Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.3 (collagenase)
 18,340 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Exposure to synovial factors or purified interleukin-1 (IL-1) induces the production of prostaglandin E2 (PGE2) and the neutral proteinases (NP) collagenase, gelatinase and stromelysin by lapine articular chondrocytes. Having frequently found our partially purified synovial preparations to elicit this process of chondrocyte activation more strongly than recombinant IL-1, Phadke's report of synergism between IL-1 and fibroblast growth factor (FGF) intrigued us. In our hands, basic FGF (1 ng/ml-1 micrograms/ml) did not activate chondrocytes but, in a dose-dependent manner, enhanced the production of PGE2 and NP by chondrocytes exposed to IL-1 alpha or IL-1 beta (1-10 U/ml). Further examination determined that the basic FGF was a better synergist than acidic FGF. In view of reports that FGF activates protein kinase C, we tested whether phorbol myristate acetate (PMA) could substitute for FGF as a synergist. Not only did it do so, but PMA alone (0.1 ng/ml-100 ng/ml), unlike FGF, provoked the production of PGE2 by chondrocytes. The Ca2+ ionophore A23187 could not substitute for FGF in enhancing induction of the NP. Using a cDNA probe, we confirmed that the synergistic effects of both FGF and PMA upon IL-1 mediated collagenase induction, were associated with an increased abundance of collagenase mRNA.
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PMID:Chondrocyte activation by interleukin-1: synergism with fibroblast growth factor and phorbol myristate acetate. 255 71

The effect of the tumor promoter 12-O-tetradecanoyl-phorbol-13-acetate (TPA) was studied using an immortalized human bronchial epithelial cell line, BEAS-2B, both in vivo and in vitro. The in vivo model consisted of tracheas reconstituted with an epithelium of BEAS-2B cells xenotransplanted into athymic nude mice. Intraluminal TPA treatment caused increased BEAS-2B cell proliferation and downgrowth into the tracheal stroma. In an in vitro invasion assay, TPA enhanced the invasive capacity of BEAS-2B cells 20- to 25-fold. A similar result was observed with diacylglycerol (DAG), an endogenous activator of protein kinase C, and the effects of TPA and DAG were abolished by simultaneous treatment with H-7, a protein kinase C inhibitor. TPA induced type IV collagenolysis, and this effect also was prevented by H-7. These data are consistent with the hypothesis that TPA causes these cells to become invasive by inducing collagenase activity and that this effect is mediated via protein kinase C.
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PMID:Enhancement of the invasive ability of a transformed human bronchial epithelial cell line by 12-O-tetradecanoyl-phorbol-13-acetate and diacylglycerol. 255 20

The early biochemical events that link interleukin-1 (IL-1) receptor occupancy to neutral proteinase production in synovial cells were studied. Addition of human r-IL-1 to human synovial cells in culture stimulated phospholipase A2 (PLA2) activity, inositol triphosphate production and plasminogen activator (PA) activity in a dose dependent manner with similar EC50 values (0.1-0.5 nM). These results, coupled with time courses and other studies, suggest that the IL-1 modulation of PA involves both products of PLA2 and phospholipase C (PLC) activation. On the other hand, the IL-1 induction of collagenase may primarily involve PLC and protein kinase C activation.
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PMID:Interleukin-1 mediated signal transduction associated with synovial cell activation. 267 53

In order to examine the involvement of protein kinase C (PKC) in the transcriptional activation of genes by TPA (12-0-tetradecanoyl phorbol 13-acetate) we have constructed a series of PKC expression plasmids. Transient expression of an active fragment of PKC in rat fibroblasts resulted in the transcriptional activation of a TRE (TPA-responsive element)-CAT chimeric gene which contains various repetitions of collagenase TREs. These provide the first direct evidence that kinase activity of PKC is involved in TPA-induced transcriptional activation through TRE.
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PMID:Direct evidence that the kinase activity of protein kinase C is involved in transcriptional activation through a TPA-responsive element. 275 29

We have begun to examine the role of protein kinase C (PKC) in chondrocyte activation by interleukin-1 (IL-1) in search of a possible signal transduction mechanism. Untreated chondrocytes synthesised little or no collagenase or gelatinase and only modest amounts of prostaglandin E2 (PGE2), while IL-1 induced considerable amounts of these. An activator of PKC, phorbol myristate acetate (PMA), alone did not influence the synthesis of the metalloproteinases to any great degree, but enhanced PGE2 production. Sphingosine and staurosporin, inhibitors of PKC, each eliminated the synergistic effect of PMA upon enzyme induction by high doses (10 U/ml) of IL-1, but failed to influence enzyme induction by this dose of IL-1 alone. However, a low dose (1 U/ml) of IL-1 in combination with these inhibitors was synergistic upon enzyme induction. Although these inhibitors reduced the synthesis of PGE2 in response to PMA, synthesis of PGE2 in response to both doses of IL-1 was greatly enhanced by the inhibitors. PMA, but not IL-1, enhanced the phosphorylation of an 80 K protein which is characteristic of PKC activity in certain types of cells. From these data, we conclude that PKC is unlikely to be involved in the induction of neutral metalloproteinases by IL-1, although once induction has occurred, PKC may modulate this effect. PKC may also act as regulator of PGE2 synthesis, although this requires further investigation.
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PMID:Protein kinase C and chondrocyte activation. 280 36

Functional gastrin-containing tumor cells (GT cells) have been maintained in short-term culture on microporous membranes, and their response to selected agents has been determined. After dispersion of gastrinoma by collagenase-DNAase digestion coupled with mechanical disruption, dispersed cells were depleted in stromal material by selective attachment to a plastic substrate, then cultured for 72 hours on porous cellulose membranes. Cultures contained 68 +/- 5% GT cells with a viability of 92 +/- 2%. Secretin stimulated the rate of gastrin release from cultured GT cells in both a time- and a dose-dependent fashion. To examine the possible involvement of adenylate cyclase- and protein kinase C-mediated mechanisms in regulating gastrin release from the neoplastic GT cells, we evaluated the effects of 8-bromoadenosine 3':5'-cyclic monophosphate (8-BrcAMP; 10(-4) - 10(-2) mol/L), the diterpene forskolin (10(-5) mol/L), 12-0-tetradencanoylphorobol 13-acetate (TPA; 10(-8) - 10(-6) mol/L), and 4 alpha-phorbol 12,13-didecanoate (4 alpha PDD; 10(-8) - 10(-6) mol/L) on gastrin release. Among all compounds tested, 8-BrcAMP (10(-2) mol/L) was the most potent, stimulating the rate of gastrin release 263% above basal. Both 8-BrcAMP and TPA stimulated gastrin release in a dose-dependent fashion. The biologically inactive phorbol ester, 4 alpha PDD, was without effect at all concentrations. Somatostatin (10(-8) - 10(-6) mol/L) inhibited 8-BrcAMP-stimulated gastrin release in a dose-dependent fashion to a maximum of 75%.
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PMID:Control of gastrin release in cultured gastrinoma-derived G cells. 289 16

The enhancer-binding protein AP-1 has been purified to greater than 95% homogeneity from HeLa cells by sequence-specific DNA affinity chromatography and identified as a 47 kd polypeptide. Purified AP-1 activates transcription in vitro of the wild-type human metallothionein IIA (hMT IIA) gene but not mutant hMT IIA promoters lacking AP-1 recognition sites. DNAase I protection analysis indicates that genetically defined enhancer elements in hMT IIA, SV40, and the human collagenase gene contain high-affinity AP-1-binding sites, each with a conserved recognition motif, TGACTCA. These three genes are transcriptionally induced by treatment of cells with the tumor promoter TPA. Here we demonstrate that multiple synthetic copies of the consensus AP-1-binding site can act as TPA-inducible enhancers in various plasmid constructs after transfection into HeLa cells. These findings suggest that AP-1 is a transcription factor that functions by interacting with a specific enhancer element, and that its activities may be modulated by treatment of cells with TPA, known to stimulate protein kinase C.
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PMID:Purified transcription factor AP-1 interacts with TPA-inducible enhancer elements. 303 33

Corpora lutea were collected from Holstein heifers on Days 10 and 12 of the oestrous cycle and the cells were dispersed with collagenase. The dispersed cells were separated into preparations of highly purified (90-99%) small (less than 20 microns) and large (greater than 25 microns) luteal cells by unit gravity sedimentation and fluorescence-activated cell sorting. Net progesterone accumulation by 1 x 10(5) small cells and 1 x 10(3) large cells during 2 and 4 h incubations, respectively, were measured after additions of LH, PGF-2 alpha, and phorbol esters, alone and in combination. Progesterone synthesis was increased (P less than 0.05) by phorbol dibutyrate (PBt2) or PGF-2 alpha (P less than 0.05) in small, but not in large, luteal cells (10.1 +/- 3.0 and 18.1 +/- 5.0 ng/10(5) cells for 0 and 50 nM-PBt2, and 19.9 +/- 3.2 and 44.2 +/- 9.3 ng/10(5) cells for 0 and 1 microgram PGF-2 alpha/ml). The previously reported stimulatory effects of PKC activation and PGF-2 alpha addition to total dispersed cell preparations are therefore entirely attributable to the small, theca-derived cells. Small cells responded to low levels of LH (9.1 +/- 1.1, 69.0 +/- 5.4 and 154.7 +/- 41.4 ng/10(5) cells for 0, 1 and 5 ng LH/ml, respectively, P less than 0.05), while large cells responded only to high levels of LH (1635 +/- 318, 2662 +/- 459 and 3386 +/- 335 pg/10(3) cells for 0, 100 and 1000 ng LH/ml, respectively, P less than 0.05). PGF-2 alpha inhibited LH-, 8-Br-cAMP- and forskolin-stimulated progesterone synthesis in the large cells (3052 +/- 380, 3498 +/- 418, 3202 +/- 391 pg/10(3) cells for 1 microgram LH/ml, and 0.5 mM-8-Br-cAMP, and 1 microM-forskolin respectively and 1750 +/- 487, 2255 +/- 468, 2165 +/- 442 pg/10(3) cells for PGF-2 alpha + LH, PGF-2 alpha + 8-Br-cAMP and PGF-2 alpha + forskolin, respectively), indicating that the inhibitory effect of PGF-2 alpha on progesterone synthesis in large cells occurs at a site distal to cAMP generation. These results suggest that the large cells are the targets of the luteolytic effects of PGF-2 alpha, while the small cells are responsible for the previously reported luteotrophic effect of PGF-2 alpha in vitro.
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PMID:Control of progesterone production in small and large bovine luteal cells separated by flow cytometry. 316 3

We characterized the effect of the tumor promoter phorbol 12-myristate 13-acetate (PMA) on osteoblast function and DNA synthesis in 21-day-old fetal rat calvaria maintained in organ culture. Protein synthesis was determined by measuring the incorporation of [3H]proline into collagenase-digestible (CDP) and noncollagen protein (NCP), respectively. Alkaline phosphatase activity was assessed as the release of p-nitrophenol from p-nitrophenol phosphate. DNA synthesis was determined by the incorporation of [3H]thymidine into acid-insoluble bone and total DNA content. PMA at 3-100 ng/ml (4-133 nM) caused a dose-related inhibition of collagen synthesis that was observed 6 hours after adding PMA to calvaria. PMA inhibited collagen synthesis in the osteoblast-rich central bone of calvaria but did not alter collagen synthesis in the periosteum. There was little effect of PMA on noncollagen protein synthesis in the central bone or periosteum. Phorbol esters that do not promote tumor formation in vivo did not alter collagen synthesis in calvaria. PMA stimulated prostaglandin E2 (PGE2) production in calvaria, but indomethacin did not alter the inhibitory effect of PMA on bone collagen synthesis. PMA decreased alkaline phosphatase activity measured after 48 hr of culture and increased the incorporation of [3H]thymidine into bone and DNA content after 96 hr of culture. These data indicate that PMA inhibits collagen synthesis and alkaline phosphatase activity, while stimulating DNA synthesis, suggesting that activation of protein kinase C might regulate osteoblast function and bone cell replication.
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PMID:Inhibition of bone collagen synthesis by the tumor promoter phorbol 12-myristate 13-acetate. 321 12

We studied PGE2-release from isolated human gastric mucosal cells. Mucosa was obtained at surgery and cells were dispersed by collagenase and pronase. Centrifugation with Percoll yielded a fraction of light density cells (70-75% parietal cells; 2-4% mast cells) revealing maximal rates of PGE2-release. A radioimmunoassay was used to measure PGE2-release into the incubation medium. Calcium ionophore A23187 which aids calcium transport across membranes caused a 3.5-fold increase of PGE2-release; this effect was abolished in calcium-free incubation medium. PGE2-release was also stimulated by phospholipase C (100 mU/ml) which is known to induce phosphoinositol breakdown, as well as by 1-oleyl-2-acetyl-sn-glycerol (OAG; 10 microM) and by 12-O-tetradecanoyl-13-acetate (TPA; 10 microM) which cause direct activation of protein kinase C without preceding induction of phosphoinositol breakdown. The response to TPA was potentiated by A23187. The calmodulin antagonist naphthalene sulfonamide W 7 reduced PGE2-release in response to A23187 and TPA (IC50: 1 microM). Our data indicate that PGE2-release of human gastric mucosal cells is stimulated by calcium influx as well as by indirect (phospholipase C) and direct (OAG, TPA) activation of protein kinase C. Stimulation of PGE2-release involves calmodulin-mediated mechanisms.
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PMID:[Calcium, phospholipase C and protein kinase C stimulate prostaglandin secretion of isolated gastric mucosa cells of the human]. 347 5


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