Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P51812 (mitogen-activated protein)
 10,636 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It has been shown that stimulation of lymphoid cells causes the activation of the extracellular signal-regulated-2 (ERK-2) which activates nuclear factor of activated T cells (NF-AT), a transcription factor involved in the regulation of interleukin-2 (1L2) gene transcription. ERK-2 is activated via a kinase cascade initiated by activation of the G protein p21Ras followed by phosphorylation and activation of Raf-1 and mitogen-activated protein kinase kinase-1 (MEK-1). Activation of this pathway has been described primarily in human T cell lines; however, using primary T lymphocytes from transgenic mice, a recent study has shown that a blockade of this cascade did not perturb lymphocyte stimulation and proliferation. In the present paper, we studied in human primary T cells the possible involvement of the Raf-1/MEK-1/ERK-2 pathway upon stimulation by jacalin, a mitogenic lectin which specifically stimulates CD4+ lymphocytes. We show here that the mitogen-activated protein (MAP) kinase pathway was stimulated in human purified lymphocytes upon activation with jacalin. Moreover, activation of this pathway appeared to be essential, since its blockade by a specific inhibitor of the MEK-1 kinase abolished IL2 gene transcription; in contrast, in T cells stimulated with phytohemagglutinin M(PHA), another potent T cell mitogenic lectin, blockade of MEK-1 reduced but did not totally inhibit either ERK-2 phosphorylation or IL2 mRNA expression. This shows, as already suggested, that another pathway in addition to the Raf-1/MEK-1/ERK-2 kinase cascade could be triggered in T cell activation. Jacalin stimulation therefore appeared to be a good model for the specific activation of the MAP kinase pathway in human primary T lymphocytes, which would allow the characterisation of drugs specifically targeted to this particular pathway.
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PMID:The Raf-1/mitogen-activated protein kinase kinase-1/extracellular signal-regulated-2 signaling pathway as prerequisite for interleukin-2 gene transcription in lectin-stimulated human primary T lymphocytes. 948 98

Nonopsonic interaction of host immune cells with pathogens is an important first line of defense. We hypothesized that nonopsonic recognition between type III group B streptococcus and human neutrophils would occur and that the interaction would be sufficient to trigger neutrophil activation. By using a serum-free system, it was found that heat-killed type III group B streptococci bound to neutrophils in a rapid, stable, and inoculum-dependent manner that did not result in ingestion. Transposon-derived type III strain COH1-13, which lacks capsular polysaccharide, and strain COH1-11 with capsular polysaccharide lacking terminal sialic acid demonstrated increased neutrophil binding, suggesting that capsular polysaccharide masks an underlying binding site. Experiments using monoclonal antibodies to complement receptor 1 and to the I domain or lectin site of complement receptor 3 did not inhibit binding, indicating that the complement receptors used for ingestion of opsonized group B streptococci were not required for nonopsonic binding. Nonopsonic binding resulted in rapid activation of cellular p38 and p44/42 mitogen-activated protein kinases. This interaction was not an effective trigger for superoxide production but did promote release of the proinflammatory cytokine interleukin-8. The release of interleukin-8 was markedly suppressed by the p38 mitogen-activated protein kinase inhibitor SB203580 but was only minimally suppressed by the mitogen-activated protein/extracellular signal-regulated kinase inhibitor PD98059. Thus, nonopsonic binding of type III group B streptococci to neutrophils is sufficient to initiate intracellular signaling pathways and could serve as an arm of innate immunity of particular importance to the immature host.
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PMID:Nonopsonic binding of type III Group B Streptococci to human neutrophils induces interleukin-8 release mediated by the p38 mitogen-activated protein kinase pathway. 1072 1

We have shown previously that administration of acyclic retinoid to cirrhotic patients who had undergone curative treatment of preceding hepatocellular carcinoma (HCC) induced the disappearance of serum lectin-reactive alpha-fetoprotein (AFP-L3) and subsequently reduced the incidence of second liver cancers. AFP-L3 is a tumor marker that indicates the presence of occult tumors below the detection limit by diagnostic images. Therefore, we have proposed a new concept of 'clonal deletion' therapy with acyclic retinoid for the cancer chemoprevention against HCC. Such eradication of AFP-L3-producing latent malignant (or premalignant) cells from the liver suggested a new strategy to prevent HCC, which may be involved in the same category as cancer chemotherapy. In the present series of studies, we explored the molecular mechanism of 'clonal deletion' and found a novel mechanism of apoptosis induction by the retinoid. We have demonstrated a modification of a retinoid receptor, RXRalpha, by mitogen-activated protein (MAP) kinase-dependent phosphorylation, resulting in the loss of transactivating activity. This may lead HCC cells to be resistant to natural retinoic acid. However, acyclic retinoid restored the function of phosphorylated RXRalpha and induced its downstream pro-apoptotic genes including tissue transglutaminase, an enzyme that is implicated in apoptosis. Tissue transglutaminase-dependent apoptosis in HCC cells was independent of the activation of caspases. This novel mechanism of retinoid-induced apoptosis may give a clue to understand the molecular mechanism of clonal deletion.
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PMID:Apoptosis induction by acyclic retinoid: a molecular basis of 'clonal deletion' therapy for hepatocellular carcinoma. 1157 27

Cytosolic phospholipase A(2)-alpha (cPLA(2)-alpha) is a calcium-sensitive enzyme involved in receptor-mediated eicosanoid production. In resting cells, cPLA(2)-alpha is present in the cytosol and nucleus and translocates to membranes via its calcium-dependent lipid-binding (CaLB) domain following stimulation. cPLA(2)-alpha is also regulated by phosphorylation on several residues, which results in enhanced arachidonic acid release. Little is known about the factors controlling the nuclear localisation of cPLA(2)-alpha. Here the nuclear localisation of cPLA(2)-alpha in the EA.hy.926 human endothelial cell line was investigated. Nuclear localisation was dependent on proliferation, with subconfluent cells containing higher levels of nuclear cPLA(2)-alpha than contact-inhibited confluent or serum-starved cells. The broad-range protein kinase inhibitor staurosporine caused a decrease in the nuclear level of cPLA(2)-alpha, whereas the protein phosphatase inhibitor okadaic acid increased the level of nuclear cPLA(2)-alpha. Using inhibitors for specific mitogen-activated protein (MAP) kinases, both p42/44(MAPK) and p38(MAPK) were shown to be important in modulating nuclear localisation. Finally, inhibition of nuclear import and export using Agaricus bisporus lectin and leptomycin B, respectively, demonstrated that cPLA(2)-alpha contains functional nuclear localisation and export signals. Thus we have identified a novel mode of regulation of cPLA(2)-alpha. This, together with the increasing body of evidence supporting the role of nuclear lipid second messengers in gene expression and proliferation, may have important implications for controlling the growth of endothelial cells in angiogenesis and tumour progression.
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PMID:Nuclear localisation of cytosolic phospholipase A2-alpha in the EA.hy.926 human endothelial cell line is proliferation dependent and modulated by phosphorylation. 1241 98

The group IV 85 kDa cytosolic phospholipase A(2) regulates many aspects of innate immunity. However, the function of this enzyme in T-cells remains controversial. We show here that human peripheral blood lymphocytes and Jurkat cells express cytosolic phospholipase A(2) and produce prostaglandin A(2) and leukotriene B(4). Selective inhibitors of this enzyme suppressed Ca(2+)-ionophore-, mitogen- and T-cell receptor-mediated expression of interleukin-2 at the level of transcription from the promoter. Activation of mitogen-activated protein kinases (MAPK), degradation of inhibitor-kappaBalpha and transactivation by nuclear factor-kappaB (NFkappaB) were impaired as was the antigen-, lectin- and interleukin-2-driven proliferation of T-cells in vitro. Ligands of peroxisome proliferator-activated receptor-gamma (PPARgamma) induced rapid phosphorylation of MAPK in human monocytic but not in Jurkat cells. These data indicated that in T-cells, eicosanoids generated upon signal-activated cytosolic phospholipase A(2) promote NFkappaB-dependent interleukin-2 transcription via a PPARgamma-independent mechanism involving the MAPK-pathway.
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PMID:Activation of cytosolic phospholipase A2 in human T-lymphocytes involves inhibitor-kappaB and mitogen-activated protein kinases. 1267 54

Endothelial dysfunction is an early and key determinant of diabetic vascular complications that is elicited at least in part by oxidized LDL (oxLDL). The recent observation that lectin-like oxLDL receptor-1 (LOX-1) expression is increased in the vascular endothelium of diabetic rats suggests a role for LOX-1 in the pathogenesis of diabetic vascular dysfunction. Because postprandial plasma glucose has been recently proposed as an independent risk factor for cardiovascular diseases in patients with diabetes, we evaluated, in the current study, the in vitro effect of high glucose on LOX-1 expression by human aortic endothelial cells (HAECs) and the role of this receptor in glucose-induced human monocyte adhesion to endothelium. Exposure of HAECs to high D-glucose concentrations (5.6-30 mmol/l) enhanced, in a dose- and time-dependent manner, LOX-1 expression, both at the gene and protein levels. The stimulatory effect of glucose on LOX-1 gene expression in HAECs was abolished by antioxidants and inhibitors of nuclear factor (NF)-kappaB, protein kinase C (PKC), and mitogen-activated protein kinases (MAPKs). Electrophoretic mobility shift assay data demonstrated that high glucose enhanced, in HAECs, the nuclear protein binding to the NF-kappaB regulatory element of the LOX-1 gene. Finally, our results showed that incubation of HAECs with high glucose increased human monocyte adhesion to endothelium through a LOX-1-dependent signaling mechanism. Overall, these results demonstrate that high glucose induces endothelial LOX-1 expression. This effect appears to be exerted at the transcriptional level through increased oxidant stress and NF-kappaB, PKC, and MAPK activation. The study also suggests a role for LOX-1 as mediator of the stimulatory effect of high glucose on monocyte adhesion.
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PMID:Glucose enhances endothelial LOX-1 expression: role for LOX-1 in glucose-induced human monocyte adhesion to endothelium. 1282 55

Glycoproteins from mammalian brain tissues contain unique N-linked oligosaccharides terminating with beta-N-acetylglucosamine residues. Lectin blot analysis of membrane glycoprotein samples from human neuroblastoma SH-SY5Y cells showed that several protein bands bind to Psathylera velutina lectin (PVL), which interacts with beta-N-acetylglucosamine-terminating oligosaccharides. No lectin positive bands were detected by digestion with jack bean beta-N-acetyl-hexosaminidase or N-glycanase before incubation with the lectin, indicating that the cells contain beta-N-acetylglucosamine-terminating N-linked oligosaccharides. When cells were cultured in dishes with different concentrations of PVL, the cell proliferation was inhibited in a dose-dependent manner. Similarly, the neurite extension, which was stimulated with nerve growth factor, was also inhibited in a manner dependent on the lectin dose. Cell proliferation and neurite extension were recovered by the addition of 10 mM N-acetylglucosamine into the medium. Immunoblot analysis of the activation of mitogen-activated protein (MAP) kinases and protein kinase C revealed that phosphorylation of 42-kDa and 44-kDa MAP kinases and 80-kDa protein kinase C are inhibited when SH-SY5Y cells are cultured in PVL-coated dishes, but are restored by the addition of the haptenic sugar into the medium, indicating that MAP kinase and protein kinase C pathways are inhibited by interaction with immobilized PVL. These results indicate that beta-N-acetylglucosamine-terminating N-linked oligosaccharides expressed on neural cells can induce intracellular signals upon binding to extracellular receptors, and are important for growth regulation of neural cells.
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PMID:Suppression of proliferation and neurite extension of human neuroblastoma SH-SY5Y cells on immobilized Psathyrella velutina lectin. 1474 51

Angiotensin II (Ang II) induces angiogenesis by stimulating reactive oxygen species-dependent vascular endothelial growth factor (VEGF) expression. Ang II via type 1 receptor upregulates the expression of LOX-1, a lectin-like receptor for oxidized low-density lipoprotein. LOX-1 activation, in turn, upregulates Ang II type 1 receptor expression. We postulated that interruption of the feedback loop between Ang II and LOX-1 might attenuate Ang II-induced VEGF expression and capillary formation. In vitro experiments showed that Ang II (1 nmol/L) induced the expression of LOX-1 and VEGF and enhanced capillary formation from human coronary endothelial cells in Matrigel assay. Ang II-mediated expression of LOX-1 and VEGF, capillary formation, intracellular reactive oxygen species generation, and phosphorylation of p38 as well as p44/42 mitogen-activated protein kinases, were suppressed by anti-LOX-1 antibody, nicotinamide-adenine dinucleotide phosphate oxidase inhibitor apocynin and the Ang II type 1 receptor blocker losartan, but not by the Ang II type 2 receptor blocker PD123319. Expression of VEGF and capillary formation induced by Ang II were also inhibited by the p44/42 mitogen-activated protein kinase inhibitor U0126 and the p38 mitogen-activated protein kinase inhibitor SB203580. In ex vivo experiments, Ang II stimulated capillary sprouting from aortic rings from wild-type mice, and this phenomenon was significantly attenuated by pretreatment of aortic rings with anti-LOX-1 antibody, apocynin, and losartan, but not by PD123319. Importantly, Ang II-induced capillary sprouting was minimal from aortic rings from LOX-1 null mice compared with wild-type mice. These findings suggest that small concentrations of Ang II promote capillary formation by inducing the expression of VEGF via Ang II type 1 receptor/LOX-1-mediated stimulation of the reactive oxygen species-mitogen-activated protein kinase pathway.
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PMID:Angiotensin II induces capillary formation from endothelial cells via the LOX-1 dependent redox-sensitive pathway. 1789 72

Transforming growth factor beta(1) (TGFbeta(1)) activation leads to tissue fibrosis. Here, we report on the role of LOX-1, a lectin-like 52-kDa receptor for oxidized low density lipoprotein, in TGFbeta(1)-mediated collagen expression and underlying signaling in mouse cardiac fibroblasts. TGFbeta(1) was overexpressed in wild-type (WT) and LOX-1 knock-out mouse cardiac fibroblasts by transfection with adeno-associated virus type 2 vector carrying the active TGFbeta(1) moiety (AAV/TGFbeta (ACT)(1)). Transfection of WT mouse cardiac fibroblasts with AAV/TGFbeta (ACT)(1) markedly enhanced the expression of NADPH oxidases (p22(phox), p47(phox), and gp91(phox) subunits) and LOX-1, formation of reactive oxygen species, and collagen synthesis, concomitant with an increase in the activation of p38 and p44/42 mitogen-activated protein kinases (MAPK). The TGFbeta(1)-mediated increase in collagen synthesis was markedly attenuated in the LOX-1 knock-out mouse cardiac fibroblasts as well as in WT mouse cardiac fibroblasts treated with a specific anti-LOX-1 antibody. Treatment with anti-LOX-1 antibody also reduced NADPH oxidase expression and MAPK activation. The NADPH oxidase inhibitors and gp91phox small interfering RNA reduced LOX-1 expression, MAPK activation, and collagen formation. The p38 MAPK inhibitors as well as the p44/42 MAPK inhibitors reduced collagen formation without affecting LOX-1 expression in cardiac fibroblasts. These observations suggest that collagen synthesis in cardiac fibroblasts involves a facilitative interaction between TGFbeta(1)-NADPH oxidase and LOX-1. Further, the activation of MAPK pathway appears to be downstream of TGFbeta(1)-reactive oxygen species-LOX-1 cascade.
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PMID:Regulation of TGFbeta1-mediated collagen formation by LOX-1: studies based on forced overexpression of TGFbeta1 in wild-type and lox-1 knock-out mouse cardiac fibroblasts. 1818 94

Angiotensin II via type 1 receptor activation upregulates the expression of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), and LOX-1 activation, in turn, upregulates angiotensin II type 1 receptor expression. We postulated that interruption of this positive feedback loop might attenuate the genesis of angiotensin II-induced hypertension and subsequent cardiac remodeling. To examine this postulate, LOX-1 knockout and wild-type mice were infused with angiotensin II or norepinephrine (control for angiotensin II) for 4 weeks. Angiotensin II-, but not norepinephrine-, induced hypertension was attenuated in LOX-1 knockout mice. Angiotensin II-induced cardiac remodeling was also attenuated in LOX-1 knockout mice. Importantly, angiotensin II type 1 receptor expression was reduced, and the expression and activity of endothelial NO synthase were preserved in the tissues of LOX-1 knockout mice given angiotensin II. Reactive oxygen species generation, nicotinamide-adenine dinucleotide phosphate oxidase expression, and phosphorylation of p38 and p44/42 mitogen-activated protein kinases were also much less pronounced in the LOX-1 knockout mice given angiotensin II. These alterations in biochemical and structural abnormalities were associated with preservation of cardiac hemodynamics in the LOX-1 knockout mice. To confirm that fibroblast function is modulated in the absence of LOX-1, cardiac fibroblasts from wild-type and LOX-1 knockout mice were treated with angiotensin II. Indeed, LOX-1 knockout mice cardiac fibroblasts revealed an attenuated profibrotic response on treatment with angiotensin II. These observations provide strong evidence that LOX-1 is a key modulator of the development of angiotensin II-induced hypertension and subsequent cardiac remodeling.
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PMID:Modulation of angiotensin II-mediated hypertension and cardiac remodeling by lectin-like oxidized low-density lipoprotein receptor-1 deletion. 1864 45


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