EC:2.7.11.24 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.24 (mitogen-activated protein kinase)
95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Matrix metalloproteinase (MMP)-7 (matrilysin-1) plays significant roles in the growth, invasion, and metastasis of colorectal tumors, while (-)-epigallocatechin-3-gallate (EGCG), a green tea polyphenol with chemopreventive properties, has been shown to be an inhibitor of MMP-2 and MMP-9. In the present study, HT-29 human colorectal cancer cells were treated with EGCG to examine its effects on pro-MMP-7 induction and production using RT-PCR and western blot analyses. Surprisingly, EGCG (10-100 microM) treatment increased both intracellular and extracellular pro-MMP-7 protein levels (2.6-8.4-fold and 1.9-6.4-fold, respectively) in dose- and time-dependent manner, with a significant upregulation of its mRNA expression. EGCG also activated extracellular signal-regulated protein kinase (ERK)1/2, c-JUN NH2-terminal kinase (JNK)1/2 and p38 mitogen-activated protein kinase (MAPK), as previously reported. In addition, the polyphenol triggered the phosphorylation of c-JUN (Ser63 and Ser73) and induced c-JUN/c-FOS, thereby increasing the DNA binding activity of activator protein-1 (AP-1), as shown by an AP-1 luciferase reporter assay. Pharmacological blockade of MAPK activities suggested that pro-MMP-7 expression was induced via JNK1/2 activation, but not in the case of ERK1/2 or p38 MAPK. N-Acetyl-L-cysteine, superoxide (O2-) dismutase and catalase attenuated the EGCG-induced pro-MMP-7 production, suggesting an involvement of oxidative stress in these events. Conversely, EGCG spontaneously generated O2- in a cell-free system that utilized a cytochrome C reduction method. Further, (-)-epicatechin-3-gallate (25 and 100 microM) and green tea polyphenols (33 and 132 microg/ml) induced pro-MMP-7 expression, whereas (-)-epicatechin and (-)-epigallocatechin (100 microM each) did not. Induction of pro-MMP-7 expression by EGCG was also shown in another human colorectal adenocarcinoma cell line, Caco-2. Our results suggest that some green tea catechins induce pro-MMP-7 production via O2- production and the activation of JNK1/2, c-JUN, c-FOS and AP-1 in HT-29 cells.
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PMID:(-)-Epigallocatechin-3-gallate promotes pro-matrix metalloproteinase-7 production via activation of the JNK1/2 pathway in HT-29 human colorectal cancer cells. 1586 May 7

Lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P) are both low-molecular-weight lysophospholipids, which promote cell proliferation, migration, and invasion via interaction with a family of specific G protein-coupled receptors. Matrix metalloproteinases (MMPs) are zinc-dependent proteolytic enzymes, which are involved in degradation of the extracellular matrix and play critical roles in endothelial cell migration and matrix remodeling during angiogenesis. Among these MMPs, MMP-2 is known to trigger cell migration. In our present study, we examined the effects of LPA and S1P on MMP-2 expression in human endothelial cells. We showed that LPA and S1P enhanced MMP-2 expression in mRNA, protein levels, and also enzymatic activity of cells of the EAhy926 human endothelial cell line. The enhancement effects occurred in concentration- and time-dependent manners. Results from real-time PCR, Western blots, and substrate gels indicated that these enhancement effects were mediated through MAPK kinase/ERK-, nuclear factor-kappaB-, and calcium influx-dependent pathways. Furthermore, we show that endothelial cell invasion of the gel was enhanced by lysophospholipids, and the induction could be prevented by an MMP inhibitor, GM6001. These observations suggest that LPA and S1P may play important roles in endothelial cell invasion by regulating the expression of MMP-2.
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PMID:Lysophospholipids enhance matrix metalloproteinase-2 expression in human endothelial cells. 1587 67

WAVE3 is a member of the WASP/WAVE family of proteins, which play a critical role in the regulation of actin polymerization, cytoskeleton organization, and cell motility. We show here that knockdown of the WAVE3 protein, using RNA interference in MDA-MB-231 cells, decreases phospho-p38 MAPK levels, but not those of phospho-AKT, phospho-ERK, or phospho-JNK. Knockdown of WAVE3 expression also inhibited the expression levels of MMP-1, MMP-3, and MMP-9, but not MMP-2. MMP production could be restored by PMA treatment, without affecting siRNA-mediated WAVE3 knockdown. The WAVE3-mediated downregulation of p38 activity and MMP production is independent of the presence of both WAVE1 and WAVE2, whose expression levels were not affected by loss of WAVE3. We also show that the downstream effect of the WAVE3 knockdown is the inhibition of cell motility and invasion, coupled with increased actin stress fiber formation, as well as reorganization of focal adhesion complexes. These findings suggest that WAVE3 regulates actin cytoskeleton, cell motility, and invasion through the p38 MAPK pathway and MMP production.
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PMID:WAVE3 promotes cell motility and invasion through the regulation of MMP-1, MMP-3, and MMP-9 expression. 1590 37

Accumulating evidence suggests that high concentrations of leptin observed in obesity and diabetes may contribute to their adverse effects on cardiovascular health. Metformin monotherapy is associated with reduced macrovascular complications in overweight patients with type 2 diabetes. It is uncertain whether such improvement in the cardiovascular outcome is related to specific vasculoprotective effects of this drug. In the present study, we determined the effect of leptin on human aortic smooth muscle cell (HASMC) proliferation and matrix metalloproteinase (MMP)-2 expression, the signaling pathways mediating these effects, and the modulatory effect of metformin on these parameters. Incubation of HASMCs with leptin enhanced the proliferation and MMP-2 expression in these cells and increased the generation of intracellular reactive oxygen species (ROS). These effects were abolished by vitamin E. Inhibition of NAD(P)H oxidase and protein kinase C (PKC) suppressed the effect of leptin on ROS production. In HASMCs, leptin induced PKC, extracellular signal-regulated kinase (ERK)1/2, and nuclear factor-kappaB (NF-kappaB) activation and inhibition of these signaling pathways abrogated HASMC proliferation and MMP-2 expression induced by this hormone. Treatment of HASMCs with metformin decreased leptin-induced ROS production and activation of PKC, ERK1/2, and NF-kappaB. Metformin also inhibited the effect of leptin on HASMC proliferation and MMP-2 expression. Overall, these results demonstrate that leptin induced HASMC proliferation and MMP-2 expression through a PKC-dependent activation of NAD(P)H oxidase with subsequent activation of the ERK1/2/NF-kappaB pathways and that therapeutic metformin concentrations effectively inhibit these biological effects. These results suggest a new mechanism by which metformin may improve cardiovascular outcome in patients with diabetes.
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PMID:Signaling pathways involved in human vascular smooth muscle cell proliferation and matrix metalloproteinase-2 expression induced by leptin: inhibitory effect of metformin. 1598 26

Expression of matrix metalloproteinase-2 and -9 (MMP-2 and MMP-9), which correlates with tumor invasion and metastasis, has been known to be regulated by several intracellular signaling pathways. Since the CD9 membrane protein has been implicated in signal transduction and malignant progression of cancer cells, we examined the functional involvement of CD9 in the regulation of MMP-2 and MMP-9 expression by using stable CD9 transfectant clones of MelJuso human melanoma cells. The CD9 cDNA-transfected cells with elevated CD9 expression displayed increased MMP-2 and decreased MMP-9 expression when compared with the mock transfectant cells. Among several signal pathway inhibitors tested, SB203580 and SP600125, which inhibit p38 MAPK and JNK respectively, completely blocked the CD9-stimulated MMP-2 expression. Phosphorylation levels of p38 MAPK and c-Jun in MelJuso cells were also significantly increased by CD9 transfection. In addition, the down-regulation of p38 MAPK and JNK by siRNA transfection resulted in a decrease in MMP-2 expression by MelJuso cells. Promoter analysis and gel shift assay showed that the CD9-induced MMP-2 expression is mediated by a functional AP-1 site through interactions with AP-1 transcription factors including c-Jun. These results suggest that CD9 induces MMP-2 expression by activating c- Jun through p38 MAPK and JNK signaling pathways in human melanoma cells.
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PMID:Tetraspanin CD9 induces MMP-2 expression by activating p38 MAPK, JNK and c-Jun pathways in human melanoma cells. 1600 Aug 78

The homeopathic compound of resonance FMS*Calciumfluor (FMS*) reportedly promotes osteogenic differentiation of rat pre-osteoblasts in vitro. Here, we show that the continuous exposure of differentiating rat osteogenic cells (ROB) to FMS* modulates the level of expression of mRNAs for 7 of the 8 osteogenic markers tested. Alkaline phosphatase (AP), osteocalcin (OC), metalloproteinases (MMP-2 and -14), procollagenase C (BMP-1), biglycan (BG) and integrin 1 are expressed at higher levels in FMS*-treated osteoblasts than in control cultures. MMP-2 and -14 mRNA are not down-modulated at mineralization. Also, the pattern of expression induced by FMS* for some of these genes (BMP-1, BG and integrin 1) is changed, but collagen type I (Coll I) mRNA levels are not affected by treatment with FMS*. This suggests that FMS* modulates mRNA levels and that this is not generalized, but gene(s) specific. We also report that exposure to FMS* rapidly and transiently induces activation of mitogen-activated protein kinases (MAPKs) 42,44 in populations of early osteoblasts, but not in pre-osteoblasts, with a cell differentiation stage-dependent and pertussis toxin (PTX)-sensitive response. Subsequent to FMS* MAPK signaling activation, an increase in AP and MMP-14 mRNA is detected, which is also inhibited by PTX, suggesting that FMS* activation of MAPK signaling could be an early event required for the induction of these genes. Exposure to FMS* does not cause changes in the activity of p125 (FAK)-mediated signaling.
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PMID:FMS*Calciumfluor specifically increases mRNA levels and induces signaling via MAPK 42,44 and not FAK in differentiating rat osteoblasts. 1602 62

Matrix metalloproteinases (MMPs), aldosterone, and reactive oxygen species (ROS) are implicated in myocardial remodeling. Although ROS, cytokines, and neurohormones regulate MMP in cardiac fibroblasts, it is unknown whether aldosterone regulates MMP in cardiomyocytes. Therefore, we tested the hypothesis that aldosterone regulates MMP in cultured adult rat ventricular myocytes (ARVMs). ARVMs were treated with aldosterone for 24 hours, and MMP-2 and MMP-9 activities were measured by zymography. Aldosterone (50 nmol/L) increased MMP-2 (43+/-5%) and MMP-9 (55+/-15%; P<0.001 for both) activities. Pretreatment with spironolactone (100 nmol/L) abolished the aldosterone-induced increase in MMP activities. Aldosterone (50 nmol/L; 30 minutes) increased mitogen/extracellular signal-regulated kinase (MEK) (31+/-3%) and extracellular signal-regulated kinase 1/2 (ERK1/2; 41+/-7%; P<0.001 for both) phosphorylation. U0126 (10 micromol/L), an MEK1/2 inhibitor, abolished the aldosterone-induced increase in MMP activities. Aldosterone increased intracellular ROS as assessed by dichlorofluorescein diacetate (27+/-4%; P<0.05). This increase was inhibited by apocynin, an NADPH oxidase inhibitor. Apocynin likewise inhibited aldosterone-induced ERK1/2 phosphorylation and the increase in MMP activities. Furthermore, the antioxidants MnTMPyP and N-acetylcysteine inhibited the aldosterone-induced increase in ERK1/2 phosphorylation and MMP activities, respectively. Protein kinase C (PKC) is implicated in the nongenomic effects of aldosterone. To test the role of PKC, ARVMs were pretreated with chelerythrine, a PKC inhibitor. Chelerythrine prevented the aldosterone-induced increase in ERK1/2 phosphorylation and MMP activities. Thus, aldosterone induces MMP activity in ARVM via activation of the mineralocorticoid receptor, PKC, and ROS-dependent activation of the MEK/ERK pathway. NADPH oxidase is a likely source of ROS in this system.
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PMID:Aldosterone stimulates matrix metalloproteinases and reactive oxygen species in adult rat ventricular cardiomyocytes. 1604 62

Prostaglandins (PGs) have been implicated in the regulation of intraocular pressure (IOP) by facilitating the remodeling of tissues involved in aqueous humor outflow. A contribution of cyclooxygenase-2 (COX-2)-dependent PGs to this process was emphasized by a recent study showing an impaired COX-2 expression in the nonpigmented ciliary epithelium (NPE) of patients with primary open-angle glaucoma. With the use of human NPE cells (ODM-2), the present study therefore investigated the effect of the antiglaucomatous drug latanoprost (PGF2alpha analog) on the expression of COX-2 and its association with the induction of matrix metalloproteinases (MMPs). In NPE cells, latanoprost led to a concentration- and time-dependent increase of COX-2 mRNA levels. Up-regulation of COX-2 expression was accompanied by phosphorylations of p38 mitogen-activated protein kinase (MAPK) and p42/44 MAPK and was abrogated by specific inhibitors of both pathways. PGE2 formation by latanoprost was abolished by the selective COX-2 inhibitor NS-398 and by the F-prostaglandin receptor antagonist AL-8810. Moreover, latanoprost led to a delayed up-regulation of MMP-1 mRNA, whereas the expression of MMP-2, MMP-9, TIMP-1, and TIMP-2 remained unchanged. Latanoprost-induced MMP-1 mRNA and protein expression was abolished by NS-398 and by COX-2-silencing small-interfering RNA. In line with this finding, MMP-1 expression was also induced by PGE2, a major COX-2 product. As a whole, our results show that MMP-1 expression by latanoprost requires prior up-regulation of COX-2. Induction of COX-2- and subsequent MMP-1 expression in the NPE may represent a potential mechanism underlying the IOP-lowering and antiglaucomatous action of latanoprost.
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PMID:Latanoprost induces matrix metalloproteinase-1 expression in human nonpigmented ciliary epithelial cells through a cyclooxygenase-2-dependent mechanism. 1607 63

Solar UV light comprises UVB wavelengths (290-320 nm) and UVA wavelengths (320-400 nm). UVB radiation reaches the epidermis and, to a lesser extent, the upper part of the dermis, while UVA radiation penetrates more deeply into human skin. Existing studies have demonstrated that UV-irradiated epidermal keratinocytes release cytokines that indirectly promote MMP-1 production in dermal fibroblasts. In this study, we first investigated the effect of IL-1 on MAPK activity, c-Jun and c-Fos mRNA expression, and MMP-1 and MMP-2 production in UVA-irradiated human dermal fibroblasts. The results showed that UVA irradiation dose-dependently increased MMP-1 but not MMP-2 production in human skin fibroblasts. IL-1alpha and IL-1beta promoted MMP-1 but not MMP-2 production in UVA-irradiated fibroblasts. Both IL-1alpha and IL-1beta activated MAP kinase, significantly elevating c-Jun and c-Fos mRNA expression. We then investigated the indirect effect of UVB-irradiated keratinocyte culture medium on MMP-1 production in UVA-irradiated primary cultured human dermal fibroblasts and the effect of IL-1Ra. The results showed that cell culture medium from UVB-irradiated keratinocytes increased MMP-1 production in UVA-irradiated fibroblasts, and IL-1Ra dose-dependently inhibited MMP-1 production. IL-1Ra dose-dependently inhibited c-Jun mRNA expression of fibroblasts with no significant effect on c-Fos mRNA expression. These results demonstrate that UVB-irradiated keratinocytes promoted MMP-1 production in UVA-irradiated fibroblasts in a paracrine manner while IL-1Ra reduced MMP-1 production through inhibiting c-Jun mRNA expression. Collectively, our data suggest that IL-1 plays an important role in the dermal collagen degradation associated with UV-induced premature aging of the skin and IL-1Ra may be applied for the prevention and treatment of photoaging.
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PMID:IL-1 receptor antagonist attenuates MAP kinase/AP-1 activation and MMP1 expression in UVA-irradiated human fibroblasts induced by culture medium from UVB-irradiated human skin keratinocytes. 1627 95

1.--Thrombin is activated during gingival tissue injury and inflammation. Thrombin (platelet)-rich plasma has been used for periodontal regeneration with success. Thrombin and other bacterial proteases also affect the functions of adjacent periodontal cells via stimulation of protease-activated receptors (PARs). 2.--We noted that thrombin (0.1-2 U ml(-1)), human, and frog PAR-1 agonist peptide (20-240 microM) induced the gingival fibroblast (GF)-populated collagen gel contraction within 2 h of exposure. However, PAR-2, PAR-3, and PAR-4 agonist peptide (20-240 microM) showed little effect on collagen gel contraction. U73122 (phospholipase C inhibitor) and 2-APB (IP3 antagonist) were effective in inhibition of GF contraction. 3.--Thrombin-induced GF contraction was inhibited by 5 mM EGTA (an extracellular calcium chelator) and verapamil (an L-type calcium channel blocker). In addition, W7 (10 and 25 microM, a calcium/calmodulin (CaM) inhibitor), ML-7 (50 microM, myosin light chain kinase (MLCK) inhibitor), and HA1077 (100 microM, Rho kinase inhibitor) completely inhibited the thrombin-induced collagen gel contraction. Thrombin also induced the phosphorylation of ERK1/ERK2 and elevated the Rho-GTP levels in GF. 4.--However, U0126 only partially inhibited the thrombin-induced GF contraction. Similarly, wortmannin (100 nM), LY294002 (20 microM) (two PI3K inhibitor) and genistein also showed partial inhibition. Moreover, NAC was not able to suppress the GF contraction, as supported by the slight decrease in reactive oxygen species production in GF by thrombin. 5.--Thrombin also stimulated metalloproteinase-2 (MMP-2) and MMP-3 production in GF. But addition of GM6001 or 1,10-phenanthroline, two MMP inhibitors, could not inhibit the thrombin-induced GF contraction. 6.--These results indicate that thrombin is crucial in the periodontal inflammation and wound healing by promoting GF contraction. This event is mainly mediated via PAR-1 activation, PLC activation, extracellular calcium influx via L-type calcium channel, and the calcium/CaM-MLCK and Rho kinase activation pathway.
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PMID:Signaling mechanism of thrombin-induced gingival fibroblast-populated collagen gel contraction. 1629 51

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