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)

Matrilysin, a member of the matrix metalloproteinase family, is structurally different from the other matrix metalloproteinases by virtue of the absence of a conserved COOH-terminal protein domain. In addition, matrilysin mRNA is regulated in a specific and distinct manner in normal and malignant tissues. Analysis of the genomic structure of the human matrilysin gene revealed that the organization of the first five exons is highly conserved among the different members of the matrix metalloproteinase family, but that matrilysin contains an atypical sixth exon. The promoter region of the matrilysin gene has several features that are conserved among several other matrix metalloproteinase family members, including the presence of TATA, AP-1, and PEA3 elements. Comparison of the expression of the human matrilysin promoter with rat stromelysin promoter/chloramphenicol acetyltransferase constructs in HeLa cells revealed that constructs containing AP-1 and PEA3 elements respond similarly to epidermal growth factor and tumor promoter (12-O-tetradecanoyl-phorbol-13-acetate) induction, but that the addition of upstream stromelysin sequences results in an increased transcriptional activity not observed with upstream matrilysin sequences. The similarities and differences observed between the promoters of matrilysin and the other metalloproteinases may provide insights into the molecular mechanisms that regulate the expression of this family of enzymes as a whole and the factors that distinguish the expression patterns of individual family members.
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PMID:Structure and expression of the human gene for the matrix metalloproteinase matrilysin. 829 54

Matrix metalloproteinases (MMPs) are expressed in normal remodeling tissues in a generally tissue-restricted pattern. Transcripts for stromelysin-1 and collagenase are expressed primarily in stromal fibroblasts, whereas transcripts for matrilysin are expressed primarily in glandular epithelial cells. These expression patterns are maintained at carcinoma tumor sites until the late stages of tumor progression at which point many epithelially-derived tumors begin to express stromal fibroblast MMPs. Coincidentally, late stage carcinomas take on other characteristics of stromal fibroblasts, indicating that these tumor cells have "transdifferentiated', that is, they have begun to exhibit characteristics of cells from a separate developmental lineage. Despite their distinct expression patterns, many of the promoters for MMP genes show the same general arrangement of the nuclear proto-oncoprotein-binding sites, AP-1 and PEA3. However, the specific interaction between these cis-elements and different combinations of Fos, Jun, and Ets proteins which recognize these sites may be important in controlling both the positive and negative regulation involved in the tissue-restricted pattern of MMP expression in normal and neoplastic tissues.
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PMID:Mechanisms controlling the transcription of matrix metalloproteinase genes in normal and neoplastic cells. 879 95

In this study, we investigated the role of E1AF, a member of ets family transcription factor, in the acquisition of metastatic capacity by non-metastatic mouse fibrosarcoma cell clone, QR-32. The QR-32 cell clone grows progressively after co-implantation with gelatin sponge in syngeneic C57BL/6 mice. The cell lines (QRsP) established from arising tumors after the co-implantation exhibited enhanced tumorigenicity and pulmonary metastasis in vivo as compared with parent QR-32 cells. The enhanced pulmonary metastasis of QRsP cells was correlated well with augmented production of matrix metalloproteinase-2 (MMP-2) and increased expression of membrane-type 1-MMP (MT1-MMP). The QRsP cells also acquired higher chemokinetic activities to fibronectin and higher invasive activities through a reconstituted basement membrane. Furthermore we observed the elevated mRNA expression of E1AF in QRsP cells compared to parent QR-32 cells. Therefore, we transfected QR-32 cells with E1AF cDNA. Overexpression of E1AF in the QR-32 cells resulted in the induction of MT1-MMP expression and converting an exogenously added precursor MMP-2 into active form. E1AF transfectants exhibited more motile and invasive activities, and moderately increased pulmonary metastatic activities than parental QR-32 cells in vivo, although their metastatic activities were lower than those of QRsP cells. These findings suggest that the increased expression of E1AF in fibrosarcoma contributes to invasive phenotypes including MT1-MMP expression and enhanced cell migration, but not sufficient for exhibiting highly metastatic activity in vivo.
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PMID:Increased E1AF expression in mouse fibrosarcoma promotes metastasis through induction of MT1-MMP expression. 1020 38

The matrix metalloproteinase matrilysin (MMP-7) is expressed in the tumor cells of a majority of mouse intestinal and human colonic adenomas. We showed previously that matrilysin is a target gene of beta-catenin-Tcf, the transcription factor complex whose activity is thought to play a crucial role in the initiation of intestinal tumorigenesis. Here we report that overexpression of a stable mutant form of beta-catenin alone was not sufficient to effect expression of luciferase from a matrilysin promoter-luciferase reporter plasmid. However, cotransfection of the reporter with an expression vector encoding the PEA3 Ets transcription factor, or its close relatives ER81 and ERM, increased luciferase expression and rendered the promoter responsive to beta-catenin-LEF-1 as well as to the AP-1 protein c-Jun. Other Ets proteins could not substitute for the PEA3 subfamily. Luciferase activity was induced up to 250-fold when PEA3, c-Jun, beta-catenin, and LEF-1 were coexpressed. This combination of transcription factors was also sufficient to induce expression of the endogenous matrilysin gene. Furthermore, all matrilysin-expressing benign intestinal tumors of the Min mouse expressed a member of the PEA3 subfamily, as did all human colon tumor cell lines examined. These data suggest that the expression of members of the PEA3 subfamily, in conjunction with the accumulation of beta-catenin in these tumors, leads to coordinate upregulation of matrilysin gene transcription, contributing to gastrointestinal tumorigenesis.
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PMID:The PEA3 subfamily of Ets transcription factors synergizes with beta-catenin-LEF-1 to activate matrilysin transcription in intestinal tumors. 1115 22

The inducible prostaglandin synthase cyclooxygenase-2 (COX-2) is aberrantly expressed in intestinal tumors resulting from APC mutation, and is also transcriptionally up-regulated in mouse mammary epithelial cells in response to Wnt1 expression. beta-Catenin stabilization is a consequence of both APC mutation and Wnt signaling. We have previously observed coordinate regulation of the matrilysin promoter by beta-catenin and Ets family transcription factors of the PEA3 subfamily. Here we show that while beta-catenin only weakly activates the COX-2 promoter, PEA3 family transcription factors are potent activators of COX-2 transcription. Consistent with this, PEA3 is up-regulated in Wnt1-expressing mouse mammary epithelial cells, and PEA3 factors are highly expressed in tumors from Wnt1 transgenic mice, in which Cox-2 is also up-regulated. Promoter mapping experiments suggest that the NF-IL6 site in the COX-2 promoter is important for mediating PEA3 responsiveness. The NF-IL6 site is also important for COX-2 transcription in some colorectal cancer lines (Shao, J., Sheng, H., Inoue, H., Morrow, J. D., and DuBois, R. N. (2000) J. Biol. Chem. 275, 33951-33956), and PEA3 factors are highly expressed in colorectal cancer cell lines. Therefore, we speculate that PEA3 factors may contribute to the up-regulation of COX-2 expression resulting from both APC mutation and Wnt1 expression.
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PMID:PEA3 is up-regulated in response to Wnt1 and activates the expression of cyclooxygenase-2. 1127 70

The expression levels of ets and MMP genes was examined in two breast cancer cell lines of differing invasive potential. The more invasive MDA-MB-231 cell line had higher levels of Ets-1, Ets-2, PEA3, ERM, Tel, Net, MMP-13 and -14 mRNA than MCF-7 cells. MMP-1, -3 and -16 mRNAs were expressed equally. TPA stimulated MMP-1, -9 and TIMP-1 mRNA expression in both cell lines. MMP-2 and MMP-7 mRNAs were not detected in either cell line. The Ets-1 protein was only detected in MDA-MB-231 cells and its level increased following TPA stimulation. TPA induced MMP-9 activity in MCF-7 cells and increased its activity in MDA-MB-231 cells, however, MMP-2 activity was not detected.
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PMID:Expression of Ets-related transcription factors and matrix metalloproteinase genes in human breast cancer cells. 1205 64

The events that mediate tumor progression in ovarian carcinoma are poorly understood to date. This review summarizes our results studying metastasis-associated molecules in advanced-stage ovarian carcinomas, details the co-expression of mRNA of these genes, and discusses their prognostic role. Fifty-five primary and metastatic FIGO stage III-IV ovarian carcinomas were analyzed for the expression of alpha v and beta1 integrin subunits, the matrix metalloproteinases MMP-2, MMP-9, and MT1-MMP, the MMP inhibitor TIMP-2, vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), interleukin-8 (IL-8), PEA3 and Ets-1 using mRNA in situ hybridization. Tumor and adjacent stromal cell expression was scored. The association between integrin subunit expression and the expression of MMP, TIMP-2, angiogenic genes, PEA3 and Ets-1 was statistically analyzed. Alpha v integrin subunit mRNA expression in carcinoma cells showed significant association with that of MMP-2 and IL-8 in this cellular compartment, while the presence of beta1 integrin subunit mRNA showed similar association with that of PEA3, Ets-1, IL-8, bFGF and MMP-2. Expression of beta1 integrin subunit mRNA in stromal cells was associated with that of TIMP-2 and Ets-1 in this compartment. In addition, significant intercellular associations were found between alpha v integrin subunit mRNA expression in carcinoma cells and stromal cell expression of Ets-1, as well as between stromal cell expression of alpha v integrin subunit and labeling for IL-8 in carcinoma cells. The presence of beta1 integrin subunit mRNA in carcinoma cells showed a significant association with that of Ets-1, IL-8 and bFGF in stromal cells, while the presence of beta1 integrin subunit mRNA in stromal cells was associated with tumor PEA3 mRNA expression. To the best of our knowledge, this is the first evidence for coordinated autocrine and paracrine expression of members of these four families of metastasis-associated genes in human cancer. The results of this analysis support experimental data regarding cross-talk between carcinoma cells and peritumoral fibroblasts. They also suggest the existence of a putative activation sequence of metastatic genes, involving the beta1 (and possibly alpha v) integrin subunits, IL-8, PEA3, Ets-1 and MMP in ovarian carcinoma.
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PMID:Coordinated expression of integrin subunits, matrix metalloproteinases (MMP), angiogenic genes and Ets transcription factors in advanced-stage ovarian carcinoma: a possible activation pathway? 1271 42

Expression of E1AF/PEA3 (ETV4), an ets family transcription factor, has been implicated in the invasive potential of several cancer cell lines through induction of matrix metalloproteinase (MMP) expression. The aim of this study was to examine E1AF mRNA expression and to determine whether it is correlated with progression of, and/or MMP expression in, human colorectal cancer. Using the semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR), 100 colorectal cancer tissues were analysed for E1AF mRNA expression. Expression of ER81 (ETV1) and ERM (ETV5), the other two members of the PEA3 subfamily, and Ets-1 and Ets-2 was also analysed. The results were correlated with clinicopathological characteristics and MMP expression. Immunohistochemical analysis and an in vitro invasion assay were also performed. E1AF mRNA expression was detected in 62% of the 100 colorectal cancer tissues, but was undetectable or only faintly detected in adjacent non-tumour tissues. E1AF mRNA was detected in all of the ten liver metastases from colorectal cancers. E1AF expression correlated significantly with depth of invasion, lymphatic and venous invasion, lymph node and distant metastasis, advance in pathological tumour-node-metastasis stage, and recurrence. Patients with E1AF-positive tumours had significantly shorter overall and disease-free survival periods than did those with E1AF-negative tumours (p < 0.0001 and p < 0.0001, respectively). E1AF expression retained its significant predictive value for overall and disease-free survival in multivariate analysis that included conventional clinicopathological factors (p = 0.0066 and p = 0.0109, respectively). Among the MMPs analysed, expression of MMP-1 and matrilysin correlated significantly with E1AF expression. In contrast, expression of ER81 and ERM did not correlate with clinicopathological characteristics or the expression of these MMPs. Immunohistochemical expression of E1AF was predominantly observed at the invasive front, where the expression of MMP-1 and matrilysin and nuclear beta-catenin expression were often co-localized. Antisense E1AF-transfected HT-29 colon cancer cells expressed reduced levels of MMP-1 and matrilysin and were less invasive in vitro than neo-transfected HT-29 cells. The results of this study suggest that E1AF, the expression of which is closely correlated with the expression of MMP-1 and matrilysin, plays a key role in the progression of colorectal cancer.
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PMID:Association of ets-related transcriptional factor E1AF expression with tumour progression and overexpression of MMP-1 and matrilysin in human colorectal cancer. 1289 92

Expression of E1AF/PEA3 (ETV4), an ets family transcriptional factor, has been implicated in tumor progression through induction of matrix metalloproteinase (MMP) expression. The aim of this study was to examine E1AF mRNA expression and to determine whether it is correlated with progression of, and/or MMP expression in, human gastric cancer. Using the semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR), we analyzed 100 gastric cancer tissues for E1AF mRNA expression. Expression of ER81 (ETV1) and ERM (ETV5), the other two members of the PEA3 subfamily, and Ets-1 and Ets-2 was also analyzed. The results were correlated with clinicopathological characteristics and MMP expression. Immunohistochemical analysis and an in vitro invasion assay were also performed. E1AF mRNA expression was detected in 64% of the 100 gastric cancer tissues, but was undetectable or only faintly detected in adjacent non-tumor tissues. E1AF expression was significantly correlated with depth of invasion, lymphatic and venous invasion, lymph node and distant metastasis, advance in pathological tumor-node-metastasis stage and recurrence. Patients with E1AF-positive tumors had significantly shorter overall and disease-free survival periods than did those with E1AF-negative tumors (P < 0.0001 and P < 0.0001, respectively). E1AF expression retained its significant predictive value for overall and disease-free survival in multivariate analysis that included conventional clinicopathological factors (P = 0.0082 and P = 0.0096, respectively). Among the MMPs analyzed, expression of matrilysin (MMP-7) was significantly correlated with E1AF expression. Immunohistochemical expression of E1AF was predominantly observed at the invasive front, where the expression of matrilysin was often co-localized. Antisense E1AF-transfected MKN45 gastric cancer cells expressed reduced levels of matrilysin and were less invasive in vitro than mock-transfected MKN45 cells. The results of this study suggest that E1AF, the expression of which is closely correlated with the expression of matrilysin, plays a key role in the progression of gastric cancer.
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PMID:Expression of ets-related transcriptional factor E1AF is associated with tumor progression and over-expression of matrilysin in human gastric cancer. 1460 92

The PEA3/E1AF/ETV4 gene encodes an Ets-related transcription factor that is expressed in the epithelial cells of the mammary gland. Previous reports have shown that PEA3 can up-regulate promoter activities of many genes associated with tumorigenesis. A significant fraction of those encode matrix metalloproteinases (MMP genes) required for degradation of the extracellular matrix. To better obtain a molecular characterization of PEA3 expression in sporadic breast cancer, we quantified PEA3 mRNA by means of real-time reverse transcriptase-polymerase chain reaction assay in a large series of human primary breast tumors. PEA3 expression showed wide variations in tumor tissues, being under-expressed in 30 of 130 (23.1%) and over-expressed in 18 of 130 (13.8%) compared with normal breast tissues. High PEA3 mRNA levels correlated significantly with Scarff-Bloom-Richardson histopathological grade III (P = 0.018) but not with poor prognosis, suggesting that PEA3 is a marker of tumor aggressiveness rather than a prognostic factor in human breast cancer. We also observed positive links between the expression of PEA3 and those of MKI67 and ERBB2 (P = 0.034 and P = 0.045, respectively) and an inverse relationship with ERalpha (P = 0.0016). Our results do not support recent findings suggesting that PEA3 could be a tumor-suppressor gene that can act therapeutically in ERBB2 over-expressed tumors. Our results also suggest major roles of the MMP2, NRG1 and CGB genes (which encode type I gelatinase, heregulin and human chorionic gonadotropin beta subunit, respectively) in the PEA3 pathway dysregulation observed in breast cancer. Taken together, the data confirm the role of the PEA3 gene in breast tumorigenesis, and suggest the existence of numerous other still unknown genes transactivated by the PEA3 transcription factor.
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PMID:Expression of PEA3/E1AF/ETV4, an Ets-related transcription factor, in breast tumors: positive links to MMP2, NRG1 and CGB expression. 1463 60


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