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)

Epidermolysis bullosa acquisita (EBA) is a chronic, uncommon, sub-epidermal blistering disease involving the skin and mucous membranes that heals with scar formation and milia. Collagens, matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) are important components that play an essential role(s) in matrix remodeling during scar formation. However, the possible involvement of these components in EBA-induced scarring is not yet known. In the present study, we examined the expression profile of collagens, collagen-binding heat shock protein 47 (HSP47), MMPs and their inhibitory enzymes, TIMPs, in matrix remodeling during conjunctival scarring. The involvement of TGF-beta1, a fibrogenic factor, was also studied. Compared to the controls, an increased expression of type I collagen, type III collagen and HSP47 was detected in conjunctival biopsy sections of patient with EBA using immunohistochemistry. Similar increase in the expression of type I collagen, type III collagen and HSP47 was noted in conjunctival fibroblasts obtained from the patient with EBA. Up-regulation in the expression of MMP-1 and MMP-14 was also noted in conjunctival fibroblasts isolated from the patient with EBA, while no significant changes in the expression of MMP-3, MMP-8, MMP-9 and MMP-13 were seen. As for TIMPs, conjunctival fibroblasts isolated from the patient with EBA, grown in vitro, exhibited increased expression of TIMP-1, TIMP-2 and TIMP-3, when compared with fibroblasts grown from control conjunctival tissues, although the expression level varies with different molecules of the same family. Additionally, compared to the control conjunctival fibroblasts, an increased expression of TGF-beta1 was detected in fibroblasts isolated from the conjunctival tissues of patient with EBA. This study suggests that there is up-regulation in the production of collagens (type I and III), collagen-binding protein (HSP47), matrix degrading collagenases (MMP-1 and 14), and their inhibitory enzymes (TIMP-1, 2 and 3) during the process of conjunctival matrix remodeling in the patient with EBA. The presented data is preliminary and could serve as a basis for further studies to enhance our understanding about the molecular mechanisms of conjunctival scarring in patients with EBA.
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PMID:Expression profiles of collagens, HSP47, TGF-beta1, MMPs and TIMPs in epidermolysis bullosa acquisita. 1282 5

Crystal structures of catalytic domains of MMP-3 and MT1-MMP bound to TIMP-1 or TIMP-2, respectively, differ in the orientation of the TIMP in the MMP active site. The orientation in solution of N-TIMP-1 in the MMP-3 active site has been investigated using residual dipolar couplings (RDCs). Fitting of the RDCs to the X-ray structures of the complexes suggests general agreement with the orientation of crystalline MMP-3(DeltaC) and TIMP-1 and a large disparity from the orientation of crystalline MT1-MMP(DeltaC) and TIMP-2. Rigid body docking of MMP-3 and N-TIMP-1 X-ray coordinates using RDCs and intermolecular NOEs provided a time-averaged orientation in solution differing from the crystal structure by a 5 degrees rotation toward the MT1-MMP(DeltaC)/TIMP-2 orientation. The slight discrepancy in orientations in solution and crystal lies within the experimental uncertainties. Intermolecular NOEs used in the docking corroborated the accuracy of mapping the interface by a paramagnetic NMR footprinting assay, a potential alternative source of contacts for docking. Some uncertainty in the N-TIMP-1 orientation in the MMP-3 active site, coupled with microsecond to millisecond fluctuations of the MMP-binding ridge of N-TIMP-1 in the complex and flexibility in MMP-3(DeltaC) S(1)' to S(3)' subsites, leaves open the possibility that N-TIMP-1 might dynamically pivot a few degrees or more in the arc toward the MT1-MMP(DeltaC)/TIMP-2 orientation. Differing TIMP orientations in MMP active sites are more likely to result from structural differences in TIMP AB hairpin loops than from crystal packing artifacts.
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PMID:Global orientation of bound MMP-3 and N-TIMP-1 in solution via residual dipolar couplings. 1283 47

The disorganization of E-cadherin/catenin complexes and the overexpression of matrix metalloproteinases (MMPs) are frequently involved in the capacity of epithelial cells to acquire an invasive phenotype. The functional link between E-cadherin and MMPs was studied by transfecting invasive bronchial BZR tumor cells with human E-cadherin cDNA. Using different in vitro (cell dispersion, modified Boyden chamber) and in vivo assays (human airway epithelial xenograft), we showed that E-cadherin-positive clones displayed a decrease of invasive abilities. As shown by immunoprecipitation, the re-expressed E-cadherin was able to sequestrate one part of free cytoplasmic beta-catenin in BZR cells. The decrease of beta-catenin transcriptional activity in E-cadherin-transfected clones was demonstrated using the TOP-FLASH reporter construct. Finally, we observed a decrease of MMP-1, MMP-3, MMP-9, and MT1-MMP, both at the mRNA and at the protein levels, in E-cadherin-positive clones whereas no changes in MMP-2, TIMP-1, or TIMP-2 were observed when compared with control clones. Moreover, zymography analysis revealed a loss of MMP-2 activation ability in E-cadherin-positive clones treated with the concanavalin A lectin. These data demonstrate a direct role of E-cadherin/catenin complex organization in the regulation of MMPs and suggest an implication of this regulation in the expression of an invasive phenotype by bronchial tumor cells.
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PMID:E-Cadherin mediates MMP down-regulation in highly invasive bronchial tumor cells. 1287 84

Pericellular proteolysis plays a pivotal function in cell invasion, a hallmark of tumor growth and metastasis. The minidegradome constituted of two matrix metalloproteinases (MMP), i.e. MMP-2 and MT1-MMP, associated with tissue inhibitor of metalloprotease-2 (TIMP-2) and integrin (alpha(v)beta(3)) or CD(44), is mainly involved in such invasive program. It catalyzes matrix degradation but, alternatively, proteolytic exposure of matricryptic sites or matrikines liberation by those enzymes regulates either positively or negatively tumor cell migration. That applies to types I and IV collagens, elastin, laminin 5, as described here, but such phenomenon might be extended to other matrix macromolecules. The development of tumors from epithelium origin is related to aging. Senescent fibroblasts are characterized by increased expression of MMPs, (particularly collagenase-1 (MMP-1) and stromelysin-1 (MMP-3)) and deposited matrix by those aged cells was shown to favor cancer cell growth. Thus, compositional variation of matrix-surrounding tumor cells, with formation of matricryptic sites and matrikines, can be considered as one main epigenetic factor contributing to tumor progression. A matrix-directed pharmacological approach in cancer is now emerging.
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PMID:Proteolyzed matrix as a template for the regulation of tumor progression. 1288 58

MMP-9 (gelatinase B) is produced in a latent form (pro-MMP-9) that requires activation to achieve catalytic activity. Previously, we showed that MMP-2 (gelatinase A) is an activator of pro-MMP-9 in solution. However, in cultured cells pro-MMP-9 remains in a latent form even in the presence of MMP-2. Since pro-MMP-2 is activated on the cell surface by MT1-MMP in a process that requires TIMP-2, we investigated the role of the MT1-MMP/MMP-2 axis and TIMPs in mediating pro-MMP-9 activation. Full pro-MMP-9 activation was accomplished via a cascade of zymogen activation initiated by MT1-MMP and mediated by MMP-2 in a process that is tightly regulated by TIMPs. We show that TIMP-2 by regulating pro-MMP-2 activation can also act as a positive regulator of pro-MMP-9 activation. Also, activation of pro-MMP-9 by MMP-2 or MMP-3 was more efficient in the presence of purified plasma membrane fractions than activation in a soluble phase or in live cells, suggesting that concentration of pro-MMP-9 in the pericellular space may favor activation and catalytic competence.
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PMID:Pro-MMP-9 activation by the MT1-MMP/MMP-2 axis and MMP-3: role of TIMP-2 and plasma membranes. 1290 81

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

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

Tissue inhibitors of metalloproteinases (TIMPs) are the endogenous modulators of the zinc-dependent mammalian matrix metalloproteinases (MMPs) and their close associates, proteinases of the ADAM (a disintegrin and metalloproteinase) and ADAM with thrombospondin repeats families. There are four variants of TIMPs, and each has its defined set of metalloproteinase (MP) targets. TIMP-1, in particular, is inactive against several of the membrane-type MMPs (MT-MMPs), MMP-19, and the ADAM proteinase TACE (tumor necrosis factor-alpha-converting enzyme, ADAM-17). The molecular basis for such inactivity is unknown. Previously, we showed that TIMP-1 could be transformed into an active inhibitor against MT1-MMP by the replacement of threonine 98 residue with leucine (T98L). Here, we reveal that the T98L mutation has in fact transformed TIMP-1 into a versatile inhibitor against an array of MPs otherwise insensitive to wild-type TIMP-1; examples include TACE, MMP-19, and MT5-MMP. Using T98L as the scaffold, we created a TIMP-1 variant that is fully active against TACE. The binding affinity of the mutant (V4S/TIMP-3-AB-loop/V69L/T98L) (K (app)(i) 0.14 nm) surpassed that of TIMP-3 (K (app)(i) 0.22 nm), the only natural TIMP inhibitor of the enzyme. The requirement for leucine is absolute for the transformation in inhibitory pattern. On the other hand, the mutation has minimal impact on the MPs already well inhibited by wild-type TIMP-1, such as gelatinase-A and stromelysin-1. Not only have we unlocked the molecular basis for the inactivity of TIMP-1 against several of the MPs, but also our findings fundamentally modify the current beliefs on the molecular mechanism of TIMP-MP recognition and selectivity.
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PMID:Threonine 98, the pivotal residue of tissue inhibitor of metalloproteinases (TIMP)-1 in metalloproteinase recognition. 1473 67

Considerable evidence has implicated matrix metalloproteinases (MMPs), a group of zinc-dependent endopeptidases, in the degradation of extracellular matrix (ECM) during the metastatic process. Most MMPs are secreted as inactive zymogens and are activated extracellularly. Over expression of MMP-1, -2, -3. -7, -9, -13, and MT1-MMP has been demonstrated in human colorectal cancers. The degree of over expression of some MMPs has been noted to correlate with stage of disease and/or prognosis. An unresolved debate has centered on whether MMPs are produced by the stromal cells surrounding a tumor or by the colorectal cancer cells themselves. MMP-7 is produced abundantly by colorectal cancer cells. The presence of a mutation in the APC gene results in nuclear accumulation of the beta-Catenin/TCF complex, which serves as a transcriptional factor that upregulates MMP-7 expression. Increased expression of MMP-3 in colorectal cancer correlates with low levels of microsatelite instability and poor prognosis. Increased levels of MMP-9 (produced primarily by inflammatory cells) have been demonstrated early in the transition from colon adenoma to adenocarcinoma. In contrast to other MMPs, overexpression of MMP-12 is associated with increased survival in colorectal cancer, presumably as a result of an inhibitory effect on angiogenesis. Based on the assumption that MMPs were responsible for metastasis, several orally active, low molecular weight inhibitors of MMPs (MMPIs) have been developed. These MMPIs have been effective in controlling cancer progression in animals, but have failed to prolong survival in phase III clinical trials in patients with advanced cancer. MMPIs have not yet been evaluated in patients with colorectal cancer.
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PMID:Role of matrix metalloproteinases (MMPs) in colorectal cancer. 1500 Jan 52

The maternal aorta undergoes substantial functional and structural adaptation in pregnancy. Both aortic diameter and compliance are increased and studies of animal and human gestation indicate that these changes are initiated in early pregnancy and maintained until delivery. The mechanisms underlying aortic adaptation in normal pregnancy remain largely unknown but matrix metalloproteinase enzymes (MMP) are likely to play a key role. Gene expression of candidate MMP and specific tissue inhibitors of MMP (TIMP) were investigated in non-pregnant, pregnant (days 7, 14, 21) and postpartum (day 7) rat aorta using real-time PCR. Of the gene transcripts studied (MMP-2, -3, -7, -9, -12, -13, MT1MMP, TIMP-1, -2) in rat aorta, only MMP-3 was significantly elevated with a 24-fold increase observed in late gestation compared to virgin control (P = 0.0001). MMP-2 mRNA appeared constitutively expressed and unchanged at time-points studied, but MMP-2 activity as assessed by gelatin zymography suggested further modulation after transcription and/or post-translation in rat aorta with activity increased in early pregnancy (P < 0.01, compared to virgin control). These data suggest that MMP-2 and MMP-3 may contribute to adaptive processes in the maternal rat aorta at different gestations and further support a role for this family of enzymes in physiological vascular remodelling.
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PMID:Aortic adaptation to pregnancy: elevated expression of matrix metalloproteinases-2 and -3 in rat gestation. 1504


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