Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.17 (MMP-3)
 3,419 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To investigate the role of the gp140trk receptor tyrosine kinase in nerve growth factor (NGF)-induced differentiation, we have overexpressed gp140trk in the NGF-responsive PC12 cell line. Here we demonstrate that overexpression of gp140trk results in marked changes in NGF-induced differentiation. Whereas PC12 cells elaborated neurites after 2 days of continuous exposure to NGF, PC12 cells overexpressing gp140trk by 20-fold(trk-PC12) began this process within hours. Compared with wild-type PC12 cells, trk-PC12 exhibited an increase in both high and low affinity NGF-binding sites. Furthermore, trk-PC12 cells displayed an enhanced level of NGF-dependent gp140trk autophosphorylation, and this activity was sustained for many hours following ligand binding. The tyrosine phosphorylation or activity of several cellular proteins, such as PLC-gamma 1, PI-3 kinase, and Erk1 and the expression of the mRNA for the late response gene transin were also sustained as a consequence of gp140trk overexpression. The data indicate that overexpression of gp140trk in PC12 cells markedly accelerates NGF-induced differentiation pathways, possibly through the elevation of gp140trk tyrosine kinase activity.
 ...
PMID:Overexpression of the trk tyrosine kinase rapidly accelerates nerve growth factor-induced differentiation. 138 75

In previous work, we found that nerve growth factor (NGF) induced expression of the mRNA transcript encoding the metalloproteinase transin/stromelysin in PC12 cells. Transin was found, moreover, to be a "late" gene product whose expression correlated with neurites extension. In this study, various aspects of the NGF intracellular signaling pathway in PC12 cells are investigated. We show that the protein kinase inhibitor staurosporine, but not various other kinase inhibitors, specifically blocked the NGF induction of transin. Preliminary characterization of this staurosporine-sensitive kinase suggest that it does not correspond to a tyrosine kinase, nor various serine kinases, and that it is involved both at the transcriptional and posttranscriptional levels of transin gene regulation. In contrast to these effects of staurosporine, various activators of protein kinases C and A augmented the NGF induction of transin. Similar effects of these kinase inhibitors and activators were also observed with the expression of various immediate-early genes that have been proposed to mediate the transcriptional effects of NGF, including c-fos and c-jun. These data suggest, therefore, that the NGF induction of transin mRNA expression involves multiple protein kinases acting at a number of postreceptor regulatory steps in the NGF signaling pathway.
 ...
PMID:NGF-induction of the metalloproteinase-transin/stromelysin in PC12 cells: involvement of multiple protein kinases. 190 68

The neuron-like differentiation of PC12 cells is induced by nerve growth factor (NGF) through stimulation of a membrane-bound protooncoprotein signaling pathway containing the NGF receptor Trk, the tyrosine kinase Src, and the GTP-binding protein Ras. The Raf-1 and B-raf protooncogenes encode cytoplasmic serine/threonine kinases that are stimulated by NGF in a Ras-dependent manner. To investigate the possible roles of cytoplasmic Raf kinases in eliciting neuronal differentiation, we have expressed the activated Raf-1 oncogene in PC12 cells. Expression of the raf oncogene results in the elaboration of a neuron-like phenotype, including neurite growth and the induction of the NGF-responsive genes NGFI-A and transin. The actions of activated Raf-1 and NGF are not additive. Furthermore, activated Raf-1 oncoprotein can prime cells for transcription-independent neurite growth by NGF and can elicit rapid neurite growth from NGF-primed cells. Our data indicate that the pathways utilized by NGF and activated raf to effect PC12 differentiation overlap and lead to the suggestion that cellular raf kinase activities play significant roles in transducing the differentiating signals of neuronal growth factors.
 ...
PMID:The cytoplasmic raf oncogene induces a neuronal phenotype in PC12 cells: a potential role for cellular raf kinases in neuronal growth factor signal transduction. 838 63

Matrix metalloproteinases participate in normal physiologic processes; however, their overproduction has been associated with connective tissue destruction in a variety of pathological states. Migrating basal keratinocytes transiently express collagenase-1 during normal cutaneous reepithelialization. However, the overexpression of both collagenase-1 and stromelysin-1 has been associated with the pathogenesis of chronic nonhealing ulcers. Aberrant expression of metalloproteinases in inflammation is mediated, at least in part, by soluble factors. Since hepatocyte growth factor/scatter factor (HGF/SF) has been reported to promote keratinocyte migration and proliferation, key events in wound repair, and since HGF/SF is produced by dermal fibroblasts and its c-Met receptor is expressed by basal keratinocytes in wounded skin, we have studied the effects of HGF/SF upon keratinocyte metalloproteinase expression. We have found that HGF/SF can stimulate keratinocyte collagenase-1 and stromelysin-1 production in a dose-dependent and matrix-dependent manner. Expression of 92-kDa gelatinase was not affected by HGF/SF. We determined that HGF/SF regulation of collagenase-1 expression is transcriptionally mediated and requires tyrosine kinase and protein kinase C activaties. HGF/NK1, a naturally occurring, truncated form of HGF/SF, also stimulates collagenase-1 production, but much less efficiently than does the parent molecule. However, HGF/NK2, another HGF/SF splice variant, as well as heparin, potently inhibit HGF/SF-induced collagenase-1 synthesis. These results indicate that HGF/SF and its naturally occurring splice variants have diverse biological effects on keratinocytes and suggest an additional mechanism whereby HGF/SF may regulate keratinocyte function during wound repair.
 ...
PMID:Mechanisms of hepatocyte growth factor stimulation of keratinocyte metalloproteinase production. 879 21

We found that pyrrolidine dithiocarbamate (PDTC) induces the matrix metalloproteinase stromelysin in cultured glomerular mesangial cells. Although PDTC is a well-known inhibitor of nuclear factor-kappa B (NF-kappa B), this effect was independent of the NF-kappa B activity, since overexpression of a dominant negative mutant of p50 NF-kappa B subunit repressed activity of the kappa B site, whereas it failed to induce stromelysin. To elucidate the intracellular mechanisms involved, we focused on the role of activator protein 1 (AP-1), since its binding site, the 12-O-tetradecanoylphorbol 13-acetate (TPA) response element (TRE), is located in the 5'-flanking region of the stromelysin gene. Northern blot analysis revealed that PDTC upregulated expression of c-jun and c-fos before the expression of stromelysin. Transient transfection studies using a TRE-LacZ reporter plasmid elucidated that activity of AP-1 was significantly increased by PDTC. Stable transfection with a c-jun antisense cDNA or pretreatment with curcumin, a pharmacological inhibitor of c-Jun/AP-1, revealed that inactivation of AP-1 diminished the induction of stromelysin by PDTC. To identify the machinery involved upstream of AP-1 activation, the role of tyrosine kinases was investigated. Western blot analysis showed that PDTC induced phosphorylation of tyrosine kinases. Treatment of mesangial cells with tyrosine kinase inhibitors suppressed activation of AP-1 as well as induction of stromelysin by PDTC. These findings demonstrate that the antioxidant PDTC induces stromelysin expression via stimulation of the tyrosine kinase-AP-1 pathway independent of its suppressive action on NF-kappa B.
 ...
PMID:Antioxidant PDTC induces stromelysin expression in mesangial cells via a tyrosine kinase-AP-1 pathway. 892 42

IL-17 is a newly described, T cell-derived cytokine with ill-defined physiologic properties. As such, we examined the release of proinflammatory mediators by human macrophages in response to recombinant human (rh) IL-17. IL-1beta and TNF-alpha expression and synthesis were up-regulated by rhIL-17 in a dose (ED50 was 50 +/- 9 ng/ml)- and time-dependent fashion, with cytokine accumulation reaching a zenith after 9 h. Release of IL-6, PGE2, IL-10, IL-12, IL-1R antagonist, and stromelysin was also stimulated by rhIL-17. IL-1beta and TNF-alpha mRNA expression levels were controlled by rhIL-17 in a complex manner with an initial 30-min inhibitory phase, and then up-regulation beginning at 1 h and reaching a plateau at about 3 h. The latter expression pattern closely mirrored the nuclear accumulation of the transcription factor nuclear factor-kappaB. cAMP mimetics isobutyl-1-methylxanthine (IBMX), forskolin, PGE2, and cholera toxin reversed rhIL-17-induced release of TNF-alpha, but had no consistent effect on induced IL-1beta synthesis. Induced release of TNF-alpha was also inhibited by serine/threonine protein kinase inhibitors KT-5720 (protein kinase A) and Calphostin C (protein kinase C), mitogen-activated protein kinase kinase inhibitor PD098059, and a nonspecific tyrosine kinase inhibitor, genistein. Calphostin C alone abrogated the rhIL-17-induced release of IL-1beta. The antiinflammatory cytokines IL-4 (p < 0.01) and IL-10 (p < 0.02) completely reversed rhIL-17-stimulated IL-1beta release, while IL-13 and TGF-beta2 were partially effective (59 and 43% diminution, respectively). IL-10 exerted a significant suppressive effect on IL-17-induced TNF-alpha release (99%, p < 0.02), while the inhibitory effects of IL-4, IL-13, and TGF-beta2 on TNF-alpha secretion were partial (48, 10, and 23%, respectively). The data suggest a pivotal role for IL-17 in initiating and/or sustaining an inflammatory response.
 ...
PMID:IL-17 stimulates the production and expression of proinflammatory cytokines, IL-beta and TNF-alpha, by human macrophages. 953 13

Neutral matrix metalloproteinases (MMPs) are responsible for the pathological features of rheumatoid arthritis (RA) such as degradation of cartilage. We herein show the up-regulation of MMP-1 (interstitial collagenase) and MMP-3 (stromelysin) mRNAs of cultured synovial fibroblasts retrieved from rheumatoid arthritis (RA) patients in response to macrophage migration inhibitory factor (MIF). The elevation of MMP-1 and MMP-3 mRNA was dose-dependent and started at 6 h post-stimulation by MIF, reached the maximum level at 24 h, and was sustained at least up to 36 h. Interleukin (IL)-1beta mRNA was also up-regulated by MIF. These events were preceded by up-regulation of c-jun and c-fos mRNA. Tissue inhibitor of metalloproteinase (TIMP)-1, a common inhibitor of these proteases, was slightly up-regulated by MIF. Similarly, mRNA up-regulation of MMP-1 and MMP-3 was observed in the synovial fibroblasts of patients with osteoarthritis. However, their expression levels were much lower than those of RA synovial fibroblasts. The mRNA up-regulation by MIF was inhibited by the tyrosine kinase inhibitors genestein and herbimycin A, as well as the protein kinase C inhibitors staurosporine and H-7. On the other hand, the inhibition was not seen after the addition of the cyclic AMP-dependent kinase inhibitor, H-8. The mRNA up-regulation of MMPs was also inhibited by curcumin, an inhibitor of transcription factor AP-1, whereas interleukin-1 receptor antagonist, an IL-1 receptor antagonist, failed to inhibit the mRNA up-regulation. Considering these results, it is suggested that 1) MIF plays an important role in the tissue destruction of rheumatoid joints via induction of the proteinases, and 2) MIF up-regulates MMP-1 and MMP-3 via tyrosine kinase-, protein kinase C-, and AP-1- dependent pathways, bypassing IL-1beta signal transduction.
 ...
PMID:Macrophage migration inhibitory factor up-regulates expression of matrix metalloproteinases in synovial fibroblasts of rheumatoid arthritis. 1061 37

Periodontitis is associated with enhanced production of cytokines, prostaglandins and matrix metalloproteinases (MMPs). The aim of this study was to investigate the production and regulation of MMP-1 and MMP-3 in human gingival fibroblasts challenged with the cytokines interleukin-lbeta (IL-1beta), tumor necrosis factor alpha (TNFalpha) or epidermal growth factor (EGF). The results showed that gingival fibroblasts constitutively produce MMP-1 and MMP-3, and that the cytokines IL-1beta, TNFalpha and EGF increase both MMP-1 and MMP-3 production in gingival fibroblasts. The upregulation by the cytokines was apparent at 8 h of incubation and increased thereafter continuously during 48 h of incubation. The upregulation of MMPs, induced by IL-1beta or TNFalpha, was reduced by the cyxlooxygenase-2 (COX-2) inhibitor NS-398, the p38 MAP-kinase inhibitor SB 203580, and the tyrosine kinase inhibitor herbimycin A. In addition, MMP-1 and MMP-3 production, induced by IL-1beta, TNFalpha or EGF, was strongly reduced by the presence of the glucocorticoid dexamethasone. Our findings demonstrate that the cytokines IL-1beta, TNFalpha and EGF, respectively, enhance both MMP-1 and MMP-3 production in human gingival fibroblasts, and that the signal pathways COX-2, MAP-kinases and tyrosine kinases are partly involved in the production of MMPs.
 ...
PMID:Signal pathways involved in the production of MMP-1 and MMP-3 in human gingival fibroblasts. 1220 92

Background/AIMS: Hepatic stellate cells (HSCs) play a key role in the production and degradation of extracellular matrix (ECM) in the liver. In the present study, we investigated the interaction between ECM and HSCs in vitro with emphasis on the modulation of matrix metalloproteinases (MMPs) by ECM. METHODS: Freshly isolated rat HSCs were cultured in several conditions on type I collagen- or matrigel-coated dishes, on thick matrigel or in three-dimensional type I collagen (3D-gel), and MMPs expression in HSCs was examined. In addition, activation and signaling pathway of MMP-9 expression modulated by 3D-gel in HSCs were examined. RESULTS: Increased expression of MMP-3, -9, -13 and -14 was markedly detected only in the 3D-gel-treated HSCs. Zymography demonstrated that only 3D-gel-treated cells showed active gelatinase activity of MMP-9 at 82 kDa. MMP-9 expression was inhibited by neutralizing antibody against integrin alpha2beta1, tyrosine kinase inhibitors, or MEK1,2 inhibitor PD 98059, but not by p38 inhibitor SB 203580. Western blotting also showed phosphorylated p38, ERK1,2, and JUN/SAPK was quickly induced in HSCs by 3D-gel. CONCLUSIONS: MMP-9 expression and activation is induced in HSCs by 3D-gel and this observed collagen-dependent induction of MMP-9 requires ERK1,2 activity.
 ...
PMID:Modulation of matrix metalloproteinase-9 in hepatic stellate cells by three-dimensional type I collagen: its activation and signaling pathway. 1296 32

Progesterone-induced decidualized human endometrial stromal cells form a hemostatic envelope that protects against hemorrhage during invasion of endometrial capillaries by implanting blastocyst-derived cytotrophoblasts (CTs). This hemostatic milieu reflects co-upregulated expression of tissue factor (TF), the primary initiator of hemostasis via thrombin generation and plasminogen activator inhibitor type 1, which inactivates tissue-type plasminogen activator, the primary fibrinolytic agent. During deep invasion of the decidua, CTs breach and remodel spiral arteries and arterioles to produce high-conductance vessels. Shallow invasion results in incomplete vascular transformation and an underperfused fetal - placental unit associated with preeclampsia and intrauterine growth restriction. Decidual hemorrhage and severe thrombophilias elicit aberrant thrombin generation from decidual cell-expressed TF. Such thrombin induces decidual cells to synthesize and secrete soluble fms-like tyrosine kinase-1 (sFlt-1), the matrix metalloproteinases MMP-1 and MMP-3, and the neutrophil chemoattractant interleukin-8. Excess sFlt-1 at the implantation site may inhibit CT invasion by altering the angiogenic factor balance. During abruptions, thrombin-enhanced MMP-1, MMP-3 by decidual cells and neutrophil-derived proteases degrade the decidual and fetal membrane extracellular matrix to promote preterm premature rupture of the membranes. In association with long-term progestin-only contraception, overexpression of decidual cell-derived thrombin promotes aberrant angiogenesis and vessel maintenance to contribute to abnormal uterine bleeding.
 ...
PMID:The role of decidualization in regulating endometrial hemostasis during the menstrual cycle, gestation, and in pathological states. 1725 97


1 2 Next >>