Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The synthesis of an 88-kDa gelatinolytic enzyme, identified as a zymogen of matrix metalloproteinase (proMMP)-9, was induced in the primary culture of rabbit articular chondrocytes by cotreatment with recombinant interleukin 1 beta (rIL-1 beta) and the protein kinase C (PKC) agonists, phorbol 12,13-dibutyrate (PDBu) or mezerein. Negligible 88-kDa gelatinolytic activity was produced by unstimulated cells or cells treated with a PKC activator alone at concentrations up to 100 ng/ml, and only a modest induction occurred with rIL-1 beta alone at concentrations of 1-100 ng/ml. However, when these cells were treated with a PKC activator in the presence of IL-1 beta (1 ng/ml), induction was striking, with enzymic activity detectable at a concentration as low as 1 ng/ml of mezerein or 10 ng/ml of PDBu. Rabbit chondrocytes in culture constitutively produced the zymogen of MMP-2 (proMMP-2) and its production was not altered by treatment with IL-1 beta or PKC agonists alone or in combination. Recombinant tumor necrosis factor alpha (rTNF alpha) did not substitute for IL-1 beta in inducing proMMP-9 in the presence of PKC activators, nor was the combination of IL-1 beta or TNF alpha alone effective. These data indicate that rabbit articular chondrocytes have a potential to synthesize and secrete proMMP-9 under certain biological and pathological conditions but that the expression of proMMP-9 is differently regulated from that of other MMPs.
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PMID:Matrix metalloproteinase 9 (92-kDa gelatinase/type IV collagenase) is induced in rabbit articular chondrocytes by cotreatment with interleukin 1 beta and a protein kinase C activator. 132 11

Six cell lines, that were cloned from murine C127 cells infected by bovine papillomavirus type 1 (BPV1), were found to differ in the degree of transformation in vitro and of tumorigenicity in vivo. In these cell lines the degree of tumorigenicity was inversely correlated with IL-6 induction by IL-1 beta. Whereas the parental C127 cell line produced 15-30 U/ml of IL-6 spontaneously, none of the transformed cell lines produced significant levels of IL-6 constitutively. On induction by human IL-1 beta the parental C127 cell line produced up to 300 U/ml of IL-6, whereas the fully transformed ID14 cell line failed to produce any. The less transformed cell lines produced lower yields of IL-1 beta-induced IL-6, dependent on their degrees of transformation and tumorigenicity. Gelatinase B (96 kDa), a matrix metalloproteinase inducible by IL-1 beta, was dose-dependently regulated in the parental C127 cell line and in the weakly transformed cell line Tlc. These data suggest that transformation processes by BPV1 generally impair IL-1-regulated gene transcription. This impairment seems not to be located at the IL-1 beta receptor level, since in all the cell lines studied the numbers and affinities of the IL-1 beta binding sites were found to be comparable. This impairment seems not to be mediated by transformation-induced inactivation of the protein kinase C pathway since phorbol 12-myristate 13-acetate (PMA) induced IL-6 production equally well in all C127 cell-derived clones. It is suggested that BPV1 transformation can change the expression of host genes that might play a functional role in tumor immune surveillance and tumorigenicity in vivo.
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PMID:The induction of IL-6 and gelatinase B by IL-1 in mouse cell lines transformed with bovine papillomavirus: decreased production in tumorigenic cells. 133 1

We investigated the effects of PAL (protocatechualdehyde), a metabolite of ACP (3,4-diacetoxy benzylidene diacetate) which is a candidate as a novel antirheumatic agent, on the production of a tissue inhibitor of metalloproteinases (TIMP) using a primary chondrocyte culture from bovine nasal septum cartilage. The addition of human recombinant interleukin-1 alpha (hrIL-1 alpha) induced proteoglycan (PG) depletion from a chondrocyte matrix. PAL significantly reduced the induction of PG depletion. HrIL-1 alpha increased the casein-degrading activity, matrix metalloproteinase (MMP) activity, and the level of TIMP secretion in the culture media. PAL significantly reduced the casein-degrading activity and further increased TIMP secretion under hrIL-1 alpha stimulation. Phorbol myristate acetate (PMA) also increased the level of TIMP secretion, and staurosporine, a specific inhibitor of protein kinase C (PKC), reduced the TIMP secretion to the control level under hrIL-1 alpha or PMA stimulation. Furthermore, PAL showed a significant increase following treatment with a low concentration of PMA which alone did not increase TIMP production. These findings suggest that the activation of the PKC pathway plays an important role in TIMP production and that PAL increases the level of TIMP production through an additive or synergistic effect with the activation of the PKC pathway. In conclusion, these findings demonstrate that the inhibition of the MMP activity and the increase of TIMP production by PAL contribute to the inhibition of PG depletion in a primary chondrocyte culture from bovine nasal septum cartilage.
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PMID:Effect of a benzylidene derivative, novel antirheumatic agent, on the production of tissue inhibitor of metalloproteinases. 814 18

Heparin inhibits the migration and proliferation of arterial smooth muscle cells and modifies the extracellular matrix. These effects may be the result of heparin's effects on proteinases that degrade the matrix. We have previously reported that heparin inhibits the induction of tissue-type plasminogen activator and interstitial collagenase mRNA. We have investigated the possibility that heparin affects other members of the matrix metalloproteinase family. Phorbol ester increased the levels of mRNA of collagenase, 92-kD gelatinase and stromelysin as well as the synthesis of these proteins. These effects were inhibited by heparin, but not by other glycosaminoglycans, in a dose-dependent manner. The induction of these matrix metalloproteinases was also inhibited by staurosporine and pretreatment with phorbol ester indicating the involvement of the protein kinase C pathway. In contrast, the 72-kD gelatinase was expressed constitutively and was not affected by phorbol ester or heparin. Tissue inhibitor of metalloproteinase-1 was expressed constitutively and was slightly increased by phorbol ester. It was not affected by heparin. Thus, heparin inhibits the production of four proteinases (tissue plasminogen activator, collagenase, stromelysin and 92-kD gelatinase) that form an interdependent system capable of degrading all the major components of the extracellular matrix.
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PMID:Heparin inhibits the induction of three matrix metalloproteinases (stromelysin, 92-kD gelatinase, and collagenase) in primate arterial smooth muscle cells. 818 30

Colonization or emergence of microbial pathogens may result in tissue destruction by activation of one or more of five distinct host degradative pathways (matrix metalloproteinase pathway, plasminogen-dependent pathway, phagocytic pathway, PMN-serine proteinase pathway and osteoclastic bone resorption) or by direct cleavage of extracellular matrix constituents by microbial proteinases. Activation of endogenous destructive pathways may be mediated by immune responses resulting in expression of degradative cellular phenotypes among both immigrant and resident cell populations. In addition, expression of degradative phenotypes may be triggered by direct influences on host cells of microbial products (LPS, enzymes, toxins). A body of evidence suggests that each of these mechanisms involves local production of proinflammatory cytokines and growth factors. The matrix metalloproteinase pathway is centrally involved in dissolution of all unmineralized connective tissues and perhaps in resorption of bone as well. The matrix metalloproteinase family consists of nine or more genetically distinct Zn++ endopeptidases which collectively cleave all of the constituents of the extracellular matrix. Recent studies have uncovered many essential elements of a complex, but still incomplete, regulatory network that governs tissue destruction. Proinflammatory cytokines and growth factors induce signalling pathways several of which are dependent on protein kinase C and result in transient expression of the transcription factors c-jun and c-fos. Initiation of transcription of most matrix metalloproteinase genes requires binding of the transcription factor AP-1 (c-jun/c-fos) to a specific promoter sequence but attainment of maximal transcription rates is dependent on interaction with other promoter elements as well. Several matrix metalloproteinases have been detected in crevicular fluids and tissues of inflamed human gingiva as have the proinflammatory cytokines (IL-1 and TNF-alpha) which regulate their transcription. Although the mere presence of enzymes and cytokines does not necessarily impart function per se, these observations suggest that some level of spatial or temporal linkage exists between metalloproteinase/cytokine expression and gingival inflammation.
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PMID:Role of cytokines and inflammatory mediators in tissue destruction. 826 20

The phorbol-ester tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) is a potent inducer of the metalloproteinase stromelysin in fibroblasts in vivo and in several cultured cell lines. Rat-1 and Rat-2 fibroblasts, however, do not respond to TPA stimulation by induction of stromelysin gene activity, although collagenase promoter-mediated activity is induced threefold by TPA treatment in these cells. We determined that rat fibroblasts expressed protein kinase C(PKC)alpha, PKCdelta, PKCepsilon, and PKCzeta but neither the mRNA nor the protein for PKCbeta. When Rat-2 fibroblasts were stably transfected with an expression vector producing PKCbeta, however, TPA treatment of these variants resulted in a 3.1-fold induction of stromelysin promoter-mediated luciferase activity compared with a 1.3-fold induction in parental Rat-2 cells (P<0.002). Transient transfection of PKCepsilon produced a small but significant increase in TPA-stimulation of both stromelysin- and collagenase-mediated gene expression. These results suggest that there are PKC isotype-specific signaling pathways that can differentially regulate matrix metalloproteinase gene expression.
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PMID:Protein kinase C isotypes required for phorbol-ester induction of stromelysin-1 in rat fibroblasts. 859 79

Platelet-derived growth factor (PDGF) induces the expression of human stromelysin-1, a matrix metalloproteinase involved in tumor invasion and metastasis. Here it is shown that stromelysin-1 gene induction by PDGF depends on Ras and involves three previously identified promoter elements (the stromelysin-1 PDGF-responsive element (SPRE) site, the two head-to-head polyomavirus enhancer A-binding protein-3 (PEA3) sites, and the activator protein-1 (AP-1) binding site). During mitogenic induction, these responsive elements appear to be organized in two independent transcriptional units, SPRE-AP-1 and PEA3-AP-1, which result from specific element cross-talking. Interestingly, expression of a dominant negative mutant of Raf-1 significantly interfered with the induction through PEA3-AP-1 but not with that operating through SPRE-AP-1. Conversely, only the induction operating through SPRE-AP-1 was affected significantly by the expression of a dominant negative mutant of the atypical lambda/iota protein kinase C (lambda/iotaPKC). These data strongly suggest that the signal triggered by PDGF flows through Ras and bifurcates toward two distinct pathways, one operating through Raf and involving PEA3-AP-1 and the other one Raf-independent, operating through lambda/iotaPKC and SPRE-AP-1. Furthermore, we present evidence suggesting that the novel SPRE-binding transcription factor SPBP cross-couples with c-Jun to transactivate the SPRE site.
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PMID:Cross-talk between different enhancer elements during mitogenic induction of the human stromelysin-1 gene. 866 78

Glomerular mesangial cells express matrix metalloproteinase-9 (MMP-9) in response to the proinflammatory cytokine interleukin-1 beta (IL-1 beta). To elucidate the signal transduction systems involved, we focused on the role of nuclear factor-kappa B (NF-kappa B) and activator protein-1 (AP-1), since the 5'-flanking region of MMP-9 gene contains binding sequences for these transacting molecules. In rat mesangial cells treated with an inhibitor of NF-kappa B, pyrrolidine dithiocarbamate, induction of MMP-9 by IL-1 beta was suppressed at both mRNA and protein levels. Mesangial cells stably transfected with a transdominant negative mutant of NF-kappa B also showed blunted induction of MMP-9. Transient transfection study with a kappa B reporter plasmid revealed that IL-1 beta indeed activated the kappa B site and that pyrrolidine dithiocarbamate abolished this activation. These results suggest that IL-1 beta induced MMP-9 via the stimulation of NF-kappa B pathway. to examine whether tyrosine kinase is involved in this pathway, mesangial cells were stimulated by IL-1 beta in the presence of a tyrosine kinase inhibitor genistein. This inhibitor dose dependently suppressed the expression of MMP-9, as well as the activation of the kappa B site by IL-1 beta, indicating the involvement of tyrosine kinase in the stimulation of NF-kappa B. Because mesangial cells stimulated by IL-1 beta transiently expressed c-fos and c-jun nRNAs prior to the expression of MMP-9, the role of these genes in mediating the IL-1 beta response was further examined. Transfection of mesangial cells with a c-jun antisense cDNA and treatment with a pharmacological inhibitor of c-Jun/ AP-1, curcumin, revealed that the induction of c-Jun/AP-1 is essential for the expression of MMP-9 by IL-1 beta. Although protein kinase C (PKC) is regarded as a potential inducer of AP-1, stimulation of mesangial cells with phorbol 12-myristate 13-acetate failed to induce MMP-9. Similarly, depletion of intracellular PKC did not obviously affect the induction of MMP-9 by IL-1 beta. These findings demonstrate that dual operation of tyrosine kinase-mediated NF-kappa B stimulation and c-Jun/AP-1 activation is essential to the induction of MMP-9 by IL-1 beta in cultured mesangial cells.
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PMID:Dual regulation of IL-1 beta-mediated matrix metalloproteinase-9 expression in mesangial cells by NF-kappa B and AP-1. 876 30

Glomerular mesangial cells express matrix metalloproteinase sromelysin in response to the proinflammatory cytokine IL-1 beta. The present study was conducted to identify intracellular machinery involved in this IL-1 action, especially focusing on the role of the TPA response element (TRE) located in the 5'-flanking region of the stromelysin gene. Using transient transfection with a pTRE-LacZ reporter plasmid, we detected no obvious up-regulation of TRE activity in rat mesangial cells following the IL-1 stimulation. However, the basal activity of TRE was found to be essential to the stromelysin induction, since (i) mesangial cells stably expressing a transdominant negative mutant of c-Jun, which effectively suppressed both basal and inducible TRE activity, exhibited the blunted expression of stromelysin in response to IL-1 beta, whereas (ii) transfection with a c-fos antisense gene, which suppressed only the inducible TRE activity, did not affect the stromelysin induction. To seek cooperative pathways required for the IL-1 action, we next focused on protein kinases, the potential regulators of the stromelysin gene. Stimulation of mesangial cells with a protein kinase C (PKC) activator, phorbol 12-myristate 13-acetate (PMA), induced the stromelysin transcript without affecting TRE activity. Depletion of intracellular PKC by high-dose PMA or inhibition of PKC activity with calphostin C suppressed the stromelysin induction by IL-1 beta, suggesting the crucial contribution of a PKC-mediated, but TRE-independent pathway. In contrast, either cAMP inducer forskolin or dibutyryl cAMP suppressed the IL-1-mediated stromelysin expression. An inhibitor of cAMP-dependent protein kinase A (PKA), HA1004, enhanced the IL-1 effect in a dose-dependent manner. Unexpectedly, the inhibitory action of PKA was not through cAMP response element (CRE) but through TRE, because (i) activation of CRE was not induced by IL-1 beta, and (ii) cAMP-mediated activation of PKA suppressed the basal TRE activity. These findings elucidated the unique, binary regulation of stromelysin by IL-1 beta; that is, IL-1 up-regulated the transcript via the PKC-dependent pathway under the cooperation with constitutively active TRE, and this stimulatory effect was in part counterbalanced by the IL-1-inducible PKA which down-regulated the basal TRE activity.
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PMID:Opposite, binary regulatory pathways involved in IL-1-mediated stromelysin gene expression in rat mesangial cells. 887 64

Regulation of two genes involved in tumor invasion, the matrix metalloproteinase (MMP)-1 and the tissue inhibitor of MMP (TIMP)-1, by activators of protein kinase C (PKC) or protein kinase A (PKA) was studied in MCF-7 mammary adenocarcinoma cells. The basal mRNA expression was undetectable for MMP-1 and low for TIMP-1. Treatment of MCF-7 cells with the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) (100 nM) was associated with a high expression of MMP-1 mRNA, as well as an induction of the level of TIMP-1 mRNA (5- to 10-fold). In the presence of actinomycin D (AMD, 4.0 microM), an inhibitor of transcription, these stimulatory effects of TPA were abolished. Similar responses were observed when protein synthesis was inhibited by cycloheximide (CHX, 50 microM). In the presence of the cyclic AMP (cAMP) analogue N6-benzoyl (N6-Bzl)-cAMP (500 microM), the MMP-1 mRNA was unaffected and still below the level of detection, whereas a non-significant increase (< 2-fold) in TIMP-1 mRNA was observed. The level of pS2 mRNA, of which the induction by TPA in MCF-7 cells is a primary transcriptional event, was up-regulated (10- to 15-fold) by TPA (100 nM), whereas a much weaker increase (2- to 3-fold) was observed by treatment with N6-Bzl-cAMP (500 microM). Again, these stimulatory effects were counteracted by AMD (4.0 microM) and CHX (50 microM). These data suggest that activation of PKC but not of PKA may induce transcription of MMP-1 and TIMP-1, possibly by the synthesis of transcription factor(s), in transformed cells of epithelial origin.
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PMID:Regulation of matrix metalloproteinase-1 and tissue inhibitor of metalloproteinase-1 in MCF-7 cells: comparison with regulatory mechanisms of pS2 expression. 887 12


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