal cancer patients using substrate zymography, Western blotting and quenched fluorescence substrate hydrolysis. The expression of the latent forms of matrix metalloproteinase-2 (MMP-2), MMP-3 and MMP-9, urokinase plasminogen activator (uPA), tissue inhibitor of metalloproteinase-1 (TIMP-1) and TIMP-2 expression were observed in both tumour and normal tissue samples from breast and colorectal tissue; however, expression was greater in the tumour tissue. Expression of active MMP-2 and MMP-9 and the total MMP activity were greater in tumour compared to normal samples in both tissues (P < 0.05). The expression of all proteinases and total MMP activity was greater in colorectal tissue than breast tissue samples. Breast and colorectal cancer demonstrated different proteinase profiles, however proteolysis in both tissues was greater in tumour tissue than normal tissue.
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PMID:Proteolysis in human breast and colorectal cancer. 1049 54

Matrix metalloproteinases (MMPs) participate in physiological remodeling of the extracellular matrix. Recently we determined that both fibrinogen (Fg) and cross-linked fibrin (XL-Fb) are substrates for selected MMPs. Specifically, XL-Fb clots were solubilized by MMP-3 (stromelysin 1) by cleavage at gamma Gly 404-Ala 405, resulting in a D-like monomer fragment. Similarly, MMP-7 (matrilysin) and MT1-MMP (membrane type 1 matrix metalloproteinase) solubilized XL-Fb clots. However, the molecular mass of fragment D-dimer, obtained after MMP-7 and MT1-MMP degradation of XL-Fb, is similar to that of fragment D-dimer from plasmin degradation ( approximately 186 kDa). In contrast, fragment D-like monomer, from MMP-3 degradation of both fibrinogen (Fg) and XL-Fb, is similar to fragment D from plasmin degradation of Fg ( approximately 94 kDa). Reduced chains from MMP-3, MMP-7, and MT1-MMP digests of Fg and XL-Fb were subjected to direct sequence analyses and D/D-dimer alpha-chain showed cleavage at both alpha Asp 97-Phe 98 and alpha Asn 102-Asn 103. Degradation of the beta-chain resulted in microheterogeneity of cleavage sites at beta Asp 123-Leu 124, beta Asn 137-Val 138, and beta Glu 141-Tyr 142, whereas all three enzymes cleaved the gamma-chain at gamma Thr 83-Leu 84. In both Fg and XL-Fb, several cleavage sites obtained by proteolysis with MMP-3, MMP-7, and MT1-MMP were found to be in very close proximity to those obtained by plasmin on these same substrates. That does not occur with other MMPs such as MMP-1, -2, and -9 and MT2-MMP. The degradation of XL-Fb by MMPs suggests both plasmin-dependent and independent mechanisms of fibrinolysis that might be relevant in inflammation, angiogenesis, arthritis, and atherosclerosis.
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PMID:Characterization of stromelysin 1 (MMP-3), matrilysin (MMP-7), and membrane type 1 matrix metalloproteinase (MT1-MMP) derived fibrin(ogen) fragments D-dimer and D-like monomer: NH2-terminal sequences of late-stage digest fragments. 1052 39

The aim of the study was to assess the differential intra- and intertumoral heterogeneity and patterns of matrix metalloproteinase expression in human glioblastomas in vivo. 12 glioblastoma samples were analyzed for MMP expression by semi-quantitative RT-PCR. A total of 56 samples (8 adjoining regions of 6 glioblastoma tumors) were immunohistochemically examined for the expression and regional distribution of gelatinase-A (MMP-2), gelatinase-B (MMP-9), matrilysin (MMP-7) and stromelysin-1 (MMP-3). Gelatinase-A mRNA was detected in all samples, gelatinase-B was found in numerous samples. Correspondingly, strong expression levels of both gelatinase protein was seen in immunohistochemistry. Gelatinase-A was expressed by both tumor cells and endothelium while gelatinase-B was found to be restricted to endothelial cells. Stromelysin-1 protein was not detected in any of the samples. Matrilysin was found around tumor cells of three samples from one patient only. The strong immunoreactivity seen for gelatinase-A around tumor cells and blood vessels suggests a role in both tissue degradation and tumor neoangiogenesis which is in accordance with previously published in vitro data. The marked localization of gelatinase-B to the endothelium and its presence in non-infiltrative benign lesions, however, makes a direct proteolytic role of gelatinase-B on ECM components during glioma invasion appear unlikely. Its close association with vascular structures, however, might indicate a link to neoangiogenesis. The significance of matrilysin which was only seen in tumor cells in three samples remains unclear. Stromelysin-1, though strongly expressed in cell lines, does not appear to play a role in glioblastoma tumors in vivo.
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PMID:Heterogeneous regional expression patterns of matrix metalloproteinases in human malignant gliomas. 1057 6

A novel strategy to understand affinity and selectivity for enzyme inhibitors using information from ligands and target protein 3D structures is described. It was applied to 2-arylsulfonyl-1,2,3, 4-tetrahydro-isoquinoline-3-carboxylates and -hydroxamates as inhibitors of the matrix metalloproteinases MMP-3 (stromelysin-1) and MMP-8 (human neutrophil collagenase). As the first step, consistent and predictive 3D-QSAR models were derived using CoMFA, CoMSIA, and GRID/Golpe approaches, leading to the identification of binding regions where steric, electronic, or hydrophobic effects are important for affinity. These models were validated using multiple analyses using two or five randomly chosen cross-validation groups and randomizations of biological activities. Second, 3D-QSAR models were derived based on the affinity ratio IC(50)(MMP-8)/IC(50)(MMP-3), allowing the identification of key ligand determinants for selectivity toward one of both enzymes. In addition to this ligands' view, the third step encompasses a chemometrical approach based on principal component analysis (PCA) of multivariate GRID descriptors to uncover the major differences between both protein binding sites with respect to their GRID probe interaction pattern. The resulting information, based on the accurate knowledge of the target protein 3D structures, led to a consistent picture in good agreement with experimentally observed differences in selectivity toward MMP-8 or MMP-3. The interpretation of all three classes of statistical models leads to detailed SAR information for MMP inhibitors, which is in agreement with available data for binding site topologies, ligand affinities, and selectivities. Thus the combined chemical analyses provide guidelines and accurate activity predictions for designing novel, selective MMP inhibitors.
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PMID:Affinity and selectivity of matrix metalloproteinase inhibitors: a chemometrical study from the perspective of ligands and proteins. 1057 15

We have devised a new drug screening assay to discover anti-cancer drugs which inhibit Ras-mediated cellular signals, by utilizing a Ras-responsive element (RRE)-driven reporter gene system. We found that hypothemycin, an anti-bacterial, reduces RRE-dependent transcription. Treatment of tumor cells with hypothemycin resulted in reduced expression of Ras-inducible genes, including MMP (matrix metalloproteinase)-1, MMP-9, transforming growth factor-beta (TGF-beta), and vascular endothelial growth factor (VEGF), but not that of the constitutively expressed gene, MMP-2. The results of zymography demonstrated that hypothemycin reduced the production of MMP-9 and MMP-3, another Ras-inducible MMP, in the culture medium. Hypothemycin selectively inhibits anchorage-independent growth of Ras-transformed cells in comparison with anchorage-dependent growth. These findings suggest that hypothemycin inhibits Ras-mediated cellular signaling. Daily treatment of tumor-bearing mice with hypothemycin resulted in significant inhibition of tumor growth. Since MMP-1, MMP-3 and MMP-9 play important roles in tumor invasion and TGF-beta and VEGF are involved in tumor angiogenesis, hypothemycin is considered to be an example of a new class of antitumor drugs, whose antitumor efficacy can be at least partly attributed to inhibition of Ras-inducible genes.
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PMID:Antitumor efficacy of hypothemycin, a new Ras-signaling inhibitor. 1059 43

The backbone mobility of the N-terminal domain of tissue inhibitor of metalloproteinases-2 (N-TIMP-2) was determined both for the free protein and when bound to the catalytic domain of matrix metalloproteinase-3 (N-MMP-3). Regions of the protein with internal motion were identified by comparison of the T(1) and T(2) relaxation times and (1)H-(15)N nuclear Overhauser effect values for the backbone amide (15)N signals for each residue in the sequence. This analysis revealed rapid internal motion on the picosecond to nanosecond time scale for several regions of free N-TIMP-2, including the extended beta-hairpin between beta-strands A and B, which forms part of the MMP binding site. Evidence of relatively slow motion indicative of exchange between two or more local conformations on a microsecond to millisecond time scale was also found in the free protein, including two other regions of the MMP binding site (the CD and EF loops). On formation of a tight N-TIMP-2. N-MMP-3 complex, the rapid internal motion of the AB beta-hairpin was largely abolished, a change consistent with tight binding of this region to the MMP-3 catalytic domain. The extended AB beta-hairpin is not a feature of all members of the TIMP family; therefore, the binding of this highly mobile region to a site distant from the catalytic cleft of the MMPs suggests a key role in TIMP-2 binding specificity.
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PMID:The effect of matrix metalloproteinase complex formation on the conformational mobility of tissue inhibitor of metalloproteinases-2 (TIMP-2). 1060 Dec 86

A high quality solution structure of the matrix metalloproteinase inhibitory N-terminal domain of recombinant human tissue inhibitor of metalloproteinases-1 (N-TIMP-1) has been determined. For the rigidly packed residues, the average RMSD to the mean structure is 0. 57 A for the backbone atoms and 1.00 A for all heavy atoms. Comparison of the solution structure of free N-TIMP-1 with the crystal structure of TIMP-1 bound to the catalytic domain of MMP-3 ( Gomis-R]uth et al., 1997 ) shows that the structural core of the beta barrel flanked by helices is nearly unchanged by the association with MMP-3, evident from a backbone RMSD of 1.15 A. However, clear differences in the conformation of the MMP-binding ridge of free and MMP-bound TIMP-1 suggest induced fit throughout the ridge. The MMP-dependent conformational changes in the ridge include a dramatic bending of AB loop residues Glu28 through Leu34, moderate hinge bending of the CD-loop about residues Ala65 and Cys70, and modest bending of the Cys1 through Pro6 segment. A large number of interresidue Nuclear Overhauser enhancements (NOEs) augmented by stereospecific assignments, torsion restraints, and dipolar couplings (an average of 18 non-trivial restraints per residue) engender confidence in these structural inferences. A tight cluster of three lysine residues and one arginine residue atop beta-strands A and B, and identical among TIMP sequences, form the heart of a highly conserved electropositive patch that may interact with anionic components of the extracellular matrix.
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PMID:NMR structure of tissue inhibitor of metalloproteinases-1 implicates localized induced fit in recognition of matrix metalloproteinases. 1062 24

Matrix metalloproteinase-9 (MMP-9) is a member of the MMP family that has been associated with degradation of the extracellular matrix in normal and pathological conditions. A unique characteristic of MMP-9 is its ability to exist in a monomeric and a disulfide-bonded dimeric form. However, there exists a paucity of information on the properties of the latent (pro-MMP-9) and active MMP-9 dimer. Here we report the purification to homogeneity of the monomer and dimer forms of pro-MMP-9 and the characterization of their biochemical properties and interactions with tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2. Gel filtration and surface plasmon resonance analyses demonstrated that the pro-MMP-9 monomeric and dimeric forms bind TIMP-1 with similar affinities. In contrast, TIMP-2 binds only to the active forms. After activation, the two enzyme forms exhibited equal catalytic competence in the turnover of a synthetic peptide substrate with comparable kinetic parameters for the onset of inhibition with TIMPs and for dissociation of the inhibited complexes. Kinetic analyses of the activation of monomeric and dimeric pro-MMP-9 by stromelysin 1 revealed K(m) values in the nanomolar range and relative low k(cat) values (1.9 x 10(-3) and 4.1 x 10(-4) s(-1), for the monomer and dimer, respectively) consistent with a faster rate (1 order of magnitude) of activation of the monomeric form by stromelysin 1. This suggests that the rate-limiting event in the activation of pro-MMP-9 may be a requisite slow unfolding of pro-MMP-9 near the site of the hydrolytic cleavage by stromelysin 1.
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PMID:Characterization of the monomeric and dimeric forms of latent and active matrix metalloproteinase-9. Differential rates for activation by stromelysin 1. 1064 27


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