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)

Previous studies implicating a role for protein kinase C (PKC) in mediating stimulation of cellular responses by physiological agonists have relied on use of non-specific inhibitors or direct stimulation of PKC by phorbol esters. However, much of this evidence is questionable. Here, we have investigated the effects of a potent and selective PKC inhibitor, Ro 31-8425, on three different responses of human neutrophils stimulated by either a physiological agonist, C5a, or a phorbol ester, PMA. The responses studied were superoxide generation, collagenase secretion and adhesion to endothelial cells. In each case, the PMA-stimulated response was more sensitive to inhibition than the C5a-stimulated response. Even the PMA-stimulated responses differed in their sensitivity to inhibition, with superoxide production being the most sensitive and adhesion at least sensitive. The different sensitivities of the PMA stimulated responses suggest that, although activation of PKC stimulates the responses, either different degrees of activation or different isozymes are required for the different responses. The lower sensitivity of the C5a-stimulated responses in each case suggests that PKC activation, if needed at all, is not rate limiting in these signal transduction pathways. These results emphasize the redundancy in intracellular signal transduction.
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PMID:Different sensitivities of neutrophil responses to a selective protein kinase C inhibitor Ro 31-8425; redundancy in signal transduction. 906 30

The purpose of this study was to determine the effects of ovine follicle-stimulating hormone (FSH), luteinizing hormone (LH); prolactin, and recombinant FSH and a protein kinase C activator (phorbol 12-myristate 13-acetate [PMA]) on progesterone production by dispersed luteal cells (large + small) from Day 4 pregnant mice. Corpora lutea (CL) were collected on Day 4 of pregnancy (Day 1 = sperm positive smear), and dispersed luteal cells were isolated using collagenase. After overnight incubation, the luteal cells were incubated with or without FSH, LH, prolactin, or recombinant human FSH or PMA for 4 hr or an additional 24 hr at 37 degrees C; media were collected and progesterone was determined by RIA. Ten nanograms and 100 ng of ovine FSH, LH and prolactin were all equally effective in stimulating progesterone synthesis in media recovered after 24 hr of incubation. Moreover, the combination of all three gonadotropins yielded maximum levels of progesterone indicating a luteotrophic complex in vitro, paralleling previous in vivo findings. Recombinant human FSH-devoid of LH contamination-at doses of 10 and 100 ng also significantly stimulated progesterone synthesis, which strongly suggests that FSH has luteotropic activity in the mouse, thus agreeing with our previous in vitro results with CL of the pregnant hamster and rat. One hundred nanomolar PMA by itself did not affect progesterone production but significantly decreased dibutyrl cAMP-, forskolin-, FSH-, and LH-induced progesterone production, suggesting that activation of protein kinase C may block the luteotropic effects of LH and FSH during murine pregnancy.
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PMID:Progesterone production in vitro by mouse luteal cells: response to follicle-stimulating hormone, luteinizing hormone, and prolactin. 908 60

The 92 kDa type IV collagenase (MMP-9), which degrades type IV collagen, has been implicated in tissue remodeling. The purpose of the current study was to determine the role of Jun amino-terminal kinase (JNK)- and extracellular signal-regulated kinase- (ERK)-dependent signaling cascades in the regulation of MMP-9 expression. Towards this end, we first determined the transcriptional requirements for MMP-9 promoter activity in a cell line (UM-SCC-1) which is an avid secretor of this collagenase. Transfection of these cells with a CAT reporter driven by progressive 5' deleted fragments of the MMP-9 promoter indicated the requirement of a region spanning -144 to -73 for optimal promoter activity. DNase I footprinting revealed a protected region of the promoter spanning nucleotides -91 to -68 and containing a consensus AP-1 motif at -79. Mutation of this AP-1 motif practically abolished the activity of the MMP-9 promoter-driven CAT reporter. Mobility shift assays indicated c-Fos and Jun-D bound to this motif and transfection of the cells with a mutated c-Jun, which quenches the function of endogenous Jun and Fos proteins, decreased MMP-9 promoter activity by 80%. UM-SCC-1 cells contained a constitutively activated JNK and the expression of a kinase-deficient JNK1 reduced the activity of a CAT reporter driven either by the MMP-9 promoter or by three tandem AP-1 repeats upstream of a thymidine kinase minimal promoter. Conditioned medium collected from UM-SCC-1 cells transfected with the dominant negative JNK1 expression vector diminished 92 kDa gelatinolysis. Similarly, interfering with MEKK, which lies upstream of JNK1, using a dominant negative expression vector reduced MMP-9 promoter activity over the same concentration range which repressed the AP-1-thymidine kinase CAT reporter construct. UM-SCC-1 cells also contained a constitutively activated ERK1. MMP-9 expression, as determined by CAT assays and by zymography, was reduced by the co-expression of a kinase-deficient ERK1. Interfering with MEK1, which is an upstream activator of ERK1, either with PD 098059, which prevents the activation of MEK1, or with a dominant negative expression construct, reduced 92 kDa gelatinolysis and MMP-9 promoter activity respectively. c-Raf-1 is an upstream activator of MEK1 and a kinase-deficient c-Raf-1 expression construct decreased the activity of a promoter driven by either the MMP-9 promoter or three tandem AP-1 repeats. Conversely, treatment of UM-SCC-1 cells with PMA, which activates c-Raf-1, increased 92 kDa gelatinolysis. These data suggest that MMP-9 expression in UM-SCC-1 cells, is regulated by JNK- and ERK-dependent signaling pathways.
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PMID:Regulation of 92 kDa type IV collagenase expression by the jun aminoterminal kinase- and the extracellular signal-regulated kinase-dependent signaling cascades. 913 92

Type II pneumocytes are multifunctional alveolar epithelial cells that play a major role in the maintenance of lung structure and function. Recent evidence supports that these cells can synthesize a variety of extracellular matrix components in vitro, suggesting an active participation in connective tissue remodeling. However, their possible role in extracellular matrix degradation is unknown. In this study the production of matrix metalloproteinases (MMPs) was examined in primary cultures of rat alveolar type II pneumocytes after 2 and 7 days in culture. Under basal conditions, at both periods type II cells expressed interstitial collagenase mRNA. The immunoreactive protein was detected both in the cells and in conditioned media, and collagenolytic activity was revealed after trypsin activation. Gelatinolytic activity was detected by zymography showing a relative molecular mass of approximately 72 and 92 kDa (gelatinases A and B). Phorbol treatment increased collagenase and gelatinase activities. In addition, three alveolar epithelial cell lines were analysed for MMP production: MLE-12 (mice), L2 (rat), and A549 (human). The cell lines A549 and MLE-12 revealed collagenase and gelatinase A and B activities whereas the L2 cell line only exhibited gelatinase A activity, even after PMA induction. These findings demonstrate that alveolar epithelial cells synthesize in vitro several MMPs that confer on them the ability to degrade extracellular matrix and basement membrane components, a capacity of considerable importance for the remodeling of the stromal/epithelial interface.
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PMID:Lung alveolar epithelial cells synthesize interstitial collagenase and gelatinases A and B in vitro. 930 5

Protein kinase C (PKC) activity and its effect on progesterone production were investigated using porcine large and small luteal cells (LLC and SLC). Corpora lutea (CL) were surgically collected from pigs on Day 10 of the estrous cycle (Day 0 = onset of standing estrus). Luteal cells were dissociated by collagenase; LLC and SLC were further separated on a discontinuous Ficoll gradient. In a dose-response experiment with phorbol 12-myristate 13-acetate (PMA, a stimulator of PKC), progesterone production was not affected by 0.01 and 0.1 microM PMA, but was stimulated by 1 microM PMA. In a time series experiment, progesterone secretion was increased by 1 and 10 microM PMA in LLC by 60-150 min, and by 1 microM PMA in SLC during 120 and 150 min of incubation. However, 4 alpha-phorbol ester did not affect progesterone synthesis. H-7, a PKC inhibitor, blocked PMA-stimulated progesterone secretion by LLC during 3 hr of incubation. Of the PKC activators tested at 10 microM, PMA significantly stimulated cytosolic PKC activity over that of natural PKC activators in both LLC and SLC, whereas 4 alpha-phorbol ester did not affect PKC activity. H-7 inhibited PMA-stimulated PKC activity. PS (1-phosphatidyl-L-serine) + CA+2 and PS+DG (1,2-dioleoyl-sn-glycerol) + Ca+2 stimulated PKC activity. The results demonstrate that activation of PKC can increase progesterone secretion by porcine luteal cells from Day 10 of the estrous cycle and suggest PKC can have multiple effects in regulating luteal function.
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PMID:Protein kinase C activity and its effect on progesterone production by large and small porcine luteal cells. 931 15

Cartilage, bone and the interstitial stroma, composed largely of the interstitial collagens, types I, II and III, are remodelled by three members of the metalloproteinase (MMP) family, collagenase-1 (MMP-1), collagenase-2 (MMP-8) and collagenase-3 (MMP-13). MMP-1 and MMP-13 may contribute directly to disease progression, since they are induced in patients with rheumatoid arthritis and osteoarthritis. The study of MMP-1 and MMP-13 gene regulation in models of arthritic disease has been problematic because mice and rats, which are typically used, only possess a homologue of MMP-13. Here we show that in contrast with mice and rats, rabbits possess distinct genes homologous to human MMP-1 and MMP-13. Furthermore, rabbit MMP-13 is expressed simultaneously with MMP-1 in chondrocytes and synovial fibroblasts in response to the cytokines interleukin-1 and tumour necrosis factor-alpha, or the phorbol ester PMA. The time course of MMP-13 induction is more rapid and transient than that of MMP-1, suggesting that distinct mechanisms regulate the expression of these two collagenases. We have cloned the rabbit MMP-13 gene from synovial fibroblasts and demonstrated that the rabbit gene shares greater homology with human MMP-13 than does the mouse interstitial collagenase. Together with the fact that mice and rats do not possess a homologue to human MMP-1, our data suggest that the rabbit provides an appropriate model for studying the roles of interstitial collagenases in connective-tissue diseases, such as rheumatoid arthritis and osteoarthritis.
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PMID:Cloning of the gene for interstitial collagenase-3 (matrix metalloproteinase-13) from rabbit synovial fibroblasts: differential expression with collagenase-1 (matrix metalloproteinase-1). 951 98

1. We recently demonstrated the presence of phospholipase C-coupled bradykinin (BK) B2-receptors in human primary and SV40 virus-immortalized corneal epithelial (CEPI) cells. 2. The aims of the present studies were to demonstrate the specific binding of [3H]-BK to CEPI cell membranes and to study its pharmacological characteristics. In addition, we wished to study the functional coupling of the BK receptors to various physiological and pathological mechanisms in the CEPI cells, including phosphoinositide (PI) turnover, intracellular Ca2+-mobilization ([Ca2+]i), cell proliferation (via [3H]-thymidine incorporation), and the release of various cytokines, collagenase-1 (matrix metalloproteinase-1) and prostaglandin E2 (PGE2). 3. Specific [3H]-BK binding comprised 83 +/- 2% of the total binding, and was of high affinity (Kd = 1.66 +/- 0.52 nM, n = 5), saturable (Bmax = 640 +/- 154 fmol g(-1) wet weight) and reversible. Competition studies yielded the following affinity values for BK and a number of BK-related peptides: Hoe-140 (D-Arg-[Hyp3,Thi5,D-Tic7,Oic8]BK; icatibant): Ki = 0.17 +/- 0.07 nM; BK: Ki = 1.0 +/- 0.11 nM; [Tyr8]-BK: Ki = 12.9 +/- 2.3 nM; [des-Arg9]-BK: Ki > 9,200 nM (all n = 3-5)). 4. BK potently stimulated PI turnover (EC50 = 2.3 +/- 0.3 nM; n = 7) and [Ca2+]i mobilization (EC50 = 8-20 nM) in CEPI cells and both responses were inhibited in a concentration-dependent manner by 100 nM-10 microM Hoe-140, a selective B2-receptor antagonist, and also inhibited by the selective phospholipase C (PLC) inhibitor, U73122 (1-(6-((17beta-3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1 H-pyrrole-2,5-dione) (IC50 = 3.0 +/- 1.6 microM). BK-induced [Ca2+]i mobilization was reduced by about 30% in the presence of 4 mM EGTA, but was not significantly affected by 100 nM nifedipine. 5. BK (0.1 nM-10 microM) significantly (P<0.05-0.001) stimulated [3H]-thymidine incorporation into CEPI cellular DNA. However, while interleukin-1alpha (IL-1alpha; 10 ng ml(-1)) potently stimulated the release of IL-6, IL-8 and granulocyte macrophage colony-stimulating factor from CEPI cells, BK (0.1 nM-10 microM) was without effect. 6. Whilst phorbol-12-myristate-13-acetate (PMA; 3 microg ml(-1)) and 10% foetal bovine serum (positive control agents) significantly stimulated the release of both MMP-1 and PGE2 from CEPI cells, BK (0.1 nM-10 microM) was without any significant effect under these conditions. 7. In conclusion, these data indicate that the CEPI cells express high-affinity [3H]-BK binding sites representing B2-subtype BK receptors coupled to PI turnover and [Ca2+]i mobilization which appear to stimulate [3H]-thymidine incorporation into cellular DNA. In contrast, BK failed to elicit the release of PGE2, various cytokines and MMP-1 from CEPI cells. These results suggest that BK may have a potential role in corneal epithelium wound healing by stimulating cell proliferation.
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PMID:Effects of bradykinin on signal transduction, cell proliferation, and cytokine, prostaglandin E2 and collagenase-1 release from human corneal epithelial cells. 955 96

We have identified an IL-10 inducible enhancer (HTE) (5'-CACGATGACTCATCACTGTTGAAAGACA-3') (-864 to -836 bp) and associated silencer element (HTS) (5'-CCACTGGCCCATCGTATAT-3') (-1284 to -1266 bp) in the 5' promoter region of the human tissue inhibitor of metalloproteinase-1 (TIMP-1) gene. Chloramphenicol acetyl transferase (CAT), electrophoretic migration shift assays (EMSAs), and DNase footprinting revealed that IL-10 (15 ng/ml for 1-2 h) induced the HTE enhancer. In comparison, phorbol ester stimulated the HTS silencer and blocked IL-10's effects in a dose-dependent, orientation- and position-independent fashion, suggesting that HTS is a true silencer element. EMSAs combined with deletion and mutation analysis of the HTE and HTS elements confirmed these observations. Finally, Northern blot, Western blot, immunoprecipitation, and ELISA analysis showed that IL-10 (15 ng/ml) induced TIMP-1 expression (approximately 10-fold by 18 h), whereas PMA (100 ng/ml) inhibited the stimulatory effects of IL-10 on TIMP-1 expression. The data indicate that HTE and HTS function as positive and negative regulatory elements that control human TIMP-1 expression.
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PMID:Identification of positive and negative regulator elements for the tissue inhibitor of metalloproteinase 1 gene. 977 93

On direct cell-cell contact, stimulated T lymphocytes potently trigger the production of pro-inflammatory factors such as interleukin-1beta (IL-1beta) and matrix metalloproteinases (MMP-1 and MMP-9), as well as anti-inflammatory factors such as IL-1 receptor antagonist (IL-1Ra) and the tissue inhibitor of metalloproteinases (TIMP-1) in peripheral blood monocytes and the monocytic cell line THP-1. Such mechanisms might play an important part in many inflammatory diseases where tissue destruction occurs. To assess whether anti-inflammatory agents such as dexamethasone (DEX) and leflunomide (LF) would affect contact-activation of monocytic cells, T lymphocytes were stimulated by PMA and PHA in the presence or absence of increasing concentrations of drug. LF and DEX (10- 4 M) inhibited the ability of stimulated T lymphocytes to activate monocytic cells by 66-97% and 43-70%, respectively, depending on the readout product. Upon contact with T lymphocytes stimulated in the presence of 10- 5 M LF, the molar ratio of IL-1Ra/IL-1beta and TIMP-1/MMP-1 produced by THP-1 cells was enhanced 3.6- and 1.9-fold, respectively, whereas it was enhanced only 1.3- and 1.4-fold upon contact with T lymphocytes stimulated in the presence of 10- 4 M DEX. Therefore, LF tends to favor the inhibition of pro-inflammatory and matrix-destructive factors over that of anti-inflammatory factors and metalloproteinase inhibitors, thus interfering with both inflammation and tissue destruction. These experiments indicate that LF and DEX have the potential to affect the capacity of stimulated T lymphocytes to activate, on direct cell-cell contact, monocytic cells. Furthermore, flow cytometric analysis revealed that surface molecules of T lymphocytes that were partially involved in contact-signaling of monocytes (i.e., CD69 and CD11) were not modulated by either LF or DEX, suggesting that factors which remain to be identified were mainly involved in the activation of monocytes on direct cell-cell contact.
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PMID:Exposure of T lymphocytes to leflunomide but not to dexamethasone favors the production by monocytic cells of interleukin-1 receptor antagonist and the tissue-inhibitor of metalloproteinases-1 over that of interleukin-1beta and metalloproteinases. 988 11

There is a growing body of evidence that implicates matrix metalloproteinases (MMPs) as major players in numerous diseased conditions. The articular cartilage degradation that is characteristic of rheumatoid arthritis (RA) is believed to be mediated by the collagenase subfamily of matrix metalloproteinases. The preference of collagenase-3 (CL-3) for collagen type II makes it a likely candidate in the turnover of articular cartilage and a potential target for drug development. In this study, RA synovial membrane tissue was shown to express CL-3 mRNA by reverse transcriptase-polymerase chain reaction (RT-PCR) and protein by immunohistochemistry. Fibroblasts isolated and cultured from RA synovial membrane tissue were induced to express CL-3 mRNA. CL-3 mRNA was detected after PMA treatment in 16 of the 18 RA synovial membrane fibroblast cell lines established for this study. These fibroblasts also expressed mRNA for collagenase-1 (CL-1, MMP-1), membrane type-1 matrix metalloproteinase, gelatinase A, gelatinase B, stromelysin-1, stromelysin-2, TIMP-1, and TIMP-2. They were further shown to express CL-1 mRNA constitutively and CL-3 mRNA only after stimulation with PMA, IL-1, TGF-beta1, TNF-alpha, or IL-6 with IL-6sR. These fibroblasts also expressed after induction both CL-1 and CL-3 at the protein level as determined by Western blot analyses and immunofluorescence.
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PMID:Induction of collagenase-3 (MMP-13) in rheumatoid arthritis synovial fibroblasts. 1104 Apr 55


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