Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.3 (collagenase)
 18,340 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.
 ...
PMID:Overview of matrix metalloproteinase expression in cultured human cells. 955 Feb 65

Matrix metalloproteinases (MMPs) are believed to be involved in the invasion and metastasis of various human carcinomas. In the present study, the production levels of seven different MMPs (MMP-1, -2, -3, -7, -8, -9, and -13), the activation of the zymogen of MMP-2 (proMMP-2), the expression of membrane-type MMPs (MT1-, MT2-, and MT3-MMPs), and the tissue localization of the activated enzyme were examined in human invasive papillary thyroid carcinomas. Sandwich enzyme immunoassays revealed that among the MMPs examined, only the MMP-2 production level is significantly enhanced in the carcinoma tissues compared with the follicular adenoma and normal control thyroid tissues. Gelatin zymography indicated that the proMMP-2 activation ratio is considerably higher in carcinomas with lymph node metastasis than it is in those without metastasis, follicular adenomas, or normal controls (P < 0.01). Northern blot analysis of the expression of MT1-, MT2-, and MT3-MMPs, which are known to activate proMMP-2 in vitro, demonstrated the predominant expression of MT1-MMP mRNA in the carcinoma tissues (15 of 15 cases), whereas MT2-MMP expression was confined to 26% of the cases (4 of 15 cases), and no consistent expression of MT3-MMP was observed. MTI-MMP mRNA expression levels correlated with the proMMP-2 activation ratio (r = 0.692; P < 0.01), but such a correlation was not obtained with MT2-MMP. There was also a direct correlation between MT1-MMP expression and lymph node metastasis (P < 0.05). In situ hybridization indicated that both carcinoma and stromal cells express MT1-MMP transcripts (five of six cases). MT1-MMP was also immunolocalized to carcinoma and stromal cells in all of the carcinoma samples (26 of 26 cases), which were positive for MMP-2. In situ zymography indicated definite gelatinolytic activity in the carcinoma cell nests, which was abolished by incubation of the carcinoma samples with a synthetic MMP inhibitor before the reaction. These results suggest for the first time that among seven different MMPs, the production of proMMP-2 and its MT1-MMP-mediated activation in the carcinoma cell nests play an important role in the lymph node metastasis of human invasive papillary thyroid carcinomas.
 ...
PMID:Enhanced production and activation of progelatinase A mediated by membrane-type 1 matrix metalloproteinase in human papillary thyroid carcinomas. 992 64

In order to assess the significance of changes in metalloproteinase activity in pancreatic carcinogenesis, the expression of matrix metalloproteinases 2 and 9 (MMP-2 and MMP-9, respectively), tissue inhibitor of metalloproteinase-1 (TIMP-1) and TIMP-2, and membrane-type 1 MMP (MT1-MMP) and MT2-MMP in ductal lesions in a rapid-production model for pancreatic duct carcinomas (PCs) in hamsters initiated with N-nitrosobis(2-oxopropyl)amine (BOP) and in subcutaneous transplantable tumors of hamster pancreatic duct carcinoma (HPDs) was investigated. Northern analysis revealed MMP-2, MMP-9, TIMP-2 and MT1-MMP mRNAs to be overexpressed in PCs. Immunohistochemically, elevated levels of MMP-2 were apparent in early duct epithelial hyperplasias and staining increased from atypical hyperplasias to carcinomas. Gelatin zymography demonstrated clear activation of proMMP-2 but not proMMP-9 in both of primary and HPD tumors, the MT1-MMP mRNA level and proMMP-2 activation being significantly correlated (r = 0.893, P < 0.001). In our rapid production model, 0.1 and 0.2% OPB-3206, an inhibitor of MMPs, given in the diet after two cycles of augmentation pressures for 48 days decreased the incidence and number of carcinomas. Gelatin zymography demonstrated that OPB-3206 inhibited activation of proMMP-2 in pancreatic cancer tissues. These results indicate that overexpression of MMP-2, TIMP-2 and MT1-MMP, and cell surface activation of proMMP-2 by MT1-MMP, are involved in the development of PCs, and that MMP-2 expression at the protein level appears in the early phase of pancreatic duct carcinogenesis. OPB-3206 may be a candidate chemopreventive agent for pancreatic ductal adenocarcinomas.
 ...
PMID:Expression of matrix metalloproteinase 2 (MMP-2), membrane-type 1 MMP and tissue inhibitor of metalloproteinase 2 and activation of proMMP-2 in pancreatic duct adenocarcinomas in hamsters treated with N-nitrosobis(2-oxopropyl)amine. 1038 7

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.
 ...
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.
 ...
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.
 ...
PMID:Messenger ribonucleic acid expression of 16 matrix metalloproteinases in bone-implant interface tissues of loose artificial hip joints. 1103 43

In order to determine key MMPs for invasion and metastasis in various human cancers, we examined the expression of ten MMPs (MMP-1, 2, 3, 7, 8, 9, 13 and MT1, 2, 3-MMPs) and tissue inhibitors of metalloproteinases (TIMP-1 and 2) in breast carcinomas, thyroid papillary carcinomas, endometrial carcinomas, ovarian carcinomas, gastric adenocarcinomas, oral squamous cell carcinomas and gliomas. Of the MMPs examined, the activation of proMMP-2 by MT1-MMP (membrane type 1-MMP) was commonly important for the invasion and metastasis of these cancers except for endometrial carcinomas. The MMP-2 and MT1-MMP were localized to the carcinoma cells and gelatinolytic activity was demonstrated within the carcinoma cell nests by in situ zymography. In endometrial carcinomas, production and activation of proMMP-7 were a key determinant of the lymph node metastasis. The activation of proMMP-2 in gliomas involved MT2-MMP as well as MT1-MMP, and a combination of decreased TIMP-2 production and enhanced MT1-MMP expression was important in the subarachnoidal dissemination of glioblastoma cells. Brevican, a major adult brain proteoglycan, was degraded with MMP-1, 2, 3, 7, 10 and ADAMTS4 (aggrecanase-1) by being cleaved at the MMP site (the Ala360-Phe361 bond) with the MMPs and ADAM site (the Glu395-Ser396 bond) with ADAMTS4. Since activated MMP-2 and ADAMTS4 are present in human glioma tissues, they may play a key role in the invasion of glioma cells through the brevican degradation. The data in the present study suggest that the extracellular matrix-degrading metalloproteinases acting probably on the cell membranes of cancer cells are essential to the invasion and metastasis of human cancers.
 ...
PMID:Tumor cell-matrix interaction: pericellular matrix degradation and metastasis. 1121 46

We measured the production levels of seven different matrix metalloproteinases (MMP-1, 2, 3, 7, 8, 9 and 13) and two tissue inhibitors of metalloproteinases (TIMP-1 and 2) in the homogenates of human oral squamous cell carcinomas and control normal squamous epithelia by the corresponding sandwich enzyme immunoassay systems. The levels of MMP-1, 2, 3, 8, 9, 13 and TIMP-1 were significantly higher in the carcinoma samples than in the control. Among them, only the production level of MMP-2 was significantly higher in the carcinomas with cervical lymph node metastasis than in those without metastasis (P < 0.05). Gelatin zymography demonstrated that activation ratio of the zymogen of MMP-2 (proMMP-2) is significantly higher in the carcinomas with lymph node metastasis than in those without metastasis (P < 0.05) or normal control (P < 0.01). Quantitative RT-PCR for membrane-types 1, 2 and 3 MMPs (MT1, 2 and 3-MMPs), which activate proMMP-2 in vitro, demonstrated that MT1-MMP is predominantly expressed in the carcinoma tissues, and the expression level is significantly higher in the carcinomas with lymph node metastasis than in those without metastasis (P < 0.05) or the control samples (P < 0.05). Although MT2-MMP and MT3-MMP were detected in approximately 30% of the carcinoma cases, their expression levels were extremely lower compared with that of MT1-MMP. There was a direct correlation between the MT1-MMP expression level and proMMP-2 activation ratio (r = 0.62, P < 0.01). In situ hybridization and immunohistochemistry indicated that carcinoma cells and stromal cells adjacent to carcinoma cell nests express MT1-MMP transcripts and protein. MMP-2 and TIMP-2 were also immunolocalized to the carcinoma cells in the carcinoma samples. By in situ zymography, gelatinolytic activity was demonstrated in the carcinoma cell nests and abolished by the treatment with an MMP inhibitor, BB94. These results suggest that among seven different MMPs, the production of proMMP-2 and its activation mediated by MT1-MMP play an important role in the cervical lymph node metastasis of the human oral squamous cell carcinomas.
 ...
PMID:Enhanced production and activation of progelatinase A mediated by membrane-type 1 matrix metalloproteinase in human oral squamous cell carcinomas: implications for lymph node metastasis. 1123 94

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.
 ...
PMID:Analysis of matrix metalloproteinase mRNAs expressed in hepatocellular carcinoma cell lines. 1156 28

Stromal expression of some matrix metalloproteinases (MMPs) has been associated with increasing tumour burden in prostate cancer. We investigated the expression of mRNA (by RT-PCR) and protein (by zymography and western blotting) of MMPs and endogenous inhibitors (tissue inhibitors of metalloproteinases, TIMPs) in two parent epithelial prostate cancer cell lines and sublines of increasing invasive/metastatic potential. Expression of membrane type MMPs, MT1-MMP and MT3-MMP mRNA was higher in PC3-derived than in LNCaP-derived lines, whereas MT2-MMP mRNA expression was higher in the LNCaPderived than in PC3-derived cell lines. Active MT1, MT2 and MT3-MMP protein levels were similar in all lines, but processed MT-MMPs, indicative of latent MMP activation, were increased in more aggressive sublines. Expression of MMP-1, MMP-13 and TIMP-1 was higher in the more aggressive sublines and may be implicated in invasive/metastatic ability. Regulation of MMP-1 and MMP-13 expression may offer important therapeutic options for treating patients with prostate cancer.
 ...
PMID:Characterization of expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases in prostate cancer cell lines. 1266 60


1 2 3 Next >>