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 matrix metalloproteinases (MMP) have been implicated in tumor invasion and metastasis both by immunohistochemical studies and from the observation that specific metalloproteinase inhibitors block tumor invasion and metastasis. Oligonucleotide primers for thirteen MMPs (MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-10, MMP-11, MMP-12, MMP-13, MMP-14, MMP-15, MMP-16) were optimized for use in RT-PCR. A semi-quantitative RT-PCR assay was used to determine the pattern of MMP mRNA expression in 84 normal and transformed or carcinogen transformed human cell lines and strains derived from different tissues. The results demonstrate one or more cell lines which express thirteen members of the MMP family. In addition, various oncogene transfected human fibroblast cell strains were analyzed for MMP expression. We confirm that over-expression of the H-ras oncoprotein correlates with up-regulation of MMP-9 and demonstrate that over-expression of v-sis also up-regulates MMP-9. A cell line immortalized following myc expression was found to up-regulate MMP-7, MMP-11 and MMP-13. Inappropriate expression of several MMP mRNAs was detected in breast, prostate, bone, colon and oral tumor derived cell lines. Identification of at least one cell line expressing each of thirteen MMPs and the observation of oncogene induced expression of several MMPs should facilitate analysis of the transcriptional mechanisms controlling each MMP.
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PMID:Overview of matrix metalloproteinase expression in cultured human cells. 955 Feb 65

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

During tissue-invasive events, migrating cells penetrate type I collagen-rich interstitial tissues by mobilizing undefined proteolytic enzymes. To screen for members of the matrix metalloproteinase (MMP) family that mediate collagen-invasive activity, an in vitro model system was developed wherein MDCK cells were stably transfected to overexpress each of ten different MMPs that have been linked to matrix remodeling states. MDCK cells were then stimulated with scatter factor/hepatocyte growth factor (SF/HGF) to initiate invasion and tubulogenesis atop either type I collagen or interstitial stroma to determine the ability of MMPs to accelerate, modify, or disrupt morphogenic responses. Neither secreted collagenases (MMP-1 and MMP-13), gelatinases (gelatinase A or B), stromelysins (MMP-3 and MMP-11), or matrilysin (MMP-7) affected SF/HGF-induced responses. By contrast, the membrane-anchored metalloproteinases, membrane-type 1 MMP, membrane-type 2 MMP, and membrane-type 3 MMP (MT1-, MT2-, and MT3-MMP) each modified the morphogenic program. Of the three MT-MMPs tested, only MT1-MMP and MT2-MMP were able to directly confer invasion-incompetent cells with the ability to penetrate type I collagen matrices. MT-MMP-dependent invasion proceeded independently of proMMP-2 activation, but required the enzymes to be membrane-anchored to the cell surface. These findings demonstrate that MT-MMP-expressing cells can penetrate and remodel type I collagen-rich tissues by using membrane-anchored metalloproteinases as pericellular collagenases.
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PMID:Regulation of cell invasion and morphogenesis in a three-dimensional type I collagen matrix by membrane-type matrix metalloproteinases 1, 2, and 3. 1085 Oct 27

Matrix metalloproteinases (MMPs) have been reported to be the major factors responsible for aseptic loosening of artificial hip joints. So far, messenger ribonucleic acid (mRNA) expression patterns of seven MMPs have been reported, but that of many other MMPs which have been newly discovered or recently considered to be responsible for prosthetic loosening is still unknown. In this study, mRNA expression pattern of 16 different types of MMPs were analyzed to evaluate which MMPs were locally produced and contributed to prosthetic loosening. Synovium-like interface tissues between bone and prosthesis were collected from 18 cases of aseptic loose artificial hip joint at revision surgery. Six cases of normal synovium were used as controls. Total RNA was extracted by single-step acid guanidinium-thiocyanate-phenol-chloroform procedure. mRNA expression of MMPs was analyzed by semiquantitative reverse transcription-polymerase chain reaction. Based on local expression pattern of MMPs at the mRNA level, aseptic loose artificial hip joint was characterized by elevated expression of MMP-1, MMP-9, MMP-10, MMP-12, and MMP-13; moderate expression of MMP-2, MMP-7, MMP-8, MMP-11, membrane type (MT)1-MMP (MMP-14), MT2-MMP (MMP-15), MT3-MMP (MMP-16), MT4-MMP (MMP-17), and MMP-19; lower expression of MMP-3; and little significance of MMP-20. The MMPs detected in this study can potentially degrade almost all components of the periprosthetic extracellular matrix. Thus, many MMP type enzymes possibly contribute to prosthetic loosening and osteolysis through pathologic extracellular matrix degradation and connective tissue/bone remodeling around prostheses.
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PMID:Messenger ribonucleic acid expression of 16 matrix metalloproteinases in bone-implant interface tissues of loose artificial hip joints. 1103 43

In this study, we describe rat NK cell-derived MMPs including membrane-type MMPs (MT-MMPs) and tissue inhibitors of MMP (TIMPs). RT-PCR analysis from cDNA of rat A-NK cells revealed mRNA for MMP-2, MMP-9, MMP-7, MMP-10, MMP-11, MMP-13, MT1-MMP, MT2-MMP, TIMP-1, and TIMP-2. The RNK-16 cells expressed mRNA for MMP-7, MMP-10, MMP-11, MT1-MMP, MT2-MMP, TIMP-1, and TIMP-2, in addition to MMP-3 and MMP-13. Western blot analysis confirmed proteins for MT1-MMP and MT2-MMP in RNK-16 cells. TIMP-1 in rat A-NK cells was present at molecular mass of 34-kDa protein which may represent a highly glycosylated form. Genistein, a natural isoflavone found in soybeans, inhibited proliferation of RNK-16 cells in dosage dependent manner. In addition, it down-regulated the expression of MMP-13, MT1-MMP, TIMP-1 and TIMP-2. Moreover, genistein greatly impaired the ability of RNK-16 cells to invade through a model basement membrane. This effect might be mediated by the observed down-regulation of MMP-13 and MT1-MMP.
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PMID:Expression of matrix metalloproteinases and their inhibitors by rat NK cells: inhibition of their expression by genistein. 1112 39

To analyze matrix metalloproteinase (MMP) mRNAs that are expressed in hepatocellular carcinoma cell lines, the kinds of MMP mRNAs were surveyed in HepG2 and Hep3B cells and normal liver by a reverse transcription-polymerase chain reaction using two degenerate primer pairs, derived from conserved domains of known MMPs. The level for each MMP mRNA was examined by Northern blot analysis in HepG2 and Hep3B cells, as well as in normal tissues. It was also examined by a reverse transcription-polymerase chain reaction analysis in 8 different hepatocellular carcinoma cell lines. MMP-2, MMP-14, and MMP-15 mRNAs were expressed at elevated levels in most of the cell lines studied, reflecting that these MMPs would play an important role in the invasion and metastasis of hepatocellular carcinoma. MMP-1, MMP-3, MMP-8, MMP-10, MMP-11, and MMP-13 mRNAs were also expressed in some or most of the cell lines. Interestingly, MMP-9 mRNA, as well as its polypeptide, was undetected in all of the cell lines studied. This implies that MMP-9, which was suggested as a tumor marker for hepatocellular carcinoma, would be expressed in stromal cells, rather than tumor cells. These results provide information for the basal levels of MMP mRNAs in various hepatocellular carcinoma cell lines. It will also facilitate study on the transcriptional regulation of each MMP mRNA by oncogenes.
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PMID:Analysis of matrix metalloproteinase mRNAs expressed in hepatocellular carcinoma cell lines. 1156 28

Matrix metalloproteinases (MMPs) are implicated in multiple sclerosis where one of their roles may be to facilitate the transmigration of circulating leukocytes into the CNS. Studies have focused on only a few MMPs, and much remains unknown of which of the 23 MMP family members is/are critical to the multiple sclerosis disease process. Using quantitative real time polymerase chain reactions, we have systematically analysed the expression of all 23 MMP members in subsets of leukocytes isolated from the blood of normal individuals. We found a distinctive pattern of MMP expression in different cellular populations: MMP-11, MMP-26 and MMP-27 were enriched in B cells, while MMP-15, MMP-16, MMP-24 and MMP-28 were prominent in T lymphocytes. Of interest is the enrichment of a majority of MMP members in monocytes: MMP-1, MMP-3, MMP-9, MMP-10, MMP-14, MMP-19 and MMP-25. MMP-2 and MMP-17 were also significantly represented in monocytes, although B cells had significant amounts of these MMPs. In correspondence with their strong expression of many MMP members, monocytes migrated more rapidly across a model of the blood-brain barrier in culture than T or B lymphocytes. Finally, we found higher levels of two of the monocyte-expressed MMPs in multiple sclerosis patients compared with normal individuals: MMP-2 and MMP-14. Tissue inhibitor of metalloproteinases (TIMP)-2 was also elevated in monocytes from multiple sclerosis patients, providing a mechanism for the reported activation of MMP-2 by MMP-14 and TIMP-2. These results emphasize that monocytes are prominent contributors of the neuroinflammation in multiple sclerosis through a mechanism that involves their high MMP expression and that they identify specific MMP members as targets for novel therapeutics in the disease.
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PMID:Analyses of all matrix metalloproteinase members in leukocytes emphasize monocytes as major inflammatory mediators in multiple sclerosis. 1450 71

Matrix metalloproteinases (MMPs) specially degrade extracellular matrix (ECM) proteins and are involved in tissue remodeling and angiogenesis. Therefore, studies on the role of MMPs in the carcinogenesis, proliferation and infiltration of hepatocellular carcinoma (HCC) may greatly contribute to the development of a new clinically applicable therapeutic approach. In the present study, we immunologically examined the expression rates of various MMPs including MMP-2, 3, 7, 9, membrane type 1-MMP (MT1-MMP), and MT2-MMP in the cancerous and noncancerous areas of resected tumor specimens from 30 patients with primary HCC. The rate of MMP-2 expression was high for both cancerous and noncancerous areas. However, the expression rates of MMP-3, MT1-MMP, and MT2-MMP were significantly higher in cancerous areas than in noncancerous areas. Next, we examined the clinicopathologic features such as the number of tumor nodules, maximal tumor size, presence or absence of capsular infiltration and portal vein invasion, histological grades of HCCs, state of noncancerous areas (chronic hepatitis: CH or liver cirrhosis: LC), and short-term recurrence after resection (within six months). In conclusion, it was found that three main networks of MMPs are predominantly involved in the case of HCC, that is, MMP-2 and MT1-MMP in the carcinogenesis and progression, MMP-7 and MMP-9 in the capsular infiltration and portal vein invasion, as well as MMP-3 and MMP-7 in the progression of HCC. Furthermore, MT1-MMP appeared to be the most important factor in HCC because of its widespread pattern of expression.
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PMID:A study on angiogenesis-related matrix metalloproteinase networks in primary hepatocellular carcinoma. 1458 7

We aimed to clarify the prime role of recurrence in stage I lung cancer. To determine the expression profiles, quantitative RT-PCR and real-time PCR were performed subsequently to evaluate the validity of meaningful molecules identified by 0.12 K c-DNA array experiment surveys. In all, 10 lung cancer patients presenting with recurrence of stage IB were selected and compared with 10 stage IB lung cancer patients without recurrence since biopsied 3 years previously. On c-DNA microarray data analysis using pairs of recurred and the corresponding nonrecurred patients, the following genes were found to be upregulated in the recurred cases: matrix metalloproteinase (MMP)-10 in five cases, MMP-12 in two cases, MMP-11, MMP-14, MMP-15, fos, cyclin E2, E2F3, TGF-alpha in each one case. The most frequently upregulated genes in recurred lung cancers were MMP-10 (stromelysin-2) and MMP-12 (macrophage elastase). On transcriptional assay by quantitative RT-PCR and real-time RT-PCR analysis to validate those molecules, both transcripts of MMP-10 and MMP-12 were significantly more upregulated in recurred stage IB lung cancer than in the non-recurred stage IB lung cancer (P=0.004). Transcript levels were identical to c-DNA array data. The protein levels of these entities were also evaluated by immunohistochemistry of archival slides. By immunohistochemistry, MMP-10 monoclonal antibody showed more intense immunoreactivity in the recurred stage IB lung cancer than in the nonrecurred stage IB lung cancer (P=0.0313). Our approach revealed that MMP-10 plays an important role in the recurrence in stage IB lung cancer, irrespective of the histologic type.
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PMID:MMP expression profiling in recurred stage IB lung cancer. 1464 37

The ability of carcinoma cells arising at primary sites to cross their underlying basement membrane (BM), a specialized form of extracellular matrix that subtends all epithelial cells, and to access the host vasculature are central features of the malignant phenotype. The initiation of the invasive phenotype has been linked to the aberrant expression of zinc-finger transcriptional repressors, like Snail1, which act by triggering an epithelial-mesenchymal cell-like transformation (EMT-like) via the regulation of largely undefined, downstream effectors. Herein, we find that Snail1 induces cancer cells to (i) degrade and perforate BM barriers, (ii) initiate angiogenesis, and (iii) and intravasate vascular networks in vivo via a matrix metalloproteinase (MMP)-dependent process. Unexpectedly, the complete Snail1 invasion program can be recapitulated by expressing directly either of the membrane-anchored metalloproteinases, MT1-MMP or MT2-MMP. The pro-invasive, angiogenic, and metastatic activities of MT1-MMP and MT2-MMP are unique relative to all other metalloproteinase family members and cannot be mimicked in vivo by the secreted MMPs, MMP-1, MMP-2, MMP-3, MMP-7, MMP-9, or MMP-13. Further, siRNA-specific silencing of MT1-MMP and MT2-MMP ablates completely the ability of Snail1 to drive cancer cell BM invasion, induce angiogenesis, or trigger intravasation. Taken together, these data demonstrate that MT1-MMP and MT2-MMP cooperatively function as direct-acting, pro-invasive factors that confer Snail1-triggered cells with the key activities most frequently linked to morbidity and mortality in cancer.
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PMID:Induction of a MT1-MMP and MT2-MMP-dependent basement membrane transmigration program in cancer cells by Snail1. 1991 48


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