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)

Human prostate cancer displays a high degree of variability in its rate of spread, which could be due largely to differences in the invasive potential of the tumor cells. The degradation of the basal lamina and stromal extracellular matrix is mediated in part by the secretion of matrix metalloproteinases (MMPs). Matrilysin (PUMP-1, MMP-7) and gelatinase A (M(r) 72,000 type IV collagenase, MMP-2) have been shown to be overexpressed in prostate carcinoma. We have expressed the single MMP matrilysin in the tumorigenic but nonmetastatic human prostate tumor cell line DU-145 to determine if matrilysin has a functional role in prostate tumor cell invasion. DU-145 cells expressing matrilysin were significantly more invasive than vector-only transfected cell lines as assayed by a severe combined immunodeficient mouse model of tumor cell invasion. Vector-only transfected DU-145 cells injected i.p. into severe combined immunodeficient mice invaded the diaphragm in only 1 of 9 mice (11%), whereas matrilysin-transfected DU-145 cells invaded the diaphragm in 12 of 18 mice (66%). The difference between the controls and matrilysin-transfected cells was statistically significant (P < 0.006). These results suggest a functional role for matrilysin in the initial invasion of prostate cancer through the epithelial basal lamina and into the surrounding stroma.
 ...
PMID:Expression of the metalloproteinase matrilysin in DU-145 cells increases their invasive potential in severe combined immunodeficient mice. 841 33

Membrane-type matrix metalloproteinase (MT-MMP) messenger RNA and protein expression were shown to be elevated in human fibroblasts following treatment with concanavalin A, coincident with the induction of the ability to process progelatinase A. CHO cells transfected with the cDNA for MT-MMP were able to process both wild type progelatinase A and a catalytically inactive mutant, E375A progelatinase A. Both proenzymes were converted to a 68-kDa intermediate (reducing gels) form, but only the wild type enzyme was processed further to a 66-kDa end product. In contrast, both forms of progelatinase were processed via the 68-kDa intermediate to 66 kDa by concanavalin A-stimulated fibroblasts. Further study of the processing of E375A progelatinase A by plasma membrane preparations from concanavalin A-stimulated fibroblasts showed that addition of active gelatinase A enhanced processing to the mature form. It was concluded that cell membrane-mediated activation of progelatinase A could be via a cascade involving both MT-MMP and intermolecular autolytic cleavage.
 ...
PMID:Intermolecular autolytic cleavage can contribute to the activation of progelatinase A by cell membranes. 853 Apr 78

Membrane-type matrix metalloprotease (MT-MMP) is an activator of gelatinase A (MMP-2), which has previously been found in carcinoma cells. We examined non-neurological and Alzheimer's disease brain tissues for MT-MMP by immunohistochemistry and in situ hybridization. The anti-MT-MMP antibodies gave positive staining of brain microglial cells in all the brain tissues. Positively stained microglia were found only in the white matter. The cells producing MT-MMP protein were also shown to be white matter microglia. These results provide further evidence that activated gelatinase A, which may be a processing enzyme for degradation of beta-amyloid protein, may be produced in white matter microglia.
 ...
PMID:White matter microglia produce membrane-type matrix metalloprotease, an activator of gelatinase A, in human brain tissues. 856 Sep 72

The metalloproteinases, a multigene family of metal-requiring enzymes, have been suggested to play a role in tumor invasion and metastasis. Previously, we demonstrated that human primary prostate tumors express higher levels of matrilysin and gelatinase A mRNA than normal prostate does. In the study presented here, we used in situ hybridization and immunohistochemical staining of serial sections of paraffin-embedded primary prostate tumors to compare the sites of matrilysin and gelatinase A expression and protein localization. These results confirmed the epithelial nature of matrilysin expression and protein localization. In contrast, gelatinase A mRNA was localized to the interstitial stroma, whereas the protein was associated with the epithelial tumor cells. In situ hybridization was also used to demonstrate that gelatinase B expression was restricted to macrophages infiltrating the tumors. Proteins isolated from an additional set of frozen tumor specimens were analyzed by western blotting to determine the relative amounts of matrilysin in the active and proenzyme forms. The western analyses demonstrated that in all cases in which matrilysin was detected, at least some of the enzyme was in the active form. These results are discussed with respect to the possible role these enzymes may play in prostate tumor progression.
 ...
PMID:Matrilysin expression in human prostate carcinoma. 856 67

We examined the anti-invasive activity of ursolic acid (UA) on the highly metastatic HT1080 human fibrosarcoma cell line. UA reduced tumor cell invasion through a reconstituted basement membrane in a transwell chamber. A significant down-regulation of matrix metalloproteinase-9 [MMP-9; Mr 92,000 gelatinase/type IV collagenase (gelatinase B)] by UA was detected by Northern blot analysis. However, MMP-2 [Mr 72,000 gelatinase/type IV collagenase (gelatinase A)] and membrane-type MMP were constantly expressed, and the expression of tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2 also was not changed after 3 and 6 days of treatment with UA. Quantitative gelatin-based zymography confirmed a markedly reduced expression of MMP-9 but not MMP-2 after treatment with UA. To confirm the UA-induced down-regulation of MMP-9 expression, we constructed a secreted alkaline phosphatase (SEAP) reporter vector including MMP-9 promoter. After transfection of MMP-9/SEAP reporter vector into HT1080 cells, reduced SEAP activity was detected after treatment with UA. These results suggest that down-regulation of MMP-9 contributes to the anti-invasive activity of UA in HT1080 cells.
 ...
PMID:Anti-invasive activity of ursolic acid correlates with the reduced expression of matrix metalloproteinase-9 (MMP-9) in HT1080 human fibrosarcoma cells. 862 99

Thirteen primary pulmonary squamous cell carcinomas, 4 specimens of normal lung from around tumours, 4 benign proliferations of the mammary gland and 16 breast carcinomas were analysed by in situ hybridisation. Northern blot and immunohistochemistry for the expression of a recently described metalloproteinase (MMP), the MT-MMP (membrane-type matrix metalloproteinase). This MT-MMP can activate gelatinase A, involved in the degradation of basement membranes. In situ hybridisation revealed MT-MMP transcripts distributed in both tumour and stromal cells in squamous cell lung cancers, whereas these mRNAs were principally detected in stromal cells in close contact to tumour clusters in breast carcinomas and in lung adenocarcinomas. Northern blot analysis showed a parallel expression of MT-MMP and gelatinase A transcripts in both lung and breast cancers. Immunohistochemistry displayed a more extensive distribution of MT-MMP in pulmonary and mammary carcinomas with numerous labelled preinvasive and infiltrating cancer cells and stromal cells near the tumour cells. The large degree of expression of MT-MMP in these cancers indicates a potential role of this enzyme in tumour progression. The finding of MT-MMP transcripts in stromal cells in the vicinity of lung and breast tumour cells emphasises the cooperation between these cells and cancer cells for the expression of MT-MMP and in tumour invasion in vivo.
 ...
PMID:MT-MMP expression and localisation in human lung and breast cancers. 864 66

Gelatinase A is secreted as a proenzyme (progelatinase A) which is activated and bound on the surface of tumor and normal cells. We have reported that the expression of a membrane-type-1-matrix metalloproteinase (MT1-MMP) induces activation of progelatinase A. Here we demonstrate that the expression of MT1-MMP in COS-1 cells induces cell-surface binding of progelatinase A which is consequently processed to an intermediate form. Processing from the intermediate to the fully active form is dependent on the gelatinase A concentration. These results suggest that the cell-surface binding concentrates the gelatinase A intermediate form locally to allow autoproteolytic processing to the fully active form.
 ...
PMID:Cell surface binding and activation of gelatinase A induced by expression of membrane-type-1-matrix metalloproteinase (MT1-MMP). 864 59

Substantial evidence indicates that proteolytic degradation of the extracellular matrix is necessary for invasion and metastasis by cancer cells. Our previous work has demonstrated elevated secretion by cultured ovarian adenocarcinoma cells of two gelatinolytic metalloproteinases, a 72-kDa enzyme resembling matrix metalloproteinase 2 (MMP-2) and a 92-kDa enzyme resembling MMP-9 (Moser et al, Int. J. Cancer 56, 552-559, 1994). To assess the potential in vivo relevance of these enzymes, we have examined ovarian carcinoma ascites using gelatin substrate zymography. MMP species identical to those secreted from several well-characterized ovarian adenocarcinoma cell lines were found in the majority of ascites: MMP-2-like gelatinase (23 of 23 cases) and MMP-9-like gelatinase (18 of 23 cases), suggesting a prevalence of these species in the ovarian carcinoma microenvironment and their availability for tumor-associated proteolysis. The contribution of these proteinases to ovarian cancer invasion was further demonstrated by experiments measuring tumor cell-mediated proteolysis of native endothelial cell extracellular matrix (ECM) and tumor cell invasion of reconstituted basement membrane (Matrigel). These data showed that secretion of type IV collagenase activity by a series of independently isolated ovarian adenocarcinoma cell lines correlated well with the ability of these cells to proteolyze the ECM and invade the basement membrane. Furthermore, we have identified and characterized an ovarian carcinoma-associated gelatinase, the 72-kDa MMP found in conditioned media of the DOV 13 cell line, as MMP-2. This enzyme was identical to the previously described MMP-2 from other sources by Western blot, amino terminal sequence, and substrate specificity. Additionally, a large portion of the MMP-2 activity found in DOV 13 conditioned media is active without organomercurial treatment, suggesting that ovarian cancer cells have an endogenous activator of the zymogen. Together, these data suggest that ECM proteolysis mediated by tumor-associated proteinases plays an important role in the invasion and/or metastasis of ovarian carcinoma.
 ...
PMID:Characterization of gelatinases linked to extracellular matrix invasion in ovarian adenocarcinoma: purification of matrix metalloproteinase 2. 869 Feb 99

Membrane type 1-matrix metalloproteinase (MT1-MMP) initiates the activation of the zymogen progelatinase A/ 72-kDa type IV collagenase by cleavage of the Asn66-Leu peptide bond. We previously pointed out that MT1-MMP possesses a unique amino acid sequence Arg-Arg-Lys-Arg111 which is a potential recognition sequence for furin-like proteases (Nature, 370 (1994) 61-65). Here, using a recombinant MT1-MMP expressed in Escherichia coli we demonstrated that furin specifically cleaves MT1-MMP between Arg111-Tyr in vitro, which resulted in a stimulation of progelatinase A-activation function. Tissue inhibitor of metalloproteinases (TIMP)-2 inhibited activation of progelatinase A by forming a stable complex with activated MT1-MMP.
 ...
PMID:Activation of a recombinant membrane type 1-matrix metalloproteinase (MT1-MMP) by furin and its interaction with tissue inhibitor of metalloproteinases (TIMP)-2. 880 34

Proteolytic and nonproteolytic methods were used to investigate the mechanism(s) by which human fibroblast progelatinase A and fibroblast-type procollagenase can be activated. Both collagenase and matrilysin were able to activate progelatinase A, resulting in an amino terminus in gelatinase A of Tyr81. The cleavage occurred distal to Cys73 within the sequence of PRCGNPDVAN80-Y81NFFPRKP. While several nonproteolytic reagents were tested, only the heavy metal Hg(II) and p-chloromercuribenzoate (PCMB) were able to induce activation of progelatinase A and resulted in the conversion of the latent 72-kDa gelatinase A to an active form of about 64.5 kDa. Matrilysin was also able to activate procollagenase and resulted in an amino terminus in collagenase of Phe81. These results suggest that fibroblast-type collagenase and matrilysin may be physiologically relevant activators of progelatinase A; the maintenance of latency and the process of activation for progelatinase A may occur through the cysteine-switch mechanism, and the proteolytic activation of procollagenase by matrilysin resulted in the same amino terminus as produced by stromelysin-1.
 ...
PMID:Activation of human progelatinase A by collagenase and matrilysin: activation of procollagenase by matrilysin. 880 71


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>