Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.23 (MMP)
 4,246 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Production of vascular endothelial growth factor (VEGF) by cancer cells at invasive and metastatic sites is an important aspect of tumor angiogenesis. Although known primarily as a mitogen and a vascular permeability factor (VPF) for endothelial cells, VEGF/VPF has been proposed to induce the expression of procoagulant factors in endothelial cells. In this study, we have explored the ramifications of VEGF induction of tissue factor (TF) in human umbilical vein endothelial cells (HUVECs) and subsequent activation of progelatinase A. Within 3 hr of incubation with VEGF/VPF, endothelial cells accelerate TF generation as measured using chromogenic substrate assays for coagulation factors Xa and thrombin. Incubation of VEGF/VPF-pre-treated cells with prothrombin and factors X, Va, and VIIa at 37 degrees C and subsequent generation of thrombin resulted in activation of secreted endothelial progelatinase A as demonstrated by gelatin zymography. Anti-thrombin III or antibodies to TF inhibited thrombin generation and progelatinase A activation. VEGF/VPF also directly increased HUVEC secretion of interstitial collagenase, tissue inhibitor of metalloproteinases (TIMP-1) and, to a lesser extent, gelatinase A. The effect of thrombin on endothelial proliferation in serum-free media was examined. Thrombin was a growth factor for HUVECs at a lower dose than that required for progelatinase A activation. Whereas TIMP-2 abrogated thrombin-induced progelatinase A activation, it had no significant effect on thrombin-induced endothelial cell growth. We propose that an early step in tumor angiogenesis involves VEGF-induced thrombin generation and increased MMP production with subsequent activation of endothelial progelatinase A and degradation of the underlying basement membrane.
 ...
PMID:Vascular endothelial growth factor induces tissue factor and matrix metalloproteinase production in endothelial cells: conversion of prothrombin to thrombin results in progelatinase A activation and cell proliferation. 949 49

Elevated expression of matrix metalloproteinases (MMPs), a family of secreted proteinases that degrade matrix components of basement membranes and connective tissues, is strongly correlated with malignant expression in various human epithelial cancers and epithelial cancer cell lines. We have tested whether elevated levels of MMP expression are also associated with malignant progression in human cutaneous squamous cell carcinoma. Constitutive levels of expression of steady-state mRNA and of secreted protein encoded by three MMP genes (matrilysin, gelatinases A and B) were compared in a unique in vitro model of human skin carcinogenesis. This model is composed of the parental immortalized non-tumorigenic human keratinocyte line (HaCaT), and three activated c-Harvey-ras-oncogene transfected variants (A-4, I-7 and II-4). Although clone A-4 is non-tumorigenic, clones I-7 and II-4 exhibit benign and malignant tumorigenic phenotypes, respectively, after subcutaneous injection into athymic nude mice. Northern blot, Western blot, and zymogram analyses revealed three MMP-specific patterns of expression. Constitutive matrilysin mRNA expression was markedly increased in the I-7 cells compared with HaCaT, A-4 or II-4 cells. Secreted promatrilysin was distinctly increased in the tumorigenic I-7 and II-4 cells compared with the non-tumorigenic HaCaT and A-4 cells. Gelatinase A mRNA and secreted gelatinase A protein levels were increased in each transfectant compared with HaCaT. Both active and inactive forms of gelatinase A were detected. Gelatinase B transcripts were not detected, but an EDTA-inhibitable gelatinase activity comigrating with gelatinase B was moderately enhanced in both tumorigenic variants compared with the non-tumorigenic cells. Because promatrilysin and 92-kDa gelatinase secretion were increased in both benign and malignant tumorigenic cells, and not related to invasiveness in this model, it is concluded that enhanced constitutive expression of these two MMPs is associated with acquisition of the tumorigenic phenotype, before acquisition of the malignant phenotype.
 ...
PMID:Differential expression of matrix metalloproteinases in activated c-ras-Ha-transfected immortalized human keratinocytes. 951 50

The close correlation observed between matrix metalloproteinase 2 (MMP-2) activation and metastatic progression in various tumors suggests that MMP-2 is a 'master switch' triggering tumor spread. Recently, membrane type 1 MMP (MT1-MMP) was identified as a potential physiological activator of MMP-2. Like all other MMPs, MT1-MMP possesses a pro-domain which must be removed for the enzyme to acquire its catalytic potential. The presence of a typical recognition motif (RXKR) for the furin-like convertases at the end of its pro-domain suggests a potential role for these proteinases in MT1-MMP processing. In order to evaluate the implication of furin in pro-MT1-MMP processing, we treated HT1080 cells with a synthetic furin inhibitor and monitored their ability to activate pro-MMP-2 as well as their invasive potential. Our results demonstrated that the furin inhibitor decreased pro-MT1-MMP processing as well as pro-MMP-2 activation and cell invasiveness. Therefore, our data bring further evidence that furin is a key factor in the maturation of MMPs associated with the invasive and metastatic potential of tumor cells.
 ...
PMID:Inhibition of matrix metalloproteinase 2 maturation and HT1080 invasiveness by a synthetic furin inhibitor. 953 63

The membrane-type 1 matrix metalloproteinase (MT1-MMP) has been reported to mediate the activation of pro-gelatinase A (proMMP-2), which is associated with tumor proliferation and metastasis. MT1-MMP can also digest extracellular matrix (ECM) such as interstitial collagens, gelatin, and proteoglycan and thus may play an important role in pathophysiological digestion of ECM. We studied the inhibitory effect of various hydroxamate MMP inhibitors, including known inhibitors such as BB-94, BB-2516, GM6001, and Ro31-9790, on a deletion mutant of MT1-MMP lacking the transmembrane domain (DeltaMT1) to further characterize the enzyme and develop a selective inhibitor for MT1-MMP. The evaluation of the inhibitory activities of various hydroxamates reveals general structural profiles affecting selectivities toward MMPs. In particular, a longer side chain at the P1' position is preferable for the binding to MMP-2, -3, and -9 and MT1-MMP. For the P2' position, an alpha-branched alkyl group is critical for the binding toward DeltaMT1, while the introduction of a bulky group at the alpha-position of hydroxamic acid seems to diminish the activity against DeltaMT1. Summation of the data on the sensitivity of DeltaMT1 to various hydroxamate inhibitors indicates that (1) the volume of the S1' subsite of DeltaMT1 is similar to that of MMP-2, -3, and -9, which is bigger than that of MMP-1, and (2) the S1 and S2' subsites are narrower than those in other MMPs. On the basis of these results, the hydroxamates with a P1' phenylpropyl and P2' alpha-branched alkyl group were synthesized and evaluated for inhibitory activity. These inhibitors (1h,i) showed strong activity against DeltaMT1 over MMP-1, but no selectivity between DeltaMT1 and MMP-9. These results are explained using molecular modeling studies conducted on MT1-MMP.
 ...
PMID:Inhibition of membrane-type 1 matrix metalloproteinase by hydroxamate inhibitors: an examination of the subsite pocket. 954 12

Matrix metalloproteinases (MMPs) comprise a group of proteolytic enzymes that are implicated in the pathogenesis of inflammatory diseases of the nervous system such as multiple sclerosis. However, the exact function and expression pattern of MMPs in the inflamed nervous system are not known. In the present study we investigated the expression of 92-kDa gelatinase (MMP-9) in spinal cord from animals with adoptive transfer experimental autoimmune encephalomyelitis (AT-EAE), using a semiquantitative competitive reverse transcriptase-polymerase chain reaction assay. Increased levels of MMP-9 mRNA were found with peak values at times of maximum disease severity. Increased mRNA expression was associated with enhanced proteolytic activity of this enzyme, as demonstrated by gelatin zymography. Immunohistochemistry revealed immunoreactivity along the meninges, around blood vessels and within the parenchyma, in diseased but not in normal spinal cord. Furthermore, the expression pattern of five other MMPs was investigated. Matrilysin (MMP-7) was also found to be upregulated with maximum mRNA levels at the peak of the disease. In contrast, mRNAs for collagenase-3, 72-kDa gelatinase, and stromelysin-1 and -3 were not changed. Our findings indicate that 92-kDa gelatinase and matrilysin are selectively upregulated during AT-EAE and thus may contribute to the pathogenesis of inflammatory diseases of the CNS.
 ...
PMID:Matrix metalloproteinase-9 and -7 are regulated in experimental autoimmune encephalomyelitis. 954 96

Matrilysin, gelatinase A and gelatinase B are matrix metalloproteinases (MMPs) implicated in normal and pathological processes that require remodelling of the extracellular matrix. In human prostate tissue, matrilysin is synthesized in ducts surrounded by inflammatory cells, and focally in prostate carcinoma, but not in normal glands. Gelatinase B expression is restricted to inflammatory cells. Gelatinase A can be found in both benign and malignant prostate tissue. MMP activities are regulated by their transition from latent to activated forms, as well as by the presence of tissue inhibitors of metalloproteinases (TIMPs). We investigated whether matrilysin can activate progelatinases A and B in the presence of their bound inhibitors TIMP2 and TIMP1 respectively. Incubation of progelatinase B-TIMP1 complex with active matrilysin resulted in 78 and 68 kDa active forms, as measured by SDS-PAGE and enzyme activity assays. TIMP-free gelatinase B was also activated by matrilysin. In addition, activation of progelatinase B by matrilysin was demonstrated in the conditioned medium of phorbol ester-treated HT1080 cells, confirming the results obtained in the in vitro experiments. In contrast, matrilysin did not proteolytically cleave gelatinase A-TIMP2 complex, but led to a transient increase in gelatinolytic activity of the proenzyme. Matrilysin did not enhance the autocatalytic conversion of its own proform. The data presented here suggest that matrilysin participates in a proteolytic cascade and can activate gelatinases in the presence of TIMPs.
 ...
PMID:Activation of gelatinase-tissue-inhibitors-of-metalloproteinase complexes by matrilysin. 956 Mar 29

Membrane-type 1 matrix metalloproteinase (MT1-MMP) is expressed both in carcinoma cells and in surrounding stromal fibroblasts. MT1-MMP localizes to the surface of tumor cells and is thought to play an important role in tumor invasion. To analyze the mechanism of MT1-MMP gene expression in epithelial tumor cells, the dog kidney epithelial cell line Madin-Darby canine kidney (MDCK) was transformed by oncogenes, including v-src, and expression of MT1-MMP was examined. Transformation of MDCK cells with v-src resulted in loss of cell-to-cell contacts and morphological change. Expression of MT1-MMP in v-src-transformed cells was identified by Northern and Western blotting. Gelatin zymography analysis showed that progelatinase A in the culture medium was processed from latent to activated form by MDCK cells transformed with v-src. The MDCK cells transformed by v-src were tumorigenic in the subcutis (ectopic) and kidney (orthotopic) of nude mice and spontaneously metastasized to the lung after orthotopic implantation. These results suggest that MT1-MMP induced by v-src transformation may promote invasiveness of transformed cells.
 ...
PMID:Transformation of epithelial Madin-Darby canine kidney cells with p60(v-src) induces expression of membrane-type 1 matrix metalloproteinase and invasiveness. 960 72

Membrane-type 1 matrix metalloproteinase (MT1-MMP)/MMP-14 is the activator of progelatinase A (proGelA)/proMMP-2 on the cell surface. However, it was a paradox that a tissue inhibitor of metalloproteinase-2 (TIMP-2), which is an inhibitor of MT1-MMP, is required for proGelA activation by the cells expressing MT1-MMP. In this study, a truncated MT1-MMP having a FLAG-tag sequence at the C terminus (MT1-F) was immobilized onto agarose beads (MT1-F/B) and used to analyze the role of TIMP-2. The proteolytic activity of MT1-F/B against a synthetic peptide substrate was inhibited by TIMP-2 in a dose-dependent manner. In contrast, TIMP-2 promoted the processing of proGelA by MT1-F/B at low concentrations and inhibited it at higher concentrations. TIMP-2 promoted the binding of proGelA to the MT1-F on the beads by forming a trimolecular complex, which was followed by processing of proGelA. A stimulatory effect of TIMP-2 was observed under conditions in which unoccupied MT1-F was still available. Thus, the ternary complex is thought to act as a means to concentrate the substrate to the bead surface and to present it to the neighboring free MT1-F.
 ...
PMID:TIMP-2 promotes activation of progelatinase A by membrane-type 1 matrix metalloproteinase immobilized on agarose beads. 963 62

Membrane type (MT) 1 matrix metalloproteinase (MMP) activates progelatinase A (pro-MMP-2), a type IV collagenase, on the cell surface of tumors; however, its function in breast cancer progression and metastasis is not fully understood. To examine the expression of MT1-MMP in breast cancer cells and fibroblasts, a specific rabbit antibody (Ab) directed against a unique synthetic peptide derived from the human MT1-MMP catalytic domain was produced, purified, and characterized. This Ab is not likely to cross-react with MT2-, MT3-, or MT4-MMP or any other MMPs. MT1-MMP expression and pro-MMP-2 activation were stimulated by concanavalin A in two human breast carcinoma cell lines (BT549 and MDA-MB-231) and in normal human fetal-lung fibroblasts (HFL-1) and were slightly upregulated by breast cancer cell-fibroblast interactions. Both pro-MT1-MMP in plasma membrane (63.4 kDa) and the soluble forms of the enzyme in culture medium (57.6 and 25-30 kDa) were detected by immunoblot analysis, suggesting that cell-surface MT1-MMP exhibits an active conformation without the removal of its propeptide domain and that the mature enzyme is shed into the medium. In breast cancer cells, MT1-MMP and a recombinant catalytic domain of MT1-MMP were unable to activate pro-matrilysin, indicating that MT1-MMP is not a universal activator of all MMPs. MT1-MMP may play an important role in the invasive growth and spread of breast cancer cells by specifically activating pro-MMP-2 to cleave the connective-tissue barrier. Furthermore, use of the specific Ab may aid in the investigation of the role of MT1-MMP in human tumors.
 ...
PMID:Immunological characterization of cell-surface and soluble forms of membrane type 1 matrix metalloproteinase in human breast cancer cells and in fibroblasts. 965 52

The activation of zymogen and the amount of proteinase and its inhibition are important in determining the eventual activity of matrix-degrading enzymes involved in tumor aggressiveness. To evaluate a gene complement leading to matrix metalloproteinase 2 (MMP-2; Mr 72,000 gelatinase) activity, membrane type 1 MMP (MT1-MMP), urokinase-type plasminogen activator, MMP-2, and tissue inhibitor of metalloproteinase 2 transcriptional levels were measured in gastric carcinoma biopsies. Comparative tumor:normal tissue reverse transcription-PCR in a cohort of 25 patients revealed up to a 10-fold difference in the expression of MT1-MMP, a metalloproteinase that has been proposed as a membrane receptor activator of MMP-2; a 1-unit increment resulted in a 30% risk to survival. A 20% risk also resulted from a 1-unit increment in the MT1-MMP: MMP-2 ratio, which showed differences of up to 15-fold. Instead, the expression of urokinase-type plasminogen activator, which trips off a cascade ending in the activation of MMP-2, as well as the expression of MMP-2 itself and its inhibitor, tissue inhibitor of metalloproteinase 2, lacked correlation with patient follow-up. Zymography revealed MMP-2 activities that were often in conflict with the transcription results and also with follow-up. The results suggest the evaluation of MT1-MMP and/or MT1-MMP:MMP-2 transcription as a new preoperative molecular-level prognostic factor for gastric carcinoma.
 ...
PMID:Augmented membrane type 1 matrix metalloproteinase (MT1-MMP):MMP-2 messenger RNA ratio in gastric carcinomas with poor prognosis. 974 37


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>