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 action of three matrix metalloproteinases (MMPs), 72- and 95-kDa gelatinases (MMP-2 and MMP-9) and PUMP (MMP-7), and a cysteine proteinase, cathepsin B, were investigated on aggrecan the major proteoglycan of cartilage. All the enzymes cleaved aggrecan although the activity of the 95-kDa gelatinase was very low. Specific cleavage sites were investigated following incubation with a purified aggrecan G1-G2 domain fragment (150 kDa). Both gelatinases produced 110-kDa G2 and 56-kDa G1 products by a single cleavage at an Asn-Phe bond within the interglobular domain close to the G1 domain. This was similar to the action of stromelysin (MMP-3) (Fosang, A. J., Neame, P. J., Hardingham, T. E., Murphy, G., and Hamilton, J. A. (1991) J. Biol. Chem. 266, 15579-15582). Cathepsin B also produced two fragments from a single cleavage at a Gly-Val bond only three amino acids C-terminal to the metalloproteinase cleavage site. PUMP cleaved at the metalloproteinase Asn-Phe site, but in addition produced a low yield of a smaller G2 fragment (56 kDa) corresponding to cleavage between Asp441 and Leu442 (human sequence), within the interglobular domain, close to the G2 domain. The apparent difference in size between the two G2 fragments released by PUMP (110 and 56 kDa) was much greater than predicted from the peptide length between the cleavage sites (100 amino acids). However, keratanase digestion greatly reduced the size of the 110-kDa G2 fragment, while producing only a small reduction in size of the 56-kDa product, showing that there was approximately 30-40 kDa of keratan sulfate attached to the interglobular domain between the PUMP cleavage sites. This new structural information on aggrecan may account for the previously observed stiffness of the interglobular domains when viewed by rotary shadowing electron microscopy (Paulsson, M., Morgelin, M., Wiedemann, H., Beardmore-Gray, M., Dunham, D. G., Hardingham, T. E., Heinegard, D., Timpl, R., and Engel, J. (1987) Biochem. J. 245, 763-772). These results show that in spite of a high keratan sulfate content the interglobular domain provides important sites for cleavage by different proteinases, including several members of the matrix metalloproteinase family.
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PMID:The interglobular domain of cartilage aggrecan is cleaved by PUMP, gelatinases, and cathepsin B. 132 52

A polymerase chain reaction (PCR)-based homology cloning strategy was used to define the spectrum of stromelysin-like matrix metalloproteinases (MMPs) synthesized by cultured glomerular mesangial cells (MC). Using this technique, cDNAs encoding an unusual, truncated member of the MMP family, punctuated (putative) metalloproteinase (PUMP-1), were exclusively isolated. Incubation with the cytokines interleukin 1 and tumour necrosis factor increased the abundance of PUMP-1 mRNA in mesangial cells. The mesangial PUMP-1 mRNA is processed in a tissue-specific manner, yielding a transcript containing repeated 3'-untranslated region ATTTA motifs commonly found in cytokines with limited mRNA stability. Polyclonal antibodies prepared against the C-terminal region of the PUMP-1 protein documented release of this enzyme by cultures of cytokine-stimulated MC and permitted identification of PUMP-1-expressing mesangial cells within clinical biopsy specimens of acute glomerulonephritis. These findings represent new molecular and clinical evidence that non-malignant cells process and secrete this unusual member of the MMP family in a cytokine-mediated, tissue-specific manner. Mesangial synthesis of PUMP-1 may contribute to the progression of injury during glomerular inflammatory states.
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PMID:Molecular characterization of a low-molecular-mass matrix metalloproteinase secreted by glomerular mesangial cells as PUMP-1. 149 27

The expression of members of the family of matrix-degrading metalloproteinases (MMPs) is believed to contribute to the complex process of invasion and metastasis. In this study, specific cDNA probes for three members of the stromelysin subfamily of MMPs--stromelysin (MMP-3), stromelysin-2 (MMP-10), and pump-1 (MMP-7)--were used to examine the expression of these three different MMPs in human gastric and colonic carcinomas and in adjacent normal mucosa. The expression of pump-1 mRNA in malignant colon and stomach samples was striking. In a total of 10 gastric carcinoma samples examined, eight (80%) expressed pump-1 transcripts; similarly, 6 of 8 (75%) colon carcinoma samples were also positive. Stromelysin and stromelysin-2 mRNAs were not detected in any of these samples. Expression of the MMPs examined was not detected in any of the adjacent, grossly normal tissue samples. Using in situ hybridization and affinity purified anti-pump-1 antibodies, the expression of pump-1 mRNA and protein was localized to tumor cells and was not detected in stromal or lymphocytic cells. This data suggests that the inappropriate expression of pump-1 by malignant cells may contribute to the neoplastic phenotype.
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PMID:Expression and localization of the matrix metalloproteinase pump-1 (MMP-7) in human gastric and colon carcinomas. 179 90

Twenty-five surgical specimens of malignant human prostate, 3 lymph nodes with metastatic prostate carcinoma, 11 normal human prostates, as well as 3 human prostate cell lines (DU-145, PC3 and LNCaP) were examined for the expression of the human matrix metalloproteinase-7 gene (MMP-7) from the human collagenase family (originally called PUMP-1 for putative metalloproteinase-1) [Quantin et al. (1989) Biochemistry 28:5327-5334; Muller et al. (1988) Biochem J 253:187-192; Matrisian and Bowden (1990) Semin Cancer Biol 1:107-115]. Northern blots were prepared using total RNA extracted from 18 prostate adenocarcinomas, 2 lymph nodes with metastatic prostate carcinoma and 11 normal human prostates. When the northern blots were hybridized with a 32P-labeled MMP-7 cDNA probe, a 1.2-kb mRNA was detected in 14 out of 18 prostate adenocarcinomas, 1 out of 2 metastatic lymph nodes, and 3 out of 11 normal prostates. The 3 human prostate cell lines did not show any evidence of the MMP-7 transcript. In situ hybridization was conducted to localize the MMP-7 mRNA to individual cells using a 35S-labeled MMP-7 cRNA. In situ hybridization was carried out on snap-frozen tissue sections of 7 prostate adenocarcinomas and 3 lymph nodes containing metastatic prostate adenocarcinoma using the same tissues previously probed by northern analysis as well as new samples. In situ hybridization revealed that the MMP-7 gene was expressed in the epithelial cells of primary prostate adenocarcinoma as well as in invasive and metastatic cells. MMP-7 expression was also seen focally in some dysplastic glands but not in stroma. Additional northern blot analysis was performed using probes to human type-IV collagenase, type-I collagenase and stromelysin I in human prostate adenocarcinoma as well as normal prostate tissue. Our results indicated that 6 out of 10 adenocarcinoma samples and none of the 4 normal samples were positive for type-IV collagenase transcripts. Tissue samples were also examined for the expression of type-I collagenase (9 adenocarcinomas and 4 normal) and stromelysin I (13 adenocarcinomas) by northern analysis. None of the tissues was found to express the transcripts of interest at detectable levels. These data suggest that certain metalloproteinases are present in prostatic adenocarcinoma and may play a role in invasion and metastasis.
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PMID:Expression of metalloproteinase genes in human prostate cancer. 184 60

Two major tenascin-C (TN-C) isoforms are generated by the alternative splicing of the pre-mRNA. The large isoform contains seven extra type three repeats that, by contrast, are omitted in the small TN-C isoform. The large TN-C isoform is mainly expressed at the onset of cellular processes that entail active cell migration, proliferation, or tissue remodeling such as occur in neoplasia, wound healing, and during development. Thus, the large TN-C isoform seems to be a specific component of the provisional extracellular matrix. Here we have studied the degradation of the large and small TN-C isoforms by matrix metalloproteinases (MMPs) 2, 3, 7, and 9. Among these proteolytic enzymes only MMP-7 can degrade the small TN-C isoform removing the NH2-terminal knob. The large TN-C isoform shows the same MMP-7-sensitive site adjacent to the NH2-terminal sequence, but is further degraded in the splicing area where three fibronectin-like type III repeats are completely digested. Moreover, the large TN-C isoform is degraded by MMP-2 and MMP-3 which completely digest a single type III repeat inside the splicing area. By contrast, the large TN-C isoform is resistant to MMP-9 digestion. The results show that the presence of the spliced sequence introduces new protease-sensitive sites in the large TN-C isoform.
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PMID:Different susceptibility of small and large human tenascin-C isoforms to degradation by matrix metalloproteinases. 753 39

Antibodies were raised against seven major matrix metalloproteinases: stromelysin-1 (MMP-3), stromelysin-2 (MMP-10), stromelysin-3 (MMP-11), interstitial collagenase (MMP-1), M(r) 72,000 type IV collagenase (72 kDa type IV collagenase, MMP-2), M(r) 92,000 type IV collagenase (92 kDa type IV collagenase, MMP-9) and matrilysin (PUMP, MMP-7) as well as against prolyl 4-hydroxylase, to study the expression of these collagenolytic enzymes in normal liver in relation to the activity of collagen synthesis. Tissue samples of four normal human livers, three hepatocellular carcinomas and one cholangiocellular carcinoma were analysed. In normal liver we found expression of stromelysin-1, stromelysin-3, interstitial collagenase, M(r) 72,000 and M(r) 92,000 type IV collagenases and varying expression of prolyl 4-hydroxylase. Stromelysin-2 was inconsistently detectable; matrilysin was not found. In hepatocellular carcinoma the expression pattern of matrix metalloproteinases showed only minor changes compared with the normal tissue; stronger signals than in normal tissue were seen for stromelysin-1, and stromelysin-2 was also strongly positive. M(r) 72,000 and M(r) 92,000 type IV collagenases and interstitial collagenase were less strongly expressed; stromelysin-3 was unchanged. Expression of prolyl 4-hydroxylase was also increased compared with normal liver. Matrilysin was only seen in cholangiocellular carcinoma, which showed a completely different pattern of matrix metalloproteinase expression. Our results show that metalloproteinases are expressed in human liver with much greater abundance than previously described. Their expression pattern is not changed fundamentally in hepatocellular carcinoma but is completely different from that of other tumour tissues such as cholangiocellular carcinoma.
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PMID:Expression pattern of matrix metalloproteinases in human liver. 763 22

We have examined the correlation between matrix metalloproteinase (MMP) expression and metastatic properties of a low metastatic osteosarcoma cell line, osteosarcoma takase (OST), under stimulation by tumour necrosis factor alpha (TNF alpha). In vivo, OST cells exhibited significantly increased colonization in the lungs of nude mice in a dose-dependent manner when they were treated by TNF alpha prior to injection. In vitro, TNF alpha enhanced tumour cell invasion through the reconstituted basement membrane in a transwell chamber up to 2.5-fold. Gelatin zymography and sandwich enzyme immunoassays demonstrated marked production of MMP-9 [92-kDa gelatinase/type IV collagenase (gelatinase B)] but not MMP-2 [72-kDa gelatinase/type IV collagenase (gelatinase A)], MMP-3 (stromelysin-1) or MMP-7 (matrilysin). Motility of the tumour cells and adhesion to cultured endothelial cells were slightly increased by the TNF alpha treatment up to 1.6-fold and 1.4-fold, respectively, while the growth rate was decreased. These results suggest that upregulation of MMP-9 together with enhanced motility and endothelial adhesion contribute to the increased metastatic ability of OST cells induced by TNF alpha treatment.
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PMID:Expression of matrix metalloproteinase 9 (92-kDa gelatinase/type IV collagenase) induced by tumour necrosis factor alpha correlates with metastatic ability in a human osteosarcoma cell line. 803 35

Matrix metalloproteinases (MMPs) play a role in tissue remodelling and angiogenesis. We have investigated the expression and regulation of MMP-1 (interstitial collagenase), MMP-2 (gelatinase A), MMP-3 (stromelysin 1), MMP-7 (matrilysin), MMP-9 (gelatinase B) and their inhibitors TIMP-1 and TIMP-2 in human umbilical vein, femoral vein and microvascular endothelial cells, and compared these data with those obtained with human synovial fibroblasts. Non-stimulated vein endothelial cells expressed the mRNAs for MMP-1, MMP-2, TIMP-1 and TIMP-2. MMP-3 mRNA and protein were undetectable or only weakly expressed, but could be stimulated by the inflammatory mediator tumour necrosis factor alpha (TNF alpha). The expression of MMP-3 and MMP-1 was further enhanced by phorbol 12-myristate 13-acetate (PMA). Phorbol ester also induced TIMP-1 and MMP-9, the expression of the latter being further enhanced by TNF alpha or interleukin 1 alpha (IL-1 alpha). Similar stimulatory effects were observed in microvascular endothelial cells. Hence the inflammatory mediator TNF alpha induces/enhances the production of several matrix metalloproteinases in human endothelial cells. On the other hand, MMP-2 and TIMP-2 were not affected or were affected in a variable way by TNF alpha and/or phorbol ester, suggesting a dissimilar regulation of these proteins. The cyclic AMP-enhancing agent forskolin affected the production of MMPs in a cell-type-specific way. In human vein endothelial cells it enhanced the PMA-mediated induction of MMP-9, whereas it suppressed this induction in human microvascular endothelial cells and in synovial fibroblasts. On the other hand, forskolin suppressed the PMA-mediated induction of MMP-1 and MMP-3 in synovial fibroblasts, while it enhanced or did not affect this induction in various types of human endothelial cells. These observations may have implications for future pharmacological intervention in angiogenesis.
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PMID:Regulation of matrix metalloproteinase expression in human vein and microvascular endothelial cells. Effects of tumour necrosis factor alpha, interleukin 1 and phorbol ester. 828 80

The matrix metalloproteinases (MMPs) gene family includes MMP-1 (interstitial collagenase), MMP-2 (72 kD type IV collagenase/gelatinase), MMP-3 (stromelysin/transin), MMP-7 (putative MMP; pump-1), MMP-8 (granulocyte collagenase) and MMP-9 (92 kD type IV collagenase/gelatinase). This gene family has the common characteristics in the gene structure as follows: All of MMPs have the active site metal ion-binding domain. All six enzymes are activated with the concomitant removal of N-terminal segment of the latent enzyme. The removed segment contains an unpaired cystein residue within the conserved amino acid sequence PRCGVPDV, located immediately adjacent to the proenzyme cleavage site. The authors showed the gene expression of MMP-1 in the process of hepatic fibrosis. The remarkable expression was noted on fibroblasts and macrophages within the newly-formed fibrous bands with lots of infiltrated lymphocytes. Liver cirrhosis did not showed the positive dots of MMP-1 mRNA. On the other hands, the expression of TIMP reported by Takahara et al., revealed the high level of expression in the advanced fibrosis.
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PMID:[Gene expression of MMPs and TIMPs in the process of hepatic fibrosis]. 846 57

During progression towards malignancy, many tumor cells display changes in their repertoire of matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs). The recent finding that many members of the MMPs are regulated by protooncogenes may explain the frequent observation of changes in MMP gene expression during progression of many tumor types. While studies involving enzymatic assays of MMPs are usually confined to one or a few MMPs, reverse transcription-PCR (RT-PCR) permitted the analysis of seven members of the MMP family and two members of the TIMP family in several normal and transformed cell lines. RT-PCR permitted us to confirm the observation that MMP-9 is activated following transformation and also to observe the previously unreported activation of MMP-7 in SV40-transformed cells. It has previously been found that MMP-1, -2, -3, -8, and -9 are upregulated by phorbol esters; we have found that MMP-10 is also upregulated by phorbol esters. The phorbol ester upregulation of MMP-1, -3, and -10 was found to be abolished in cells transformed by SV40 virus. Several studies have shown that MMP-1 is upregulated by an integrin-mediated signal transduction pathway. This study demonstrates that MMP-3 and MMP-10 are also regulated by integrin-mediated signal transduction and that upregulation by this pathway is abolished following SV40 transformation. In summary, the more global view of MMP expression afforded by RT-PCR indicates that MMP-1, -3, and -10 are regulated by both integrin-mediated signal transduction and phorbol esters. While fibroblasts and transformed bone cells express several members of the MMP gene family, several other cell types do not express MMPs.
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PMID:Regulation of matrix metalloproteinases following cellular transformation. 869 36


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