Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.24.17 (MMP-3)
 3,419 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The activation of procollagenase and prostromelysin by mechanisms that might be functional in vivo has been investigated. Studies with cell monolayers plated onto collagen films have indicated key roles for plasmin and TIMP in these processes. Prostromelysin activation could be rapidly effected by fibroblast monolayers in the presence of plasminogen, with identical kinetics to plasminogen-streptokinase generated plasmin. Procollagenase activation by plasmin was shown to be poor, although an M(r) shift of 11,000 occurred. Activation was enhanced ten-fold by the presence of active stromelysin even at a very low molar ratio. A tumour cell line secreting procollagenase but not stromelysin was found to be dependent upon the addition of both stromelysin and plasminogen to effect degradation of collagen films. Biochemical studies of metalloproteinase activation were carried out using other purified proteinases synthesized by connective tissue cells including endopeptidase 24.11, endopeptidase-2, cathepsin B and cathepsin L. None was a particularly effective activator relative to plasmin, but cathepsin B was shown to activate stromelysin. By use of both cell model systems and biochemical studies of purified enzymes we have found that the role of plasmin as the major metalloproteinase activator in normal connective tissue cells remains unchallenged.
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PMID:Physiological mechanisms for metalloproteinase activation. 148 31

We have reported that down-modulation of tissue inhibitor of metalloproteinases (TIMP) by means of antisense RNA converts non-tumorigenic Swiss 3T3 cells into malignant cells capable of forming metastasizing tumors in nude mice [Science 243:947 (1989)]. We now describe changes in the expression of specific genes associated with tumor progression of two lines down-modulated with TIMP, LA1 and LA7. Six independent variant cell lines, generated from different primary tumors produced by LA1 and LA7, lacked (like LA1 and LA7) many characteristics of typical transformed cells. However, their tumorigenicity in nude mice was enhanced; tumors appeared with a shorter lag (1-3 weeks versus 8-10 weeks for the parental clones, LA1 and LA7) and grew very rapidly. Increases, substantial in some cases, in the expression of a cysteine proteinase, cathepsin L, and metalloproteinases homologous to rat transin (stromelysin) and transin-2 were characteristic of these variant clones. The mRNA levels encoding the transformation-associated secreted phosphoprotein (osteopontin) and the calcium-binding protein calcyclin were also augmented. No evidence for gene amplification was found, and we did not detect any change in the mRNA levels of the proto-oncogenes that were examined. These novel cell lines represent a new paradigm for the transformed cell. Our data suggest that a reduction in TIMP secretion enhances the cell's oncogenic capacity by altering the extracellular environment in a way conducive to further changes in gene expression necessary for tumor progression.
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PMID:Increased proteinase expression during tumor progression of cell lines down-modulated for TIMP levels: a new transformation paradigm? [corrected]. 206 53

Cysteine proteinases, particularly cathepsins B and L, have been strongly implicated in fostering metastasis in mice. In this work four different inhibitors of cysteine proteinases have been shown to inhibit the invasion of the human amnion by murine melanoma and mammary carcinoma cells in vitro. Two of the inhibitors are synthetic peptides [ZPhePheCHN2 (benzyloxycarbonyl-L-phenylalanyl-L-phenylalanyldiazomethane) and ZPheAlaCH2F [3-(N-benzyloxycarbonylphenylalanylamido)-DL-1-fluoro-2-butanone]] and two are thiol protease inhibitors (TPIn, TPId) isolated from the skeletal muscle of the hind limbs of normal and dystrophic mice, respectively. The inhibitors (ZPhePheCHN2, TPId), with apparent selectivity for cathepsin L, blocked invasion as effectively as inhibitors (ZPheAlaCH2F, TPIn) effective on both cathepsins. The data reveal that in these cell lines the cysteine proteinases contribute significantly to the invasive capacity of the cells, but to a lesser extent than do the metalloproteinases. We suggest that the cysteine proteinases facilitate the action of metalloproteinases (collagenase, gelatinase, and stromelysin), possibly by activating them, by inactivating the tissue inhibitor of metalloproteinases, and/or by making basement membrane matrix more accessible.
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PMID:Suppression by cathepsin L inhibitors of the invasion of amnion membranes by murine cancer cells. 273 Nov 77

Neoplastic transformation mediated by ras oncogenes is associated with deregulated expression of genes encoding, for example, various proteases, lysyl oxidase, and smooth-muscle alpha-actin. To define the role of these genes in the initiation or maintenance of the ras-transformed state, we compared their steady-state mRNA levels in two different sets of preneoplastic fibroblast lines, ras-transformed clones, and phenotypic revertants derived from them. Compared with the preneoplastic fibroblasts, the ras-transformed derivatives exhibited elevated levels of cathepsin L (major excreted protein), transin (stromelysin I, matrix metalloproteinase-3), and collagenase I (matrix metalloproteinase-1) mRNA but undetectable levels of lysyl oxidase mRNA. Partial restoration of lysyl oxidase transcription was observed in four of five phenotypic revertants derived from rat FE-8 and NIHpEJcl3 cells. The elevated levels of transin mRNA found in NIHpEJcl3 cells were diminished to the pretransformation level in interferon revertants but were not reduced in phenotypic rat FE-8 revertants expressing a high level of the ras oncoprotein. High steady-state levels of collagenase I mRNA were dependent on ras expression but were not closely associated with the transformed phenotype. High levels of cathepsin L mRNA were associated with neither high ras expression nor neoplastic transformation. The downregulation of smooth-muscle alpha-actin, characteristic of transformed cell lines, was not reversible in phenotypic revertants.
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PMID:Partial restoration of pre-transformation levels of lysyl oxidase and transin mRNAs in phenotypic ras revertants. 772 41

The mechanism or mechanisms by which ras oncogenes induce morphological transformation and anchorage-independent growth are poorly understood but are thought to involve stable alterations in gene expression. We previously described a genetically dominant, mutant rat fibroblast cell line (ER-1-2) that is resistant to ras-induced anchorage-independent growth. We now describe a cell line derived from ER-1-2 cells, termed ER-1-2T, that has apparently sustained a second, dominant mutation that conferred on these cells the ability to form colonies in soft agar. Analysis of these and control cell lines demonstrated that deregulation of many of the genes commonly associated with the transformed phenotype could be dissociated from anchorage-independent growth. After infection with a ras-expressing retrovirus, both control and ER-1-2 cell lines constitutively expressed elevated levels of the c-jun, junB, fosB, c-myc, collagenase, ornithine decarboxylase, osteopontin, stromelysin, cathepsin L, and insulin-like growth factor 1 genes. These data indicate that signaling events downstream of ras were largely intact in ER-1-2 cells and that the defect in these cells lies either on a pathway separate from those that control stable, ras-mediated expression of these genes or at a point in the cell-division cycle distinct from those that control expression of the genes. In contrast, only c-jun, junB, c-myc, and ornithine decarboxylase were expressed at a significantly elevated level in ER-1-2T cells. Thus, deregulated expression of the genes analyzed was not sufficient for anchorage-independent growth. Furthermore, deregulation of most of them was also not necessary.
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PMID:Dissociation of ras oncogene-induced gene expression and anchorage-independent growth in a series of somatic cell mutants. 868 49

To determine whether tumor-derived CCL5 contributes to the metastatic potential of murine mammary carcinoma, we used the 4T1 tumor which spontaneously metastasizes and constitutively produces CCL5. Mice bearing 4T1 that expressed less CCL5 had significantly fewer lung and liver metastasis. The decrease in tumor-derived CCL5 also correlated with decreased cathepsin L, MMP-2, MMP-3, MMP-10 and MMP-17 gene expression. Thus, inhibition of tumor-derived CCL5 can impact the metastatic capability of 4T1 and may do so by modulating protease expression.
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PMID:Inhibition of metastasis by inhibition of tumor-derived CCL5. 1569 64

To determine the involvement of cathepsins G and L in the mechanism of spontaneous resorption of herniated intervertebral discs, localization of these cathepsins in this process was examined immunohistochemically using a rat model of autologous transplantation of coccygeal discs. Rat coccygeal discs were resected and autotransplanted into the subcutaneous space of the skin of the back. Paraffin-embedded sections of intervertebral disc tissue, harvested at various post-transplantational periods, were immunohistochemically stained with antibodies for cathepsin G, cathepsin L, MMP-1, MMP-3 and ED-2. The number of positive cells was counted in each part of the transplanted discs. Immunolocalization of cathepsins G and L in various types of disc cells was first observed early in the post-transplantation period. From two days after the operation, histology showed invasion by granulation tissue, with many macrophages, in all sections. Subsequently, the number of macrophages in granulation tissue was observed to increase, along with a gradual increase in the percentage of cells positive for MMP-1 and MMP-3. In addition to the ability of cathepsins G and L to degrade major extracellular matrix components of intervertebral discs, cathepsin G is capable of activating latent pro-MMPs. The up-regulation of cathepsins G and L in the intervertebral disc tissue in this spontaneous resorption model suggests that these proteinases may be involved in degradation of extracellular matrix, leading to the natural resorption of herniated discs.
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PMID:Localization of cathepsins G and L in spontaneous resorption of intervertebral discs in a rat experimental model. 1575 67

The analysis of migration and gene expression patterns of normal and Ha-ras transformed rat liver epithelial cells revealed differences of diagnostic relevance. The normal cells are induced to migrate by EGF/TGF alpha and to express a set of secreted proteins including fibronectin, EIP-1/PAI-1, and MEP cathepsin L, which the malignant, constitutively migratory cells express constitutively. Only the transformed cells produce proteins of Mr 58/60,000 identified by peptide sequencing as stromelysin-1. The constitutively migratory cells produce invasive tumors and, after intravenous injection, metastatic colonies in the lung ('experimental metastasis'). The results demonstrate specific differences between the migration/invasion of normal and malignant epithelial cells, with PAI-1 as a general biochemical marker for migration/invasion. Constitutive migration and the described gene expression pattern are proposed as in vitro indicators of an invasive phenotype. EGF inducibility of the transformed cells to maximal migration and to an increased expression of stromelysin indicates susceptibility to a paracrine stimulation of malignancy.
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PMID:Constitutive migration and expression of three protease systems define in vitro the malignant phenotype of Ha-ras transformed rat liver epithelial cells. 2154 65