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)

Tissue inhibitor of metalloproteinases-3(TIMP-3), a novel member of TIMP family genes, has been recently cloned and shown to be expressed in preneoplastic but not in neoplastic mouse JB6 epidermal cells (Sun et al. 1994 Cancer Res., 54, 11139). This down regulation of the gene appears to be attributable at least in part to alteration of gene methylation (Sun et al. 1995 J. Biol. Chem., 270, 19312). Little is known, however, about the role of TIMP-3 in human cancers. We screened several human tumor cell lines for TIMP-3 expression and found that a colon carcinoma line, DLD-1, did not express TIMP-3. If down regulation of TIMP-3 is causally related to carcinogenesis, re-expression by transfection may reverse the tumor cell phenotype. We therefore overexpressed human TIMP-3 in DLD-1 cells. TIMP-3 transfectants showed a serum-dependent growth inhibition in monolayer culture and a decreased growth potential in nude mice in a manner dependent on the level of TIMP-3 expression. A transfectant expressing a high level of active hTIMP-3 completely lost the ability to form tumors following s.c. injection into nude mice. We also tested TIMP-3 expressing cells and neocontrol TIMP-3 negative cells for their ability to grow in liquid suspension culture, since both cells grew in semi-solid soft agar. As compared to neocontrol cells, TIMP-3 overexpressors formed large aggregates, followed by cell death. This effect was not mimicked by BB94, a broad MMP inhibitor. We conclude from this study that (i) TIMP-3 overexpression in human colon carcinoma cells induces growth arrest in low serum conditions and inhibits in vivo tumor growth and (ii) the TIMP-3-induced large aggregate formation and subsequent cell death under suspension growth cannot be explained by its MMP inhibitory activity.
Carcinogenesis 1996 Sep
PMID:Suppression of in vivo tumor growth and induction of suspension cell death by tissue inhibitor of metalloproteinases (TIMP)-3. 882 99

Matrilysin (PUMP-1) is a member of the matrix metalloproteinase (MMP) family of extracellular matrix degrading enzymes that has been found to be overexpressed in human prostate cancer. The rat ventral prostate (RVP) following castration has been used as a model for both tissue involution and apoptosis. Northern analysis and in situ hybridization were used to determine the time course and localization of matrilysin during 8 days of RVP involution. Northern analysis revealed that the 1.2 kb matrilysin mRNA was undetectable in normal RVP. An increase in the steady-state levels of matrilysin mRNA was observed 5 days after castration, and the levels began to decline by 8 days after castration. The mRNAs for tissue inhibitor of metalloproteinase-1 and urokinase-type plasminogen activator also showed a time-dependent induction during the course of involution. Localization of matrilysin by in situ hybridization indicated that the mRNA was produced by epithelial cells of the involuting RVP. The matrilysin message was observed in a small number of glands within the whole RVP. Matrilysin protein was present in the RVP and peaked 3 days after castration. The combination of proteinase genes expressed in the RVP following castration indicate that the MMP and serine protease families of enzymes may interact during tissue remodeling of the RVP following castration.
Prostate 1996 Sep
PMID:Matrilysin expression in the involuting rat ventral prostate. 882 84

Fibulin-1 and fibulin-2 are two novel rod-like proteins which occur either in basement membranes or in interstitial fibrils in close association with fibronectin. They were examined for their sensitivity to proteolysis by matrix metalloproteinases (stromelysin, matrilysin), circulating proteases (thrombin, plasmin, kallikrein), leucocyte elastase and mast cell chymase. Fibulin-1 (95 kDa) was readily cleaved by leucocyte elastase, weakly by matrilysin and not by the other proteases. Cleavage occurred in a domain-connecting link region close to the N-terminus, giving rise to fragments of 70 kDa and 26 kDa. A much more extensive cleavage by all seven proteases was observed for fibulin-2 (195 kDa), giving rise to many fragments in the range 15-150 kDa. Vulnerable sites included two central link regions, the cysteine-free part of the large N-terminal globular domain but also several regions of epidermal-growth-factor(EGF)-like repeats which are a major part of the rod-like domain. The latter domain became much more sensitive to proteolysis in the presence of EDTA, demonstrating that calcium is required for stabilization. Edman degradation demonstrated cleavage of peptide bonds corresponding to the known specificities of these proteases. A similar proteolysis was also observed for fibulin-2 deposited by cultured fibroblasts into a dense fibrillar network. Since fibulin-2 is an abundant component of small and large blood vessels it could be a major target for proteolysis during vascular injuries.
Eur J Biochem 1996 Sep 01
PMID:Different susceptibilities of fibulin-1 and fibulin-2 to cleavage by matrix metalloproteinases and other tissue proteases. 884 8

The objective of the present analyses was to determine whether matrix metalloproteinases interact with alpha 2HS glycoprotein, the human homologue of bovine fetuin. Alpha 2HS glycoprotein was incubated with metalloproteinases at 1:1 and 1:10 molar ratios. The serum glycoprotein was completely degraded by gelatinase-A and matrilysin at the higher enzyme concentration after an overnight incubation at 37 degrees C. The data show that gelatinase-A, matrilysin and gelatinase-B do interact with alpha 2HS glycoprotein and that gelatinase-B associates most tightly with the serum glycoprotein.
Biochem Mol Biol Int 1996 Sep
PMID:The interactions of alpha 2HS glycoprotein with metalloproteinases. 888 65

The studies described here examine the involvement of the fibrinolytic cascade and its endogenous inhibitors in the regulation of activity of matrix metalloproteinases and cartilage degradation related to non-inflammatory joint disease, like osteoarthritis. An interleukin-1-induced model of degradation using [35S]-labeled bovine and human articular cartilage explants was utilized. One goal of these studies was to compare the responses of bovine and human articular cartilage. Degradation was not inhibited by alpha 1-PI, PAI-1, alpha 2-macroglobulin, alpha 2-antiplasmin or TIMP-2, when IL-1 alone was added. Addition of human plasminogen to bovine explants, at concentrations found in human synovial fluid, increased degradation by three to four-fold. Under these conditions, the degradation was inhibited effectively by all of the endogenous inhibitors tested, indicating the presence of a cascade where activated chondrocytes are a source of u-PA. Plasminogen activated by u-PA gives plasmin, which is known to further activate pro-stromelysin. Stromelysin is essential for activation of collegenase. Not only TIMP, but also inhibitors at earlier steps of activation like PAI-1, alpha 2-antiplasmin, alpha 1-PI and alpha 2-macroglobulin inhibited degradation, and could provide cartilage protection in vivo. An experiment with human articular cartilage explants showed that very little or no degradation occurred when human articular cartilage explants were stimulated with interleukin-1 alone. Addition of human plasminogen (at physiologically relevant concentrations) resulted in significant degradation, which was inhibited in the same manner as in bovine explants, by inhibitors of the fibrinolytic cascade and TIMP. TIMP is much more efficient in human explants, indicating the limited participation of human plasmin in the degradation of human cartilage. Although speculative, it is possible that in vivo, cartilage degradation could be promoted not only by TIMP/MMP imbalance, but also accelerated by decreased levels of certain serpins in synovial fluid (e.g. PAIs, alpha 2-antiplasmin and alpha 1-PI).
Inflamm Res 1996 Sep
PMID:Plasminogen modulation of IL-1-stimulated degradation in bovine and human articular cartilage explants. The role of the endogenous inhibitors: PAI-1, alpha 2-antiplasmin, alpha 1-PI, alpha 2-macroglobulin and TIMP. 889 58

Hepatocyte growth factor (HGF) is known to have a number of biological properties including promoting tumor progression of human carcinomas. Metastasis involves a number of events that are attributed to induction by paracrine factors such as HGF. Identification of natural inhibitors of these events would allow better control of tumor progression. Recently we demonstrated that interleukin 4 (IL-4) can regulate proliferation of various human carcinoma cell lines. In the present study, we used established human colon carcinoma cell lines and primary colon carcinoma cell cultures to determine if IL-4 could regulate HGF-induced cell proliferation and other events of tumor progression such as MMP (matrix metalloproteinases)-1, -2, and -9 production, cell migration and cell-matrix invasive activity. All colon carcinoma cell lines expressed HGF and IL-4 receptors. IL-4 significantly inhibited HGF-induced proliferation of one cell line. Cell-matrix invasion was significantly enhanced by HGF (0.1-10 ng/ml); IL-4 (1-10 U/ml) significantly inhibited HGF-induced invasion in a dose-dependent manner. IL-4 also inhibited HGF-induced cell-matrix invasion of metastatic colon carcinoma cells and HGF-induced cell migration. HGF enhanced MMP-1, -2, and -9 production by cell lines. This effect could be inhibited by IL-4. These findings indicate that IL-4 is a potent inhibitor of HGF-induced invasion and metastasis-related functions of human colon carcinoma cells.
J Cell Biochem 1996 Sep 15
PMID:Interleukin 4 inhibits hepatocyte growth factor-induced invasion and migration of colon carcinomas. 889 90

The Paneth cell lineage is one of four epithelial lineages derived from the adult mouse small intestine's multipotent stem cell. Mature Paneth cells secrete antimicrobial peptides (cryptdins), growth factors, as well as two gene products, a secreted phospholipase A2 and matrilysin, that has been implicated as modifiers of adenoma formation in mice containing a mutation in the tumor suppressor Apc. Immature Paneth cells are located just above and below the cell layer, in intestinal crypts, that has been proposed to contain the multipotent stem cell. Paneth cells differentiate during a downward migration to the crypt base. The location and direction of Paneth cell migration, their high density and long residency time at the crypt base, and the nature of their secreted gene products, suggest that they may influence the structure and/or function of the stem cell niche. Paneth cell ablation can therefore be viewed as an experimental manipulation of the cellular microenvironment that purportedly contains the stem cell and its immediate descendants. Two types of ablation experiments were performed in transgenic mice. Nucleotides -6500 to +34 of the mouse cryptdin-2 gene (CR2) were used to express an attenuated diphtheria toxin A fragment. Light and electron microscopic immunohistochemical analyses of several pedigrees of postnatal day 28 to 180 animals established that ablation of Paneth cells is accompanied by an increase in the proportion of undifferentiated crypt base columnar cells. These cells normally co-exist with Paneth cells. The ablation does not produce a detectable effect on the proliferation or terminal differentiation programs of the other three lineages or on host-microbial interactions. The last conclusion is based on the ability of crypts to remain free of microbes detectable by Gram and Warthin-Starry stains and by retention of the normal crypt-villus distribution of components of the diffuse gut-associated lymphoid tissue. CR2-directed expression of simian virus 40 large T antigen also results in a loss of mature Paneth cells but produces a marked amplification of crypt cells having a morphology intermediate between Paneth and granule goblet cells. EM immunohistochemical analyses suggest that intermediate cells can differentiate to mature goblet cells but not to Paneth cells, as they migrate up the crypt-villus axis. Our findings suggest that (i) stemness in the crypt is not defined by instructive interactions involving the Paneth cell; (ii) expressing a Paneth cell fate may require that precursors migrate to the crypt base; (iii) antimicrobial factors produced by Paneth cells are not required to prevent colonization of small intestinal crypts; and (iv) this lineage does not function to maintain the asymmetric crypt-villus distribution of components of the diffuse gut-associated lymphoid tissue.
J Biol Chem 1997 Sep 19
PMID:Examining the role of Paneth cells in the small intestine by lineage ablation in transgenic mice. 929 17

CDK inhibitor, Butyrolactone I inhibited CDK1, 2 and 5 in CDKs. In syncronized human lung fibroblast WI38 cells, it inhibited G1/S transition by inhibiting the phosphorylation of RB protein and G2/M transition by inhibiting the phosphorylation of H1 histone. Also, it selectively inhibited the initiation of DNA replication. The MMP inhibitor, BE16627B, reversively inhibited metalloproteinases including MMPs. It showed the MMP-dependent inhibition of the growth and metastasis of human tumor cells in nude mice without any cytotoxicity and severe side effects. The MMP inhibitor, Marimastat, showed remarkable prolongation of the life span of patients with pancreatic tumors in clinical trials.
Gan To Kagaku Ryoho 1997 Sep
PMID:[CDK and MMP inhibitors]. 930 54

Intermittent doses of parathyroid hormone (PTH) stimulate bone formation in animals and humans, but the molecular mechanisms underlying this phenomenon are not understood. Bone formation culminates with the expression of type I collagen, osteocalcin, and alkaline phosphatase, but genes that initiate and support the anabolic response are not known. To identify novel PTH-regulated genes in bone during the anabolic response, we used differential display-polymerase chain reaction (DDRT-PCR) to analyze RNA from young male rats injected with either human PTH (1-34) or vehicle control, once daily for 5 days. Total RNA was isolated from the distal femur metaphysis at 1, 6, and 48 h after the final injection and subjected to DDRT-PCR. We identified three PTH-responsive transcripts as matrix metalloproteinase-9 (MMP-9), creatine kinase, and the alpha1 (I) polypeptide chain (COL1A1) of type I collagen. The concomitant upregulation of MMP-9 and COL1A1 during bone formation was particularly intriguing. Further characterization of MMP-9 expression revealed that it was localized to osteoblasts, osteocytes, megakaryocytes, and cells of the bone marrow in the rat distal femur metaphysis. Northern analysis for MMP-9 expression in other tissues indicated that this transcript was present in the kidney and brain. In vitro, PTH regulated the protein synthesis of MMP-9 by osteoblasts of the primary spongiosa. We propose that PTH may promote bone formation by mediating the subtle variation in MMP activities, thus preparing the extracellular matrix for the subsequent bone cell migration and deposition of new osteoid.
J Cell Biochem 1998 Sep 01
PMID:Intermittent administration of parathyroid hormone (1-34) stimulates matrix metalloproteinase-9 (MMP-9) expression in rat long bone. 970 76

The aim of this study was to examine the relationship between force and rate of force development with electroencephalogram correlates. The primary question was whether the different components of movement related potentials (MRPs) were related to specific properties of force output while subjects performed index finger force production tasks. The peak force and rate of force development (e.g., a product of peak force over time-to-peak force) were manipulated, and the effects of these manipulations on components of MRPs preceding and accompanying force production tasks were examined. The hypothesis was that the rate of force development, rather than level of force itself, would directly influence the later component of MRPs. Consistent with this hypothesis was the finding that the amplitudes of MRP components preceding (MP) and accompanying (MMP, MTP) finger force production movements were significantly correlated with force development rate.
Psychophysiology 1998 Sep
PMID:Movement-related potentials accompanying unilateral finger movements with special reference to rate of force development. 971 98


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