Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.24.3 (collagenase)
18,340 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The present study was undertaken to determine the role of the metalloproteinase MMP-9 in the invasive phenotype of squamous-cell carcinoma of the oral cavity and the regulation of its expression. Zymographic analysis of conditioned medium from 2 highly invasive squamous-cell-carcinoma cell lines indicated large amounts of an enzyme which was indistinguishable, in size (92 kDa) from the MMP-9 pro-enzyme. Conversion of the 92-kDa gelatinase into a lower-molecular-weight species (84 kDa), identical in size to the activated gelatinase, was evident when both cell lines, which are avid secretors of urokinase, were cultured in the presence of plasminogen. Penetration of an extracellular-matrix-coated filter was dramatically reduced in the presence of the collagenase inhibitor, tissue inhibitor of metalloproteinase-2, suggesting a critical role for MMP-9 in the invasive process. Immunohistochemical studies demonstrating the presence of MMP-9 in tumor cells of resected squamous-cell cancers suggested that secretion of this collagenase by cells in vitro was reflective of the in vivo setting. Since several phorbol-ester response elements are present in the MMP-9 promoter, we determined the role of protein-kinase-C pathways in the regulation of MMP-9 expression in cultured SCC. Treatment of cells with PMA resulted in a more-than-20-fold increase in the level of protein and mRNA. Conversely, culturing of cells in the presence of the protein-kinase-C inhibitor, calphostin-C, led to a dose-dependent decrease in the amount of MMP-9 mRNA and protein, suggesting that the constitutive expression of this collagenase reflects activation of this signal transduction pathway. In summary, our data suggest that, for a sub-population of squamous-cell carcinomas, secreted MMP-9 is an important determinant of the invasive phenotype, and that the expression of this metalloproteinase is regulated by protein-kinase-C pathways.
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PMID:Role and regulation of expression of 92-kDa type-IV collagenase (MMP-9) in 2 invasive squamous-cell-carcinoma cell lines of the oral cavity. 768 50

In this study we have investigated whether direct cell to cell contact between activated paraformaldehyde-fixed T cell clones obtained from synovial tissue of patients with osteoarthritis (OA) or rheumatoid arthritis and target monocytic cells or dermal fibroblasts influenced the balance between interstitial collagenase and its specific inhibitor tissue inhibitor of metalloproteinases (TIMP) produced by the latter cell types. PHA/PMA-activated fixed T cell clones or their membranes strongly induced the production of collagenase both in monocytic THP-1 cells and in dermal fibroblasts. In contrast, only low levels of TIMP were induced in THP-1 cells and no change of TIMP expression was observed in fibroblasts as a result of stimulation with PHA/PMA-activated T cells or T cell membranes. Anti-CD3-activated T cell clones stimulated the production of collagenase both in THP-1 cells and fibroblasts, whereas TIMP levels were not influenced. Collagenase production in THP-1 cells induced by anti-CD3-activated T cell clones was 1) dependent on the dose of anti-CD3 used to stimulate the T cells, 2) initiated only when CD3 was cross-linked, and 3) inhibited when cyclosporin A was included during T cell activation. Our data collectively indicate that activated T cells in contact with monocytic cells or fibroblasts may alter the balance between interstitial collagenase and its specific inhibitor TIMP. This selective induction of a mediator profile representative of matrix breakdown as a result of target cell interaction with activated T cells may be an important factor in the local process of tissue destruction that characterizes osteoarthritis and rheumatoid arthritis.
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PMID:Immobilized anti-CD3 antibody activates T cell clones to induce the production of interstitial collagenase, but not tissue inhibitor of metalloproteinases, in monocytic THP-1 cells and dermal fibroblasts. 787 39

In this study we examined the stimulatory effects of PGF2 alpha on progesterone secretion by porcine luteal cells on different days of the estrous cycle, and the effects of PGF2 alpha, A23187 and PMA on progesterone secretion by isolated large and small luteal cells, in vitro. Corpora lutea were obtained from cycling pigs (days 6-16), collagenase dispersed and luteal cells incubated in medium 199 in the absence or presence of increasing doses of PGF2 alpha, A23187, and PMA. Progesterone concentrations in spent media were measured by RIA. PGF2 alpha stimulation of progesterone secretion by mixed luteal cells did not vary significantly throughout the estrous cycle. Progesterone secretion by large, but not small, luteal cells was increased (p < 0.05) in a dose-dependent fashion by PGF2 alpha. A23187 also caused a dose-dependent increase in progesterone secretion by large luteal cells but inhibited small luteal cells. Progesterone secretion by both large and small luteal cells was significantly increased by increasing doses of PMA. We conclude that the stimulatory response of luteal cells to PGF2 alpha in vitro did not correlate with PGF2 alpha receptor concentrations (not measured in this study), and we speculate that calcium/protein kinase C may be involved in mediating the stimulatory action of PGF2 alpha on luteal cell progesterone secretion.
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PMID:Prostaglandin F2 alpha stimulates progesterone secretion by porcine luteal cells in vitro throughout the estrous cycle. 799 75

Activation of protein kinase C (PKC) by the phorbol ester 4 beta-phorbol myristate acetate (4 beta-PMA) stimulated (pro)insulin biosynthesis in collagenase-isolated rat islets of Langerhans, as assessed by measuring the incorporation of [35S]cysteine into proinsulin and insulin after fractionation by high performance liquid chromatography. The stimulatory effects of 4 beta-PMA were observed at a substimulatory concentration of glucose (2 mM) but were not additive to the stimulatory effects of 20 mM glucose on insulin biosynthesis. Prolonged exposure to 4 beta-PMA caused a marked down-regulation of PKC activity in islets. PKC-depleted islets showed a much reduced biosynthetic response to 20 mM glucose, but this was caused, at least in part, by an enhanced basal rate of (pro)insulin synthesis. These elevations in the basal rate of insulin synthesis were not secondary to an increase in the amount of preproinsulin mRNA in PKC-depleted islets since Northern blot analysis showed that prolonged exposure to 4 beta-PMA, and the subsequent loss of PKC activity, did not detectably alter basal levels of preproinsulin mRNA. These results suggest that the activation of PKC stimulates (pro)insulin synthesis in rat islets by enhancing translation of existing preproinsulin mRNA, and that this may play some part in the biosynthetic responses of beta-cells to glucose.
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PMID:The role of protein kinase C in insulin biosynthesis. 821 66

In rabbit fibroblasts the AP-1 sequence (5'-ATGAGTCAC-3') is necessary but not sufficient for induction of collagenase transcription by phorbol esters (PMA) (Auble and Brinckerhoff: Biochemistry 30(18):4629-4635, 1991). In this study we identified additional sequences involved in PMA-induced transcription. Using fibroblasts transiently transfected with chimeric constructs containing fragments of the rabbit collagenase 5'-flanking DNA linked to the chloramphenicol acetyl transferase (CAT) gene, we found that deletion of nucleotides -182 to -141 in a 380 bp promoter construct resulted in about a 7-fold loss of induction by PMA. Mobility shift assays revealed that nuclear proteins from fibroblasts specifically bound to 20-bp at -182 to -161. Binding was competed completely by self and only partially by the AP-1 sequence, implying that proteins binding to the AP-1 sequence could also bind to this region. In vitro transcribed and translated c-Fos and c-Jun bound to both the AP-1 site and to the sequences from -182 to -141. DNAase I footprinting of the collagenase promoter with purified c-Jun or c-Fos/c-Jun protected the AP-1 sequence at -77 to -69 in addition to a region from -189 to -178 which overlaps a putative AP-1-like site, 5'-ATTAATCAT-3'. Finally, deletion of the -182 to -161 region in a 380-bp CAT construct resulted in a substantial reduction of PMA responsiveness. Thus, we have identified a novel phorbol-responsive region that binds c-Fos and c-Jun, and we suggest that these or similar proteins may regulate transcription of the collagenase gene by binding to sequences within and adjacent to the -182 to -161 region.
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PMID:Novel phorbol ester response region in the collagenase promoter binds Fos and Jun. 836 45

Lysophosphatidylcholine (LPC) increases extracellularly during ischemia in vivo in both animals and man as judged by measurements from venous effluents, but more recent studies have shown little or no increase in buffer-perfused, isolated heart preparations. The appearance of LPC in blood and lymph in animals and in venous effluents in man in response to ischemia suggests a vascular site for the production of LPC. The present study was performed to assess whether thrombin could stimulate phospholipase A2 in endothelial cells and whether this would evoke an increase in and release of LPC. Endothelial cells were disassociated from canine aortas by incubating with 0.1% collagenase for 20 min. Cells were plated and allowed to grow to confluence. Measurement of LPC was performed using Bligh and Dyer extraction of lipids, high performance liquid chromatography separation, and quantification of LPC using a recently developed radiometric assay employing [3H]acetic anhydride. Incubation of endothelial cells with thrombin (0.05 unit/ml) resulted in a 2.5-fold increase in LPC to 2.3 +/- 0.1 nmol/mg of protein at 2 min (p < 0.01) and returned to control levels within 20 min. The increase in LPC induced by thrombin exhibited a concentration-dependent response with an ED50 = 0.04 unit/ml. A concentration-dependent increase in LPC was also elicited by stimulation with the peptide portion of the thrombin receptor's tethered ligand SFLLRNPNDKYEPF with an ED50 = 8 microM. The LPC produced was rapidly and completely released into the surrounding media. Hirudin completely blocked the thrombin-induced increase in LPC. Dansylarginine N-(3-ethyl-1,5-pentanediyl)amide (0.1 microM), which rapidly inactivates thrombin's proteolytic activity in situ without impairing binding, or phenyl-prolyl-arginyl-chloromethyl ketone (PPACK, 5 nM), which inactivates thrombin due to chemical alteration of the proteolytic site, each prevented the increase in LPC in response to thrombin. Stimulation of protein kinase C with phorbol 12-myristate-13-acetate (PMA, 1 microM) enhanced the response to thrombin. In contrast, staurosporine (100 nM), H7 (15 microM), or chronic treatment with PMA for 20 h to down-regulate protein kinase C completely prevented the increase in LPC in response to thrombin. Thus, thrombin stimulation of endothelial cells in vivo during ischemia may be a primary mechanism contributing to the marked increase in LPC extracellularly during ischemia.
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PMID:Thrombin-induced release of lysophosphatidylcholine from endothelial cells. 839 49

The expression of lipoprotein lipase (LPL) mRNA and the LPL activity were studied in macrophages (CD14 positive) from human atherosclerotic tissue. Macrophages were isolated after collagenase digestion by immunomagnetic isolation. About 90% of the cells were foam cells with oil red O positive lipid droplets. To analyze the mRNA expression, PCR with specific primers for LPL was used. Arterial macrophages were analyzed directly after isolation and the data showed low expression of LPL mRNA when compared with monocyte-derived macrophages. To induce the expression of LPL mRNA in macrophages, PMA was used. When incubating arterial macrophages with PMA for 24 h we could not detect any increase in LPL mRNA levels. Similarly, the cells secreted very small amounts of LPL even after PMA stimulation. In conclusion, these studies show a very low expression of LPL mRNA in the CD14-positive macrophage-derived foam cells isolated from human atherosclerotic tissue. These data suggest that the CD14-positive cells are a subpopulation of foam cells that express low levels of lipoprotein lipase, and the lipid content could be a major factor for downregulation of LPL. However, the cells were isolated from advanced atherosclerotic lesions, and these findings may not reflect the situation in early fatty streaks.
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PMID:Expression of lipoprotein lipase mRNA and secretion in macrophages isolated from human atherosclerotic aorta. 840 28

Ovine endometrial cells (epithelial plus stromal), prepared from ovariectomized ewes treated with oestrogen and progesterone to mimic the luteal phase of the oestrous cycle were maintained in serum-free medium for 48 h in the presence or absence of phorbol myristate acetate (PMA, 100 nmol l-1), a known stimulus for production of matrix metalloproteinases (MMP) in other cells. Matrix metalloproteinase-1 (MMP-1, interstitial collagenase) and matrix metalloproteinase-2 (MMP-2, gelatinase A) activities were expressed by the cells in the absence of PMA; most were in the latent form and required activation by (4-aminophenyl) mercuric acetate (APMA). Exposure to PMA over 48 h resulted in a significant increase in MMP-1 activity but only a modest and nonsignificant increase in MMP-2 activity. Gelatin zymography demonstrated that proMMP-2 (72 kDa) was produced by both PMA-treated and untreated cells and an active form of 67 kDa was also present. Immunolocalization of MMP-1 and MMP-2 was seen within the cells following treatment with monensin. Highly purified epithelial and stromal cells were similarly cultured and analysis of the conditioned medium showed that MMP-1 and MMP-2 were produced predominantly by stromal rather than epithelial cells. Thus, both MMP-1, which degrades interstitial collagens, and MMP-2, an important enzyme for degradation of type IV and V collagens, are synthesized and released by ovine endometrial stromal cells in culture, but MMP-1 is produced primarily upon stimulation, whereas MMP-2 production is constitutive.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Production of matrix metalloproteinase 1 (interstitial collagenase) and matrix metalloproteinase 2 (gelatinase A: 72 kDa gelatinase) by ovine endometrial cells in vitro: different regulation and preferential expression by stromal fibroblasts. 841 Aug 28

Prostatic carcinoma cells have a propensity to metastasize to bone, and we propose that this phenomenon may be promoted by the adhesion of metastatic cells to bone matrix. Bone matrix is produced by osteoblasts, and we have developed an in vitro model of bone matrix by isolating the substratum deposited by human osteoblast-like U2OS cells. The collagenous nature of this matrix was demonstrated by the incorporation of [3H]proline and its subsequent release by purified collagenase. Both U2OS matrix and purified type I collagen stimulated the adhesion of human PC-3 prostatic carcinoma cells. Human laminin supported adhesion to a much lesser extent, and PC-3 cells did not adhere to fibronectin. Adhesion of PC-3 cells to U2OS matrix closely resembled adhesion to purified type I collagen with respect to (a) inhibition by a collagen-derived peptide and by antibodies raised against alpha 2 or beta 1 integrin collagen receptor subunits; (b) lack of inhibition by RGD (Arg-Gly-Asp) peptides; (c) stimulation by Mn2+ and Mg2+ ions but not by Ca2+ ion; and (d) stimulation by the phorbol ester PMA (phorbol 12-myristate 13-acetate). This adhesion was also stimulated (2.3-fold) by transforming growth factor beta (TGF-beta), which is a major bone-derived growth factor. We conclude that human osteoblast-like matrix is an adhesive substrate for PC-3 prostate carcinoma cells. This adhesion appears to be mediated by the interaction of alpha 2 beta 1 integrin on PC-3 cells with matrix-derived collagen. The stimulation of this adhesion by TGF-beta suggests that the co-expression of TGF-beta and type I collagen in bone may synergistically facilitate the adhesion of metastatic cells to bone matrix proteins and thereby increase their localization in the skeleton.
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PMID:Bone cell matrix promotes the adhesion of human prostatic carcinoma cells via the alpha 2 beta 1 integrin. 852 12

A three-dimensional collagen lattice can provide skin fibroblasts with a cell culture environment that simulates normal dermis. Such a collagen matrix environment regulates interstitial collagenase (type I metalloproteinase [MMP-1], collagenase-1) and collagen receptor alpha2 subunit mRNA expression in both unstimulated or platelet-derived growth factor-stimulated dermal fibroblasts (Xu, J., and R.A.F. Clark. 1996. J. Cell Biol. 132:239-249). Here we report that the collagen gel can signal protein kinase C (PKC)-zeta activation in human dermal fibroblasts. An in vitro kinase assay demonstrated that autophosphorylation of PKC-zeta immunoprecipitates was markedly increased by a collagen matrix. In contrast, no alteration in PKC-zeta protein levels or intracellular location was observed. DNA binding activity of nuclear factor kappaB (NF-kappaB), a downstream regulatory target of PKC-zeta, was also increased by fibroblasts grown in collagen gel. The composition of the NF-kappaB/Rel complexes that contained p50, was not changed. The potential role of PKC-zeta in collagen gel-induced mRNA expression of collagen receptor alpha2 subunit and human fibroblast MMP-1 was assessed by the following evidence. Increased levels of alpha2 and MMP-1 mRNA in collagen gel-stimulated fibroblasts were abrogated by bisindolylmaleimide GF 109203X and calphostin C, chemical inhibitors for PKC, but retained when cells were depleted of 12-myristate 13-acetate (PMA)-inducible PKC isoforms by 24 h of pretreatment with phorbol PMA. Antisense oligonucleotides complementary to the 5' end of PKC-zeta mRNA sequences significantly reduced the collagen lattice-stimulated alpha2 and MMP-1 mRNA levels. Taken together, these data indicate that PKC-zeta, a PKC isoform not inducible by PMA or diacylglycerol, is a component of collagen matrix stimulatory pathway for alpha2 and MMP-1 mRNA expression. Thus, a three-dimensional collagen lattice maintains the dermal fibroblast phenotype, in part, through the activation of PKC-zeta.
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PMID:A three-dimensional collagen lattice induces protein kinase C-zeta activity: role in alpha2 integrin and collagenase mRNA expression. 901 16


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