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)

In colorectal cancer, matrilysin (matrix metalloproteinase-7) is mainly produced by the tumor cells themselves and is thought to play an important role in tumor invasion and metastasis. In the study reported here, we examined the effects of matrilysin antisense phosphorothioate oligonucleotides on both the expression of matrilysin and the invasive potential of the human colon cancer cell line CaR-1 in vitro. To select the most specific and potent oligonucleotide sequence, we performed extensive analyses of the binding specificities of all antisense candidates in the GenBank database by using a computer program we developed. As a result, a 15-mer matrilysin-specific antisense oligonucleotide that hybridizes to the coding region of matrilysin mRNA (AS-1) and a random control oligonucleotide (CL-1) were designed. Reverse transcription-polymerase chain reaction and western blot analysis demonstrated that 10 microM AS-1 suppressed matrilysin expression at both the mRNA level (92%) and protein level (64%). In vitro invasion assays demonstrated that this same concentration of AS-1 inhibited the ability of cells to invade a reconstituted basement membrane by 50% as compared with the ability of untreated cells to do so. On the other hand, CL-1, which had the same length and GC content as AS-1, did not show any inhibitory effect. These results demonstrate that the antisense oligonucleotide AS-1 inhibits matrilysin activities in a sequence-specific manner and suggest that AS-1 has the potential to be used as an anti-metastatic agent in an in vivo experimental model of colon cancer.
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PMID:Inhibitory effect of matrilysin antisense oligonucleotides on human colon cancer cell invasion in vitro. 960 1

Human colon cancer frequently develops liver metastasis. Matrilysin (MMP-7), the smallest member of the matrix metalloproteinase (MMP) family, is commonly produced by human colon carcinoma cells and has been suggested to be involved in the progression and metastasis of this type of cancer. In the present study, we tested the effect of a matrilysin-specific antisense phosphorothioate oligonucleotide on liver metastasis of the human colon carcinoma cell line WiDr in nude mice. In culture, the antisense oligonucleotide moderately inhibited the secretion of matrilysin by WiDr cells. Injection of WiDr cells into the spleen of nude mice produced many metastatic tumor nodules in the liver. When the antisense oligonucleotide was injected daily into the mice for 11 days, the formation of the metastatic tumor nodules was strongly inhibited in a dose-dependent manner. An inhibition of liver metastasis of over 70% was obtained at a dose of 120 micrograms of the oligonucleotide per mouse. The antisense oligonucleotide did not inhibit tumor growth in spleen and in liver. A scrambled control oligonucleotide had no effect on liver metastasis of WiDr cells. Our results demonstrate an important role of matrilysin in liver metastasis of human colon cancer and the therapeutic potential of matrilysin antisense oligonucleotides for the prevention of metastasis.
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PMID:Matrilysin-specific antisense oligonucleotide inhibits liver metastasis of human colon cancer cells in a nude mouse model. 962 46

Matrilysin is a member of the matrix metalloproteinase gene family which is believed to play an important role in tumor progression. Expression of matrilysin mRNA was examined by reverse transcription-polymerase chain reaction combined with Southern blot analysis in 46 human primary gastric cancers. Overexpression of matrilysin was observed in 28 (61%) of gastric cancer tissues. The positive expression ratio of matrilysin was significantly higher in the gastric cancers of subserosa or beyond it than in those within the submucosal layer. Immunohistochemical study with anti-matrilysin monoclonal antibody revealed that matrilysin was mainly expressed on cancer cells but not or very weakly expressed on other cells. In addition, an activated form of matrilysin detected by zymographic analysis was observed in gastric cancer tissues whereas none was detected in non-cancerous tissues, suggesting that matrilysin may directly and powerfully contribute to the invasion step of human gastric cancer. In order to gain more insight into the relationship of this metalloproteinase to invasive activity, we also modulated the expression of matrilysin in gastric cancer cells by DNA transfection using gastric cancer cell lines. Overexpression of matrilysin rendered the gastric cancer cells more invasive in vitro. Concomitant with clinical investigations, matrilysin may be an important metalloproteinase in the progression of gastric cancer.
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PMID:Relation of matrilysin messenger RNA expression with invasive activity in human gastric cancer. 962 10

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.
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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.
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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

Intermittent doses of parathyroid hormone (PTH) stimulate bone formation in animals and humans, but the molecular mechanisms underlying this phenomenon are not understood. Bone formation culminates with the expression of type I collagen, osteocalcin, and alkaline phosphatase, but genes that initiate and support the anabolic response are not known. To identify novel PTH-regulated genes in bone during the anabolic response, we used differential display-polymerase chain reaction (DDRT-PCR) to analyze RNA from young male rats injected with either human PTH (1-34) or vehicle control, once daily for 5 days. Total RNA was isolated from the distal femur metaphysis at 1, 6, and 48 h after the final injection and subjected to DDRT-PCR. We identified three PTH-responsive transcripts as matrix metalloproteinase-9 (MMP-9), creatine kinase, and the alpha1 (I) polypeptide chain (COL1A1) of type I collagen. The concomitant upregulation of MMP-9 and COL1A1 during bone formation was particularly intriguing. Further characterization of MMP-9 expression revealed that it was localized to osteoblasts, osteocytes, megakaryocytes, and cells of the bone marrow in the rat distal femur metaphysis. Northern analysis for MMP-9 expression in other tissues indicated that this transcript was present in the kidney and brain. In vitro, PTH regulated the protein synthesis of MMP-9 by osteoblasts of the primary spongiosa. We propose that PTH may promote bone formation by mediating the subtle variation in MMP activities, thus preparing the extracellular matrix for the subsequent bone cell migration and deposition of new osteoid.
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PMID:Intermittent administration of parathyroid hormone (1-34) stimulates matrix metalloproteinase-9 (MMP-9) expression in rat long bone. 970 76

Neutrophil collagenase or collagenase 2 (MMP-8) is unique among the family of matrix metalloproteinases (MMPs) because of its exclusive pattern of expression in inflammatory conditions. At present, no evidence of the occurrence of this enzyme in tissues other than human has been reported. In this work, we have cloned the murine homologue of human collagenase 2. The isolated cDNA contains an open reading frame coding for a polypeptide of 465 amino acids, which is 74% identical to its human counterpart. The mouse collagenase 2 exhibits the domain structure characteristic of several MMPs, including a signal sequence, a prodomain with the cysteine residue essential for enzyme latency, an activation locus with the Zinc-binding site, and a COOH-terminal fragment with sequence similarity to hemopexin. It also contains the three conserved residues (Tyr-209, Asp-230, and Gly-232) located around the Zinc-binding site and are distinctive of the collagenase subfamily. Northern blot analysis of RNAs isolated from a variety of mouse tissues revealed that collagenase 2 is expressed at late stages during mouse embryogenesis, coinciding with the appearance of hematopoietic cells. In addition, collagenase 2 was highly expressed in the postpartum uterus starting at 1 day postpartum and extending up to 5 days. Enzymatic analysis revealed that matrilysin, another MMP overexpressed in uterine tissue, is able to activate murine procollagenase 2. These data suggest that both enzymes could form an activation cascade resulting in the generation of the collagenolytic activity required during the process of massive connective tissue resumption occurring in the involuting uterus.
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PMID:Collagenase 2 (MMP-8) expression in murine tissue-remodeling processes. Analysis of its potential role in postpartum involution of the uterus. 972 11

A comprehensive sequence alignment of 64 members of the family of matrix metalloproteinases (MMPs) for the entire sequences, and subsequently the catalytic and the hemopexin-like domains, have been performed. The 64 MMPs were selected from plants, invertebrates, and vertebrates. The analyses disclosed that as many as 23 distinct subfamilies of these proteins are known to exist. Information from the sequence alignments was correlated with structures, both crystallographic as well as computational, of the catalytic domains for the 23 representative members of the MMP family. A survey of the metal binding sites and two loops containing variable sequences of amino acids, which are important for substrate interactions, are discussed. The collective data support the proposal that the assembly of the domains into multidomain enzymes was likely to be an early evolutionary event. This was followed by diversification, perhaps in parallel among the MMPs, in a subsequent evolutionary time scale. Analysis indicates that a retrograde structure simplification may have accounted for the evolution of MMPs with simple domain constituents, such as matrilysin, from the larger and more elaborate enzymes.
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PMID:Matrix metalloproteinases: structures, evolution, and diversification. 973 11

The terminal end of the short arm of human chromosome 1, 1p36.3, is frequently deleted in a number of tumors and is believed to be the location of multiple tumor suppressor genes. Thus far, a bona fide tumor suppressor gene from this region has not been identified. The isolation and characterization of new 1p36 genes is, therefore, of some interest. Two novel matrix metalloproteinase genes, MMP21 and MMP22, have been identified in the Cdc2L1-2 locus, which spans approximately 120 kb on 1p36.3. These genes encode novel metalloproteinases that contain prepro, catalytic, cysteine-rich, interleukin-1 receptor-related, and proline-rich domains. Their catalytic domains are most closely related to stromelysin-3 and contain the consensus HEXXH zinc-binding region required for enzyme activation, while their cysteine-rich domains appear to be related to a number of human, mouse, and Caenorhabditis elegans metalloproteinase sequences. Of some possible interest is the absence of a highly conserved cysteine residue in the proenzyme domain, the so-called "cysteine switch," which has been shown to be involved in the autocatalytic activation of many metalloproteinases. The MMP genes are located less than 1 kb from the 3' regions of Cdc2L1 and Cdc2L2, suggesting that the MMP and Cdc2L genes are part of a larger region that has been duplicated. Finally, the MMP21/22 genes express multiple mRNAs, some of which are derived by alternative splicing, in a tissue-specific manner.
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PMID:Isolation and characterization of two novel metalloproteinase genes linked to the Cdc2L locus on human chromosome 1p36.3. 974 Jun 77

Recently, we have shown that the tumor necrosis factor-alpha (TNF-alpha)-induced morphological change of EA.hy 926 human endothelial cells is associated with a decrease in the net synthesis of two proteoglycans (PGs), biglycan and syndecan-1, both of which have been suggested to play a role in cell adhesion. Here we have examined whether this phenotypic modulation of EA.hy 926 cells also involves altered expression of matrix metalloproteinases (MMPs) or their tissue inhibitors (TIMPs). We demonstrate that, when forming cobblestone-like monolayer cultures, these cells express and synthesize collagenase-1 (MMP-1), stromelysin-1 (MMP-3) and 72 kDa (MMP-2) and 92 kDa (MMP-9) gelatinases, all of which have previously been found in either normal or pathological human vascular wall. EA.hy 926 cells also express membrane-typel MMP (MT1-MMP), but not matrilysin (MMP-7) and collagenase-3 (MMP-13). As regards TIMPs, we show that these cells express TIMP-1 and TIMP-2, but not TIMP-3 or TIMP-4. Exposure of the cells to TNF-alpha changed the cell morphology from a polygonal shape into a spindle shape and also increased the mRNA levels of MMP-1, MMP-3 and MMP-9, but slightly decreased the MMP-2 mRNA level. No change at the mRNA level of MT1-MMP was observed. Similarly to unstimulated cultures, no mRNA for MMP-7 or MMP-13 was detected in the TNF-alpha treated cultures. TNF-alpha had no effect on the TIMP-1 and TIMP-2 mRNA levels and did not induce TIMP-3 or TIMP-4 expression. Gelatin zymography and Western blot analysis revealed that the increase observed at the mRNA level of MMP-3 and MMP-9 was similar to that of their net protein level; furthermore, the active form of MMP-1 was induced. Our results indicate that the TNF-alpha-induced morphological change of EA.hy 926 cells is associated not only with specific changes in the expression of PGs by the cells, but also with specific changes in the expression of MMPs.
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PMID:Collagenase-1, stromelysin-1 and 92 kDa gelatinase are associated with tumor necrosis factor-alpha induced morphological change of human endothelial cells in vitro. 974 45


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