Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.17 (MMP-3)
 3,419 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) and the cytokines interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha) on matrix metalloproteinases (MMP) and metalloproteinase inhibitors was studied in a variety of human cell lines. Expression of the mammalian collagenase (MMP-1), 72-kD gelatinase/type IV collagenase (MMP-2), stromelysin (MMP-3), 92-kD gelatinase/type IV collagenase (MMP-9), and tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2) was assessed by zymography and Northern blot analysis. MMP-2 and TIMP-2 activities were refractory to TPA, IL-1 and TNF-alpha treatment in most of the cell lines. In contrast, MMP-3, MMP-9 and TIMP-1 activities were markedly stimulated by TPA in most of the tumor cell lines and human umbilical vein endothelial cells (HUVEC), whereas the fibroblast lines were minimally stimulated or unresponsive to TPA. The MMP-3, MMP-9 and TIMP-1 stimulation in response to IL-1 and TNF-alpha treatment was detected in some of the tumor cell lines and HUVEC. The increase in activity was less marked than in TPA. A breast carcinoma cell line, MDA-MB-231, which did not express MMP-2, had high expression of MMP-3 and MMP-9 which were unaffected by TPA and cytokine treatment. Northern blot analysis of MMP and TIMP mRNA expression reflected the zymogram findings for most of the cell lines. TPA-mediated stimulation of MMP-1 was similar to that of MMP-3 and MMP-9. Exceptions were the fibroblast cell lines which showed either a much more marked mRNA response of MMP-9 to TPA than observed at protein level, or a high constitutive MMP-9 mRNA when MMP-9 activity was not detectable by zymography. TPA-mediated stimulation of MMP-9 and TIMP-1 activity was blocked by staurosporine, an inhibitor of protein kinase C (PKC). A non-PKC-activating phorbol ester, 4 alpha-phorbol-12,13-didecanoate, did not stimulate MMP-9 and TIMP-1 activity. TPA treatment caused the increased expression of c-fos containing AP-1-specific binding activity in selected tumor cell lines. This activity was maximal at 6 h. An association was observed between AP-1 binding activity and increased expression of MMP-1, MMP-3 and MMP-9, which possess TPA-responsive elements (TRE). TPA-sensitive MMPs and TIMP-1 were variably stimulated by biologically relevant cytokines, such as IL-1 and TNF-alpha.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Effect of phorbol ester and cytokines on matrix metalloproteinase and tissue inhibitor of metalloproteinase expression in tumor and normal cell lines. 128 26

Uncontrolled expression of matrix metalloproteinases 2, 3 and 9 (MMP-2, -3 and -9) is believed to be a critical part of the invasive potential of tumor cells because of their ability to degrade type IV collagen, a major structural component of basement membranes. Availability of proteolytic activity in the vicinity of the cell surface is further affected by a local balance between the enzymes and their inhibitors produced by the cell. To determine how frequently deregulated expression of the MMPs and tissue inhibitors of metalloproteinases (TIMPs) is associated with tumor cells, 26 human tumor cell lines were examined by Northern blotting. Transcripts for MMP-2 and MMP-9 were more frequently expressed in mesenchymal tumor cells (9/9 for MMP-2 and 6/9 for MMP-9) than in epithelial tumor cells (4/17 for MMP-2 and 2/17 for MMP-9). Although expression of MMP-2 mRNA was clearly cell type-specific, MMP-9 mRNA expression in mesenchymal cells correlated well with the reported tumorigenicity of the cells. Enhanced expression of MMP-9 mRNA was also associated with the tumorigenic transformation of cells by an activated c-H-ras gene in human embryonic fibroblasts. Only 3 of the 26 tumor cells expressed MMP-3 mRNA, and 2 of the 3 were epithelial tumor cells which coordinately expressed MMP-9 and TIMP-1 mRNAs. TIMP-1 mRNA was almost undetectable in 50% of the tumor cells, but TIMP-2 mRNA was expressed in the majority of the cells. These findings provide comprehensive information about mRNA expression of the MMPs and TIMPs in tumor cells, the deregulation of which is thought to be an integral part of the invasive potential of tumor cells.
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PMID:Expression of genes encoding type IV collagen-degrading metalloproteinases and tissue inhibitors of metalloproteinases in various human tumor cells. 131 Oct 64

Secreted metalloproteases initiating proteolytic degradation of collagens and proteoglycans play a critical role in remodeling of the connective tissue. Activation of the secreted proenzymes and interaction with their specific inhibitors TIMP and TIMP-2 are responsible for regulation of enzyme activity in extracellular space. We have previously demonstrated that 92- and 72-kDa Type IV procollagenases, in contrast to interstitial collagenase (ClI), form specific complexes with TIMP and the related inhibitor TIMP-2, respectively. The physiologic significance of the proenzyme-inhibitor complex and the mechanism of activation of Type IV collagenases remained unclear. Here, we demonstrate that in the absence of TIMP, 92-kDa Type IV procollagenase (92T4Cl) can form a covalent homodimer and a novel complex with ClI. In the presence of TIMP, the formation of a 92T4Cl proenzyme complex with TIMP prevents dimerization, formation of the complex with ClI, and activation of the 92T4Cl proenzyme by stromelysin, a related metalloprotease. The proenzyme homodimer is unable to form a complex with TIMP. All TIMP-free forms of the proenzyme can be activated by stromelysin. The 92T4Cl-ClI complex can be activated to yield a complex active against both gelatin and fibrillar Type I collagen, suggesting a mechanism for cooperative action of two enzymes in reducing collagen fibrils to small peptides under physiologic conditions.
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PMID:Interaction of 92-kDa type IV collagenase with the tissue inhibitor of metalloproteinases prevents dimerization, complex formation with interstitial collagenase, and activation of the proenzyme with stromelysin. 131 14

Progelatinase A was purified as a complex with TIMP-2 from the conditioned medium of a human glioblastoma cell line. The TIMP-2/progelatinase complex was resistant to the activation by p-aminophenylmercuric acetic acid (APMA), and showed less than 10% of the activity of the TIMP-2-free active enzyme. When the complex was incubated with stromelysin in the presence of APMA, the 64-kDa progelatinase was effectively converted to the 57-kDa mature enzyme, increasing its gelatinolytic activity about 8-fold. These results suggest that stromelysin is a natural activator of TIMP-2-bound progelatinase A.
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PMID:Activation of TIMP-2/progelatinase A complex by stromelysin. 132 Aug 76

In this study, we have identified and characterized metalloproteinases and tissue inhibitors of metalloproteinases (TIMPs) in human plasma. Treatment of plasma with trypsin or aminophenylmercuric acetate resulted in activation of latent gelatinolytic activity. Fractionation of plasma by gelatin Sepharose chromatography resulted in the isolation of 72 kDa and 92 kDa gelatinases/type IV collagenases. The 72 kDa gelatinase was purified by gel filtration chromatography. Stromelysin-1 was isolated from plasma by Matrex green A affinity chromatography. Immunoblotting of plasma fractions with antibodies to unique peptide regions of human gelatinases differentiated the 72 kDa gelatinase from the 92 kDa gelatinase. Antibodies to the amino terminal peptides of each enzyme were used to determine that plasma gelatinases circulate as latent proenzymes. Immunoblotting with antibodies directed against human stromelysin identified a 57 kDa stromelysin. TIMP-1 (28 kDa) and TIMP-2 (21 kDa) were also identified by immunoblotting of gelatin Sepharose bound plasma proteins using non-crossreacting antibodies to each protein.
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PMID:Characterization of metalloproteinases and tissue inhibitors of metalloproteinases in human plasma. 146 8

Metalloproteinase inhibitors were surveyed with the culture media of 19 kinds of human tumor cell lines, using transin (rat stromelysin) as the target enzyme. This survey showed that most of the cell lines more or less secreted inhibitor activity, and that a human hepatoma cell line, HLE, secreted an extremely high inhibitor activity into the culture medium. Two kinds of metalloproteinase inhibitors were purified from the serum-free conditioned medium of HLE cells. The major inhibitor, which showed a single protein band with a molecular weight (Mr) of 21,000 (21k) (nonreduced) or 24k (reduced) on SDS-polyacrylamide gel electrophoresis, was identified as TIMP-2 (tissue inhibitor of metalloproteinases-2) by the analysis of its N-terminal amino acid sequence. The other was immunologically identified as TIMP. Purified TIMP-2 inhibited the activities of transin, matrin (pump-1), Mr 72k gelatinase, and interstitial collagenase with 1:1 stoichiometry. When the latent precursor form (Mr 57k) of transin was incubated with p-aminophenylmercuric acetate as an activating reagent, TIMP-2 inhibited the conversion of the intermediate form (Mr 45k) into the mature enzyme (Mr 42k). This indicated that TIMP-2 regulates not only the activity of the mature enzyme but also the autolytic processing of the proenzyme. TIMP-2 also inhibited in vitro tumor invasion through reconstituted basement membrane (matrigel) in chemotaxis chambers, showing that the metalloproteinase inhibitors as well as the extracellular matrix metalloproteinases are involved in tumor invasion through basement membrane and other extracellular matrices.
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PMID:Efficient purification of TIMP-2 from culture medium conditioned by human hepatoma cell line, and its inhibitory effects on metalloproteinases and in vitro tumor invasion. 166 1

The invasion and metastasis of cancer cells is a complex multistep process involving attachment of tumor cells to the basement membrane, proteolysis of the local connective tissue stroma, and migration through the proteolyzed stroma. Recent evidence implicates metalloproteinases such as type IV collagenase and transin/stromelysin in the proteolytic aspects of this process. Type IV collagenase activity is modulated by tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2). Immunohistochemical and biochemical studies of several human tumors show correlations between invasive potential and type IV collagenase activity.
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PMID:Metalloproteinases and cancer invasion. 210 92

Primitive biliary cells are known to migrate from the ductal plate into the mesenchyme during human intrahepatic bile duct development, and this migration process is essential for normal development of intrahepatic bile ducts. However, its molecular mechanism is unknown. Matrix proteinases play an important role in cell migration during cancer invasion and organ development. In this study, we therefore investigated in situ expression of matrix metalloproteinases (MMP) and tissue inhibitors of MMP (TIMP) during human intrahepatic bile duct development, using 32 human fetal livers. We also examined in situ expression of trypsinogen/trypsin, chymotrypsinogen/chymotrypsin, and cathepsin B, which are matrix proteinases and activators of MMP. MMP-1 expression was noted in the ductal plate and migrating primitive biliary cells. MMP-2, MMP-3, and MMP-9 were expressed in the ductal plate. TIMP-1 and TIMP-2 were expressed in the ductal plate and migrating primitive biliary cells. Trypsinogen/trypsin, chymotrypsinogen/chymotrypsin, and cathepsin B were also expressed in primitive biliary cells. These data suggest that MMP, trypsinogen/trypsin, chymotrypsinogen/chymotrypsin, and cathepsin B play a critical role in biliary cell migration during human intrahepatic bile duct development by degrading extracellular matrix proteins. The data also suggest that MMP inhibitors (TIMP-1 and TIMP-2) and MMP activators (trypsin, chymotrypsin, and cathepsin B) play an important role in biliary cell migration. The coordinated expression of MMP, MMP inhibitors, and MMP activators may be necessary for the normal development of human intrahepatic bile ducts.
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PMID:Expression of matrix proteinases during human intrahepatic bile duct development. A possible role in biliary cell migration. 748 84

We investigated whether stromelysin activity in the medium of canine articular cartilage explants is associated with proteoglycan degradation in these explants. Cartilage explants were treated with recombinant human interleukin 1 alpha (rh-IL-1 alpha), lipopolysaccharide, or canine monocyte-conditioned medium. Proteoglycan synthesis and degradation were measured. Metalloproteinase activity (inhibitable by tissue inhibitor of metalloproteinase 2) in the culture medium was measured by use of fluorimetry with a quenched fluorescent substrate. Western blots of the medium were probed with polyclonal antibodies to human stromelysin, collagenase, and gelatinase. Neither metalloproteinase activity nor proteoglycan degradation were inducible in canine cartilage explants treated with rh-IL-1 alpha. However, proteoglycan synthesis was significantly (P < 0.05) decreased by concentrations of 10 and 100 ng of rh-IL-1 alpha/ml. Metalloproteinase activity in the medium accompanied proteoglycan degradation of cartilage treated with lipopolysaccharide and monocyte-conditioned medium. The metalloproteinase released into the medium was identified as prostromelysin by results of western blotting.
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PMID:Effects of stromelysin activity on proteoglycan degradation of canine articular cartilage explants. 748 6

Plasmin-mediated extracellular proteolysis has been implicated in the degradation of bone in normal and pathological conditions. Normal and malignant osteoblasts can produce both tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA). We have used the osteosarcoma cell line MG63 to address the question of whether the enhanced bone turnover in osteosarcomas is mediated by t-PA or by u-PAA and to study the effect of the cytokine interleukin-1 alpha (IL-1 alpha), known to influence bone degradation, on the plasminogen activator production and extracellular matrix degradation in malignant osteoblastic cells. Furthermore, the effect of IL-1 alpha on the synthesis of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) was analyzed. u-PA production by MG63 was high (approximately 180 ng/10(6) cells/24 h). Also t-PA and PAI-1 production was observed. u-PA production was rapidly increased in MG63 by IL-1 alpha (10 ng/ml), whereas an effect on t-PA production was only found after a prolonged incubation and hardly any effect of IL-1 alpha on PAI-1 production was observed. mRNA analysis revealed similar effects. u-PA receptor (u-PAR) mRNA was detectable in MG63 cells and could be increased by IL-1 alpha after 24 h. In MG63, u-PA-mediated extracellular matrix degradation was detectable, and IL-1 alpha increased the u-PA-mediated matrix degradation (approximately 2-fold). Under control conditions in MG63, only MMP-2, TIMP-1, and TIMP-2 mRNA could be observed. After the addition of IL-1 alpha, a very rapid increase in MMP-1 and MMP-3 mRNA could be observed as well as a moderate increase in TIMP-1 mRNA. The presence of MMP-2 was demonstrated by gelatin zymography. These results show that IL-1 alpha can stimulate u-PA production and can regulate extracellular proteolytic activity mainly via u-PA induction in the MG63 osteosarcoma cell line. Furthermore, IL-1 alpha has a strong stimulating effect on the production of MMP-1 and MMP-3. These findings suggest that u-PA and possibly MMP-1 and MMP-3 play an important role in the process of bone turnover in osteosarcomas.
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PMID:Regulation of plasminogen activation, matrix metalloproteinases and urokinase-type plasminogen activator-mediated extracellular matrix degradation in human osteosarcoma cell line MG63 by interleukin-1 alpha. 750 10


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