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

Elastin peptides, such as kappa-elastin (kE), bind to the elastin receptor at the cell surface of human dermal fibroblasts and stimulate collagenase-1 expression at the gene and protein levels. Using specific inhibitors and phosphospecific antibodies, we show here that the binding of elastin peptides to their receptor activates the extracellular signal-regulated kinase (ERK) pathway; this activation is essential for the induction of pro-collagenase-1 production. Moreover, protein kinase A (PKA) and phosphatidylinositol 3-kinase (PI(3)K) signaling were found to participate in ERK activation. Concomitantly, we demonstrate that stimulation by elastin peptides leads to enhanced DNA binding of activator protein-1 (AP-1). Our data indicate that the up-regulation of collagenase-1 following treatment of fibroblasts with elastin peptides results from a cross-talk between PKA, PI(3)K and the ERK signaling pathways and that this regulation is accompanied by activation of AP-1 transcription factors.
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PMID:The elastin peptides-mediated induction of pro-collagenase-1 production by human fibroblasts involves activation of MEK/ERK pathway via PKA- and PI(3)K-dependent signaling. 1213 66

Using array technology that allows the simultaneous detection of gene expression of hundreds of genes, four patients with chronic myeloid leukemia (CML) were investigated at diagnosis and after starting administration of hydroxyurea. To detect the gene expression of peripheral blood mononuclears and granulocytes Human Cancer cDNA Array (CLONTECH) with 588 gene probes was used. Gene expression mononuclear and granulocyte profiles of patients at diagnosis were compared with the control profiles. The significant expression changes observed in most patients seemed to be important. Increased expression of c-jun N-terminal kinase 2 (JNK2), integrin alpha E, MMP-8, MMP-9 was detected in both fractions of most patients. In some samples PCNA, HDGF, MAPK p38, CD59 increased expressions were found. Significant down-regulation of expression in patients was detected in genes CDK4 inhibitor A, PURA, notch1 in mononuclears; STAT2, STAT5, RAR-alpha, MCL-1, junB, caspase 4 in granulocytes; CDK6, GADD153, ERBB-3, cadherin 5 in both fractions. Expression profiles detected in patients at diagnosis did not differ markedly from those after one-week treatment with hydroxyurea. Only in a few genes were significant changes after hydroxyurea administration observed and inter-individual expression differences were rather common.
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PMID:Gene expression profiling in chronic myeloid leukemia patients treated with hydroxyurea. 1215 98

Incubation of human dermal fibroblasts in keratinocyte-conditioned culture medium led to a 5.7-fold increase in the level of matrix metalloproteinase-1. Virtually all of the matrix metalloproteinase-1 - inducing activity could be related to agonists acting through members of the epidermal growth factor receptor family or to agonists acting through the interleukin-1 receptor. The same keratinocyte-conditioned medium also induced a modest increase in fibroblast proliferation (approximately 1.8-fold). Growth-stimulating activity could be attributed to epidermal growth factor receptor (but not interleukin-1 receptor) function. In fibroblasts exposed to keratinocyte-conditioned medium, mitogen-activated protein kinase signalling through both the extracellular signal-related kinase pathway and p38 pathway occurred. When recombinant epidermal growth factor or recombinant interleukin-1beta were used as a control, they induced mitogen-activated protein kinase signalling consistent with the combined effects of epidermal growth factor receptor - specific and interleukin-1 receptor - specific agonists in keratinocyte-conditioned medium. Recombinant epidermal growth factor stimulated both matrix metalloproteinase-1 induction and proliferation while recombinant interleukin-1beta stimulated matrix metalloproteinase-1 elaboration but not fibroblast growth. An inhibitor of extracellular signal-related kinase pathway signalling (U0126) blocked induction of matrix metalloproteinase-1 production induced by keratinocyte-conditioned medium (as well as by epidermal growth factor or interleukin-1beta), and also inhibited proliferation. A p38 signalling inhibitor (SB203580) blocked matrix metalloproteinase-1 elaboration induced by keratinocyte-conditioned medium or interleukin-1beta, but did not inhibit matrix metalloproteinase-1 elaboration or cell growth induced by epidermal growth factor. These data indicate that keratinocyte-fibroblast interactions are mediated by multiple stimulating agents acting on specific receptors to induce signalling through different mitogen-activated protein kinase pathways leading to altered expression of key biological functions.
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PMID:Keratinocyte stimulation of matrix metalloproteinase-1 production and proliferation in fibroblasts: regulation through mitogen-activated protein kinase signalling events. 1217 84

Upon termination of bone matrix synthesis, osteoblasts either undergo apoptosis or differentiate into osteocytes or bone lining cells. In this study, we investigated the role of matrix metalloproteinases (MMPs) and growth factors in the differentiation of osteoblasts into osteocytes and in osteoblast apoptosis. The mouse osteoblast cell line MC3T3-E1 and primary mouse calvarial osteoblasts were either grown on two-dimensional (2-D) collagen-coated surfaces, where they morphologically resemble flattened, cuboidal bone lining cells, or embedded in three-dimensional (3-D) collagen gels, where they resemble dendritic osteocytes constituting a network of cells. When MC3T3-E1 osteoblasts were grown in a 3-D matrix in the presence of an MMP inhibitor (GM6001), the cell number was dose-dependently reduced by approximately 50%, whereas no effect was observed on a 2-D substratum. In contrast, the murine mature osteocyte cell line, MLO-Y4, was unaffected by GM6001 under all culture conditions. According to TUNEL assay, the osteoblast apoptosis was increased 2.5-fold by 10 microm GM6001. To investigate the mechanism by which MMPs mediate the survival of osteoblasts, we examined the effect of GM6001 on MC3T3-E1 osteoblasts in the presence of extracellular matrix components and growth factors, including tenascin, fibronectin, laminin, collagenase-cleaved collagen, gelatin, parathyroid hormone, basic fibroblast growth factor, vascular epidermal growth factor, insulin-like growth factor, interleukin-1, and latent and active transforming growth factor-beta (TGF-beta). Only active TGF-beta, but not latent TGF-beta or other agents tested, restored cell number and apoptosis to control levels. Furthermore, we found that the membrane type MMP, MT1-MMP, which is produced by osteoblasts, could activate latent TGF-beta and that antibodies neutralizing endogenous TGF-beta led to a similar decrease in cell number as GM6001. Whereas inhibitors of other protease families did not induce osteoblast apoptosis, an inhibitor of the p44/42 mitogen-activated protein kinase showed the same but non-synergetic effect as GM6001. These findings suggest that MMP-activated TGF-beta maintains osteoblast survival during trans-differentiation into osteocytes by a p44/42-dependent pathway.
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PMID:Matrix metalloproteinase-dependent activation of latent transforming growth factor-beta controls the conversion of osteoblasts into osteocytes by blocking osteoblast apoptosis. 1222 90

A recently identified lectin-like oxidized low-density lipoprotein receptor (LOX-1) mediates endothelial cell injury and facilitates inflammatory cell adhesion. We studied the role of LOX-1 in myocardial ischemia-reperfusion (I/R) injury. Anesthetized Sprague-Dawley rats were subjected to 60 min of left coronary artery (LCA) ligation, followed by 60 min of reperfusion. Rats were treated with saline, LOX-1 blocking antibody JXT21 (10 mg/kg), or nonspecific anti-goat IgG (10 mg/kg) before I/R. Ten other rats underwent surgery without LCA ligation and served as a sham control group. LOX-1 expression was markedly increased during I/R (P < 0.01 vs. sham control group). Simultaneously, the expression of matrix metalloproteinase-1 (MMP-1) and adhesion molecules (P-selectin, VCAM-1, and ICAM-1) was also increased in the I/R area (P < 0.01 vs. sham control group). There was intense leukocyte accumulation in the I/R area in the saline-treated group. Treatment of rats with the LOX-1 antibody prevented I/R-induced upregulation of LOX-1 and reduced MMP-1 and adhesion molecule expression as well as leukocyte recruitment. LOX-1 antibody, but not nonspecific IgG, also reduced myocardial infarct size (P < 0.01 vs. saline-treated I/R group). To explore the link between LOX-1 and adhesion molecule expression, we measured expression of oxidative stress-sensitive p38 mitogen-activated protein kinase (p38 MAPK). The activity of p38 MAPK was increased during I/R (P < 0.01 vs. sham control), and use of LOX-1 antibody inhibited p38 MAPK activation (P < 0.01). These findings indicate that myocardial I/R upregulates LOX-1 expression, which through p38 MAPK activation increases the expression of MMP-1 and adhesion molecules. Inhibition of LOX-1 exerts an important protective effect against myocardial I/R injury.
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PMID:LOX-1 inhibition in myocardial ischemia-reperfusion injury: modulation of MMP-1 and inflammation. 1238 56

The purpose of this study was to determine the role of p42/p44 mitogen-activated protein kinase (MAPK) in alpha(1)-adrenergically and cholinergically stimulated protein secretion in rat lacrimal gland acinar cells and the pathways used by these agonists to activate MAPK. Acini were isolated by collagenase digestion and incubated with the alpha(1)-adrenergic agonist phenylephrine or the cholinergic agonist carbachol, and activation of MAPK and protein secretion were then measured. Phenylephrine and carbachol activated MAPK in a time- and concentration-dependent manner. Inhibition of MAPK significantly increased phenylephrine- and carbachol-induced protein secretion. Inhibition of EGF receptor (EGFR) with AG1478, an inhibitor of the EGFR tyrosine kinase activity, significantly increased phenylephrine- but not carbachol-induced protein secretion. Whereas phenylephrine-induced activation of MAPK was completely inhibited by AG1478, activation of MAPK by carbachol was not. Phenylephrine stimulated tyrosine phosphorylation of the EGFR, whereas carbachol stimulated p60(Src), and possibly Pyk2, to activate MAPK. We conclude that, in the lacrimal gland, activation of MAPK plays an inhibitory role in alpha(1)-adrenergically and cholinergically stimulated protein secretion and that these agonists use different signaling mechanisms to activate MAPK.
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PMID:Alpha 1-adrenergic and cholinergic agonists activate MAPK by separate mechanisms to inhibit secretion in lacrimal gland. 1238 18

Expression of 12 matrix metalloproteinases (MMPs) after exposure of human melanoma cell lines C32TG and Mewo to nitric oxide (NO) was investigated by the reverse transcription-polymerase chain reaction. Expression of the mRNA of MMP-1, -3, -10 and -13 in C32TG cells was transcriptionally enhanced in a dose-dependent manner by exposure to an NO donor, S-nitroso-N-acetyl-DL-penicillamine (SNAP) and mRNA expression of MMP-1 and -10 was similarly enhanced in Mewo cells. Exposure of C32TG cells to NO increased the MMP-1 protein concentration in the culture medium. Testing with the luciferase gene fused to the 1.5 Kbp 5'-flanking region of the human MMP-1 gene showed that exposure to NO upregulated MMP-1 promoter activity in C32TG cells. Endogenous NO production after introduction of inducible NO synthase cDNA also enhanced MMP-1 promoter activity in C32TG cells. Deletion and mutational analysis identified a critical AP-1 binding site required for NO regulation of MMP-1. A neighboring Ets motif from the AP-1 site in the promoter region acted as an accessory to enhance MMP-1 expression. Electromobility shift analysis using the AP-1 binding site showed that NO enhanced the AP-1 binding ability of nuclear factors in C32TG cells. PD98059, a selective MEK inhibitor and SB202190, a p38 MAPK inhibitor, attenuated the MMP-1 mRNA expression enhanced by NO. Thus, MMP-1 was transcriptionally enhanced by NO via MAPK (ERK and p38) pathways. The results of our study suggest that the increased expression of MMPs in response to NO may be associated with tumor progression under inflammation.
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PMID:Induction of matrix metalloproteinase gene transcription by nitric oxide and mechanisms of MMP-1 gene induction in human melanoma cell lines. 1245 29

The present studies were designed to investigate the sites of PGE(2), prostacyclin and leptin formation in human adipose tissue. Most of the PGE(2) and prostacyclin formation by adipose tissue explants from obese humans after 48 h in primary culture was due to blood vessels and other tissues not digested by collagenase. However, there was appreciable PGE(2) formation by adipocytes over a 48 h incubation and leptin formation was only seen in adipocytes. An increase in COX-2 immunoreactive protein was also seen after incubation of isolated human adipocytes for 48 h. The release of PGE(2) by adipocytes incubated for 48 h was about 4% that by intact adipose tissue explants while the release of prostacyclin was about 1.5% that by tissue. However, in a different experimental design where PGE(2) formation was measured over 2 h in the presence of 20 microM arachidonic acid the formation of PGE(2) by adipocytes after 48 h prior incubation in primary culture was 38% of that by tissue explants. Dexamethasone enhanced leptin release by adipocytes while inhibiting PGE(2) release and COX-2 up-regulation. The mechanisms involved in up-regulation of COX-2 activity during primary culture of adipocytes and the inhibition of this by dexamethasone do not appear to involve p38 MAPK or p42-44 MAPK. Interleukin I(beta) further enhanced PGE(2) formation by adipocytes but did not affect leptin formation. In conclusion, these data indicate that leptin release is exclusively a function of adipocytes while prostanoids are made by both adipocytes and the other cells present in human adipose tissue
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PMID:Comparison of PGE2, prostacyclin and leptin release by human adipocytes versus explants of adipose tissue in primary culture. 1246 69

Replicative senescence is characterized by numerous phenotypic alterations including loss of proliferative capacity and numerous changes in gene expression such as impaired serum inducibility of the immediate early gene c-fos and increased expression of collagenase. Transcription of c-fos in response to mitogens depends on the activation of a multiprotein complex formed on the c-fos serum response element (SRE), which includes the transcription factors serum response factor (SRF) and ternary complex factor (TCF). TCF is activated after phosphorylation by the Extracellular signals Regulated Kinase 1 and 2 (ERK1/2), two kinases of the Raf/MEK/ERK signaling pathway. We have previously demonstrated that collagenase expression is under positive regulation by the transcription factor FKHRL1 and that this transcription factor is under negative regulation by the phosphatidylinositol 3-kinase(PI3K)/Akt(PKB) pathway. Although total activity of ERK and Akt was similar in total cell lysates from early and late passage fibroblasts our data indicate that in senescent cells neither ERK nor Akt are able to phosphorylate efficiently their nuclear targets. Our findings suggest that although they can be fully activated in the cytosol of both early and late passage cells, the Raf/MEK/ERK and the PI3K/Akt pathways, which are essential for cellular proliferation, are down regulated in the nuclei of senescent cells.
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PMID:Role of the Raf/MEK/ERK and the PI3K/Akt(PKB) pathways in fibroblast senescence. 1247 Aug 26

The balance between matrix metalloproteinases (MMPs) and their inhibitors, the tissue inhibitors of metalloproteinases (TIMPs), is pivotal in the remodeling of extracellular matrix. TGF-beta has profound effects on extracellular matrix homeostasis, in part via its ability to alter this balance at the level of gene expression. The intracellular signaling pathways by which TGF-beta mediates its actions include the Smad pathway, specific to the TGF-beta superfamily, but also, for example, mitogen-activated protein kinase pathways; furthermore, cross-talk between the Smads and other signaling pathways modifies the TGF-beta response. The reciprocal effect of TGF-beta on the expression of Timp-1 and MMP-1 supports its role in matrix anabolism, yet the mechanisms by which TGF-beta induces Timp-1 and represses induced MMP-1 have remained opaque. Here, we (i) investigate the mechanism(s) by which TGF-beta1 induces expression of the Timp-1 gene and (ii) compare this with TGF-beta1 repression of phorbol ester-induced MMP-1 expression. We report that the promoter-proximal activator protein 1 (AP1) site is essential for the response of both Timp-1 and MMP-1 to TGF-beta (induction and repression, respectively). c-Fos, JunD, and c-Jun are essential for the induction of Timp-1 gene expression by TGF-beta1, but these AP1 factors transactivate equally well from both Timp-1 and MMP-1 AP1 sites. Smad-containing complexes do not interact with the Timp-1 AP1 site, and overexpression of Smads does not substitute or potentiate the induction of the gene by TGF-beta1; furthermore, Timp-1 is still induced by TGF-beta1 in Smad knockout cell lines, although to varying extents. In contrast, Smads do interact with the MMP-1 AP1 site and mediate repression of induced MMP-1 gene expression by TGF-beta1.
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PMID:The comparative role of activator protein 1 and Smad factors in the regulation of Timp-1 and MMP-1 gene expression by transforming growth factor-beta 1. 1252 89


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