Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.11.18 (MAP)
 7,412 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

EMMPRIN (extracellular matrix metalloproteinase inducer) stimulates fibroblast metalloproteinases (MMP) 1, 2 and 3 (Kataoka et al. (1993) Cancer Res. 53, 3154-3158). Here we focus on MMP-1, showing that in lung tumors, MMP-1's cognate mRNA is strongly expressed in stromal fibroblasts adjacent to EMMPRIN-expressing tumor cells. In vitro, EMMPRIN upregulates MMP-1 mRNA expression in a concentration-dependent manner, with a peak accumulation at 24 h. The response is genistein-sensitive, suggesting it is dependent on tyrosine kinase activity. Analysis of tyrosine phosphorylation-dependent MAP kinases ERK 1/2, SAPK/JNK, and p38 showed that the activity of p38 but not that of the other 2 kinases was elevated in response to EMMPRIN. That p38 activity was required for EMMPRIN stimulation of MMP-1 was evident from results showing that the p38 inhibitor SB203580 blocked this response. This is the first available information regarding the mechanism by which tumor-associated molecules upregulate MMP synthesis in stromal fibroblasts.
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PMID:Tumor-derived EMMPRIN (extracellular matrix metalloproteinase inducer) stimulates collagenase transcription through MAPK p38. 987 71

In this study, we show that the ETS transcription factor ER81 directly binds to and activates the promoter of the matrix metalloproteinase gene, MMP-1. Further, the oncoprotein HER2/Neu synergizes with ER81 to stimulate MMP-1 transcription. The activation of ER81 by HER2/Neu is mediated by MAP kinases, which phosphorylate ER81 in its N-terminal activation domain. Four respective phosphorylation sites have been identified. Blocking phosphorylation at these sites decreases ER81 transcriptional activity, which can be further diminished by abolishment of phosphorylation at two non-MAP kinase sites. Altogether, our results reveal mechanisms of how phosphorylation of ER81 regulates the expression of target genes such as MMP-1, which may be important for many physiological processes from embryogenesis to adulthood as well as for tumor metastasis.
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PMID:HER2/Neu-mediated activation of the ETS transcription factor ER81 and its target gene MMP-1. 1159 30

The aim of the work was to analyze, on a comparative basis, the signaling pathways operating in the regulation of a panel of matrix metalloproteinases (MMP) expressed by human dermal fibroblasts submitted to mechanical stress relaxation by cytochalasin D (CD) and in a retracting collagen gel (RCG). The mRNA steady-state level of MMPs was measured by a quantitative RT-PCR procedure using a synthetic RNA as internal standard. In monolayer, most MMPs were barely detected, except MMP-2. Disruption of the actin stress fibers by CD induced a moderate increase of MMP-2 mRNA and a much larger stimulation of MMP-3, -9, -13 and -14 mRNAs. In RCG, a significant up-regulation of these MMPs was also observed although to a lower extent than in CD-treated monolayers. Among the investigated MMPs, the MMP-8 and -11 were not reproducibly detected. MMP-2 was processed to its active form both by CD and in RCG. The CD-induced up-regulation of gene expression was largely repressed by blocking protein synthesis by cycloheximide for all the MMPs, by inhibiting the tyrosine-kinases of the src family by herbimycin A for all MMPs, except MMP-2, and by inhibiting the TPA-inducible PKC isoforms by bisindoyl maleimide for all MMPs, except MMP-14. The up-regulation induced by stress relaxation in RCG was protein synthesis-dependent for MMP-2 and MMP-13, tyrosine kinases-dependent for MMP-3 and MMP-13, as previously described for MMP-1. Inhibiting TPA-inducible PKC did not affect any MMP in RCG except MMP-13, which was strongly induced. The processing of MMP-2 was tyrosine kinases-dependent but PKC-independent. Inhibitors of the ERK1,2 and p38 MAP kinases pathways diversely affected the MMPs expression. Inhibiting the Rho-kinase activity by Y-27632 was inactive. These results point to the potent regulation operated by the status of the cytoskeleton on the cell phenotype, and to distinct regulatory pathways involved in the control of different MMPs expression.
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PMID:Distinct pathways in the over-expression of matrix metalloproteinases in human fibroblasts by relaxation of mechanical tension. 1169 80

A lot of parallels have been described between invasion of malignant tumor cells and leukocyte movement during inflammatory responses. Concerning these similarities, we investigated the function of cytokine-suppressive anti-inflammatory drugs (CSAIDs), which act via inhibition of stress-activated MAP-kinases, in regulation of expression of proteolytic enzymes and in vitro invasion of malignant melanoma cells. The p38MAPK inhibitor SB203580 reduced matrigel invasion of MeWo cells by 60%, while the MEK-1 inhibitor PD98059 did not have any effect on invasion. Active p38MAPK was detected in MeWo cells by immunoblotting and confocal microscopy. Cells showed a constitutive expression of matrix-metalloproteinase (MMP)-2 as well as tissue inhibitor of metalloproteinases (TIMP)-1 and TIMP-2 mRNAs. Expression of MMP-1 or urokinase-type plasminogen activator (uPA) was not detected by Northern blot. Inhibition of p38MAPK by the specific inhibitor SB203580 resulted in downregulation of MMP-2 mRNA and protein levels as well as gelatinolytic activity, while expression levels of TIMP-1 and TIMP-2 mRNAs were not changed. The specific MEK-1 inhibitor PD98059 did not change expression of MMP-2 or TIMPs. Neither SB203580 nor PD98059 changed proliferation of cells. The results suggest that stress-activated protein kinases like p38MAPK are involved in regulation of expression of MMP-2 as well as in vitro invasion of malignant melanoma cells. Inhibitors of p38MAPK may be promising substances to interfere with a signaling cascade associated with invasion of malignant tumor cells.
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PMID:An inhibitor of stress-activated MAP-kinases reduces invasion and MMP-2 expression of malignant melanoma cells. 1191 86

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.
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PMID:Signal pathways involved in the production of MMP-1 and MMP-3 in human gingival fibroblasts. 1220 92

Statins inhibit HMG-CoA reductase and thus block cholesterol and isoprenoid biosynthesis. Since statins also have anti-inflammatory effects, we investigated the effect of fluvastatin on monocyte Fcgamma receptor function. Fluvastatin (0.5-20 microM) inhibited Fcgamma receptor signal transduction at the level of tyrosine kinase activation, in a time and dose dependent manner. Initiation of tyrosine phosphorylation is not thought to involve prenylated proteins; thus, we hypothesised that fluvastatin might disrupt cholesterol and sphingolipid membrane rafts to impair signalling. Consistent with this hypothesis, fluvastatin decreased (and mevalonate rescued) signalling molecules within membrane rafts in parallel with effects on tyrosine phosphorylation events. Raft integrity was unaffected by prenyl transferase inhibitors. In addition, Fcgamma receptor mediated immune complex trafficking, activation of MAP kinases (ERK and p38), and downstream inflammatory mediator release (MMP-1 and IL-6) were blocked by fluvastatin. Thus, HMG-CoA reductase inhibition alters immune receptor signalling by disrupting membrane rafts essential for the initiation of signal transduction. Inhibition of Fcgamma receptor function may limit development and progression of atherosclerosis by decreasing monocyte/macrophage inflammatory mediator release. Since many receptors utilise cholesterol rich rafts this mechanism may have broader significance given the pleiotropic effects of statins.
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PMID:Fluvastatin inhibits raft dependent Fcgamma receptor signalling in human monocytes. 1501 31

Retinoic acid and its synthetic analogs exert major effects on many biological processes including cell proliferation and differentiation and are now considered as promising pharmacological agents for prevention and treatment of various cancers. The capacity of retinoids to inhibit AP1-responsive genes seems to be the basis for the chemopreventive and chemotherapeutic effects of these agents against hyperproliferative diseases. However, the molecular basis of retinoid antiproliferative properties remains to this day largely unknown. Here, we showed that retinoids inhibit phorbol ester-induced MMP-1 and MMP-3 expression in human breast cancer cells. Transcriptional interference was observed for both retinoid agonist and antagonist treatments, revealing separated transactivation and transrepression functions of retinoids. In addition, we examined MAP kinases as potential targets of retinoid signalling in human breast cancer cells and demonstrated that retinoids repress AP1-responsive gene expression by inhibiting MKK6/p38 and mainly MEK/ERK signalling pathways. On the contrary, the JNK-dependent pathway was not identified as a molecular relay for AP1 activity and was insensitive to retinoid treatments. Finally, we established that overexpressed c-fos and c-jun partially abolished the ability of retinoids to inhibit AP1 activity, suggesting that c-jun and/or c-fos containing dimers may constitute one target of retinoids for transrepression of AP1. All together, our data help to improve our understanding of how retinoids antagonize AP1 activity and may regulate tumoral cell proliferation.
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PMID:Retinoids interfere with the AP1 signalling pathway in human breast cancer cells. 1617 68

Many age-associated degenerative diseases commonly involve degradation of the extracellular matrix and aberrant matrix metalloproteinase-1 (MMP-1) expression. In diverse cell lines MMP-1 or interstitial collagenase (CL) expression is tightly regulated through a network of signals involving reactive oxygen species (ROS). However, whether the in vivo age-associated increase in CL expression is also sensitive to ROS-mediated signaling has not been established. To evaluate the contribution of ROS to the age-dependent increase in CL we monitored the levels of murine CL in two well-established models of oxidant stress. Analysis of murine CL levels in mice deficient in either of the intracellular superoxide dismutases (Sod2(+/-) or Sod1(-/-)) revealed its age- and redox-dependent expression relative to WT controls. Both age- and redox-dependent increases in murine CL expression were associated with elevations in phosphorylation of the MAP Kinases, Erk, JNK and p38. CL expression was highest in renal and skeletal muscle tissue from the aged Sod1(-/-) mice and was associated with a decrease in collagen staining. These findings suggest that MAPK signaling and CL production are both age- and redox-responsive. The redox sensitivity of age-associated CL expression suggests that degenerative disease associated with aberrant matrix remodeling and oxidant stress may be amenable to antioxidant-based therapies.
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PMID:Age-dependent increases in interstitial collagenase and MAP Kinase levels are exacerbated by superoxide dismutase deficiencies. 1940 72

Toll-like receptors (TLRs) on epidermal keratinocytes are the first line of defense against microbe invasion, and matrix metalloproteases (MMPs) regulate inflammation, cell migration and wound healing. In this study, we demonstrate that the mRNA and protein expressions of MMP-1 and MMP-9 in human epidermal keratinocytes are induced by ligands for TLR2, TLR3 and TLR5 [Pam3CSK4, Poly(I:C) and flagellin, respectively] in a dose-dependent manner. We also found that the ligands for TLR2, TLR3 and TLR5 activate the MAP kinases, JNK and p38 MAPK, but not ERK1/2. Furthermore, treatment with the ligands for TLR2, TLR3 and TLR5 also induced the degradation of IkappaB-alpha and activated the nuclear translocation of NF-kappaB. MMP-1 induction by the ligands for TLR2, TLR3 and TLR5 was inhibited by pretreatment with BAY11-7082 (NF-kappaB inhibitor) or SP600125 (JNK inhibitor), whereas MMP-9 expression was inhibited by pretreatment with BAY11-7082, SP600125 or SB203580. These findings demonstrate that the activation of TLR2, TLR3 or TLR5 induces the expression of MMP-1 and MMP-9 in human epidermal keratinocytes. In addition, NF-kappaB or JNK mediated the MMP-1 expression induced by TLR2, TLR3 and TLR5, whereas NF-kappaB, JNK or p38 MAPK mediated the MMP-9 expression induced by TLR2, TLR3 and TLR5.
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PMID:Activation of toll-like receptors 2, 3 or 5 induces matrix metalloproteinase-1 and -9 expression with the involvement of MAPKs and NF-kappaB in human epidermal keratinocytes. 1975 22

Prostaglandin E2 (PGE2) is one of pro-inflammatory mediators. PGE2 maintains the homeostasis of many organs including articular cartilage, and a previous report showed that continuous inhibition of PGE2 accelerates the progression of osteoarthritis (OA). While PGE2 inhibits matrix metalloprotease (MMP) expression in several types of cells, little is known on direct effects of PGE2 on MMP expression in articular chondrocytes. The objective of this study was to investigate direct effects of PGE2 on IL-1beta-induced MMP-1 and MMP-13 expression and the intracellular signaling in articular chondrocytes. PGE2 showed inhibitory effects on IL-1beta-induced MMP-1 and MMP-13 expression demonstrated by immunoblotting both in OA and normal chondrocytes, which was further confirmed by enzyme-linked immunosorbent assay and immunohistochemistry of explant cultures of articular cartilages. An EP4 agonist, ONO-AE1-329, mimicked the inhibitory effect of PGE2, while an EP4 antagonist, ONO-AE3-208, blocked the effects. PGE2 suppressed the phosphorylation of JNK and ERK MAP kinases, but only knockdown of JNK by specific siRNA mimicked the effect of PGE2. PGE2 further inhibited the phosphorylation of MKK4 without suppression of MKK7 phosphorylation, and of c-JUN to decrease expression levels of MMP-1 and MMP-13. These results demonstrate that PGE2 inhibits IL-1beta-induced MMP-1 and MMP-13 productions via EP4 by suppressing MKK4-JNK MAP kinase-c-JUN pathway.
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PMID:PGE2 inhibits MMP expression by suppressing MKK4-JNK MAP kinase-c-JUN pathway via EP4 in human articular chondrocytes. 1999 10


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