Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

TERE1, a recently discovered gene/protein appears to play a role in bladder tumor growth regulation but to date does not have clear functional correlates. The objective of this study was to gain further insight into the function of the TERE1 protein by identifying potential protein to protein interactions with TERE1 and determining whether these interactions are associated with putative growth regulatory pathways and/or bladder tumor formation. Towards this aim, we have performed a bacterial two hybrid assay and isolated interacting clones, which then were sequenced and further examined by affinity chromatography and immunoprecipitation. From among several positive clones, we isolated a putative interacting plasmid containing the C-terminal portion of preapolipoprotein E starting from amino acid number 124 from the pBT-TERE1/pTarget-cDNA bacterial two hybrid system. The C-terminal portion of apoE interaction with the TERE1 was confirmed using ProBond columns by the expression of 6XHis recombinant and (35)S methionine/cysteine labeled proteins. We found that there was ubiquitous expression of the apoE transcript in normal bladder and in various grades and stages of transitional cell carcinoma (TCC) of the bladder. Likewise, we detected the apoE protein in both normal and malignant bladder tissues by Western blot. There was a significant decrease in the apoE protein in 12 of 16 muscle invasive TCCs of the bladder compared to normal bladder mucosa samples. Previous studies in rat fibroblasts have found that expression of apoE can decrease the phosphorylation of the growth factor-related p42/44 MAP kinase. A significant decrease in p44/p42 MAPK phophorylation was also apparent using a phosphorylation specific antibody in human 293 kidney cells upon transfection and expression of apoE. In conclusion, the results from this study suggest that the expression and regulation of the apoE pathway may yield clues toward understanding the function of TERE1.
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PMID:An interaction between apolipoprotein E and TERE1 with a possible association with bladder tumor formation. 1578 23

The obligate intracellular parasite Leishmania must survive the antimicrobial activities of its host cell, the macrophage, and prevent activation of an effective immune response. In order to do this, it has developed numerous highly successful strategies for manipulating activities, including antigen presentation, nitric oxide and oxygen radical generation, and cytokine production. This is generally the result of interactions between Leishmania cell surface molecules, particularly gp63 and LPG, and less well identified macrophage surface receptors, causing the distortion of specific intracellular signaling cascades. We describe some of the signaling pathways and intermediates that are repressed in infected cells, including JAK/STAT, Ca(2+)-dependent protein kinase C (PKC) isoforms, and mitogen-activated protein kinases (especially ERK1/2), and proteasome-mediated transcription factor degradation. We also discuss protein tyrosine phosphatases (particularly SHP-1), intracellular Ca2+, Ca(2+)-independent PKC, ceramide, and the suppressors of cytokine signaling family of repressors, which are all reported to be activated following infection, and the role of parasite-secreted cysteine proteases.
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PMID:Subversion mechanisms by which Leishmania parasites can escape the host immune response: a signaling point of view. 1583 26

There is increasing evidence of cross-talk between dyslipidemia and renin-angiotensin system (RAS) in atherogenesis. Both dyslipidemia and RAS activation enhance the expression of a newly described receptor for oxidized-low density lipoprotein (ox-LDL), lectin-like ox-LDL receptor-1 (LOX-1). We postulated that the blockade of dyslipidemia with rosuvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor and RAS with candesartan, an angiotensin II type 1 receptor blocker, would have a synergistic inhibitory effect on LOX-1 expression and atherogenesis. Apo-E knockout mice were fed a high-cholesterol diet (1% cholesterol, HC-diet) alone, or HC-diet with rosuvastatin (1mg/(kgd)), candesartan (1mg/(kgd)) or with both. Twelve weeks later the extent of atherosclerosis was determined by Sudan IV staining. Apo-E knockout mice on HC-diet had extensive atherosclerosis. Both rosuvastatin and candesartan decreased the extent of atherosclerosis (by 23 and 26%, respectively), despite the HC-diet; however, the combination of rosuvastatin and candesartan reduced atherosclerosis further (by 67%). Rosuvastatin decreased plasma levels of total cholesterol by over 50%, whereas candesartan had no effect. LOX-1 protein expression was found to be markedly up-regulated in HC-diet-fed apo-E knockout mice. While rosuvastatin and candesartan each had a small inhibitory effect on the expression of LOX-1 in the atherosclerotic tissues, the combination totally blocked the up-regulation of LOX-1. P38 mitogen-activated protein kinase (MAPK) expression and phosphorylation were increased in apo-E knockout mice, attenuated by rosuvastatin or candesartan alone, and completely blocked by the combination of the two agents. P44/42 MAPK expression and phosphorylation were not affected by the HC-diet, rosuvastatin, candesartan, or their combination. This study demonstrates the potent effect of rosuvastatin and candesartan on atherogenesis, as well as on the expression of LOX-1 and on the activation of p38 MAPK, but not p44/42 MAPK.
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PMID:Cross-talk between dyslipidemia and renin-angiotensin system and the role of LOX-1 and MAPK in atherogenesis studies with the combined use of rosuvastatin and candesartan. 1600 8

Antiphospholipid syndrome (APS) is characterized by recurrent thrombosis or pregnancy morbidity associated with antiphospholipid antibodies (aPL). Impaired fibrinolysis is a contributing factor for the development of thrombosis, and the effect of aPL in the fibrinolytic system has been investigated. Impaired release of tPA and enhanced release of PAI-1 after endothelial activation is reported in patients with APS. Elevated Lipoprotein (a) levels have been found in APS, which results in inhibition of fibrinolytic activity. Phospholipid-bound beta(2)-glycoprotein I (beta(2)GPI) is a major autoantigen for aPLs. beta(2)GPI exerts both anti-coagulant and pro-coagulant properties mainly by interacting with other phospholipid-binding proteins such as coagulation factors and protein C. Dramatic increase in the affinity of beta(2)GPI to the cell surface is induced by binding of pathogenic anti-beta(2)GPI antibodies, which may modify the physiological function of beta(2)GPI and may affect the coagulation/fibrinolysis balance on the cell surface. Using chromogenic assays for measuring fibrinolytic activity, we demonstrated that addition of monoclonal anticardiolipin antibody (aCL) decreases the activity of extrinsic/intrinsic fibrinolysis. Significantly lower activity of intrinsic fibrinolysis was also demonstrated in the euglobulin fractions from APS patients. Endothelial cells and monocytes are activated by aPLs in vitro, resulting in production of tissue factor (TF), a major initiator of the coagulation system. Recently, aPLs are reported to induce thrombocytes to produce thromboxane. The importance of apoE receptor 2 on platelets for the binding of artificially dimerized beta(2)GPI was suggested. By investigating aPL-inducible genes in peripheral blood mononuclear cells, we found that the mitogen-activated protein kinase (MAPK) pathway was up-regulated. Using a monocyte cell line, phosphorylation of p38 MAPK, NF-kappaB translocation to the nuclear fraction, and up-regulated TF mRNA expression were demonstrated after treatment with monoclonal aCL. These phenomena were observed only in the presence of beta(2)GPI. Moreover, a specific p38 MAPK inihibitor SB203580 decreased aCL/beta(2)GPI-induced TF mRNA expression. Thus, aCL/beta(2)GPI plays dual roles in the pathogenesis of APS, firstly by deranging the fibrinolytic system and secondly by activating monocytes, endothelial cells and thrombocytes to produce TF or thromboxane.
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PMID:Pathogenesis of antiphospholipid antibodies: impairment of fibrinolysis and monocyte activation via the p38 mitogen-activated protein kinase pathway. 1632 97

Inflammation plays an essential role in atherosclerosis and post-angioplasty restenosis and the synthesis and release of inflammatory cytokines from vascular smooth muscle cells is an important contributor to these pathologies. It is assumed that drugs that prevent the overproduction of inflammatory cytokines may inhibit cardiovascular disorders. In the present study, the effects of a water-soluble antioxidant, salvianolic acid B (Sal B), derived from a Chinese herb, on the expression of cyclooxygenase (COX) in lipopolysaccharide (LPS)-treated human aortic smooth muscle cells (HASMCs) and in the aortas of cholesterol-fed apoE deficient mice were investigated. In unstimulated HASMCs, COX-2 mRNA and protein were almost undetectable, but were strongly upregulated in response to LPS. In contrast, HASMCs with or without LPS treatment showed constitutive expression of COX-1 mRNA and protein. The activation of COX-2 protein synthesis in LPS-stimulated HASMCs was shown to involve the activation of the extracellular-signal-regulated kinase 1/2 (ERK1/2), c-Jun NH(2)-terminal kinase (JNK), and p38 mitogen-activated protein kinase pathway. Incubation of HASMCs with Sal B before LPS stimulation resulted in pronounced downregulation of COX-2 expression. Sal B treatment suppressed ERK1/2 and JNK phosphorylation and attenuated the increase in prostaglandin E(2) production and NADPH oxidase activity in LPS-treated HASMCs. When apoE-deficient mice were fed a 0.15% cholesterol diet with or without supplementation with 0.3% Sal B for 12 weeks, the intima/media area ratio in the thoracic aortas was significantly reduced in the Sal B group (0.010 +/- 0.009%) compared to the apoE-deficient group (0.114 +/- 0.043%) and there was a significant reduction in COX-2 protein expression in the thickened intima. These results demonstrate that Sal B has anti-inflammatory properties and may explain its anti-atherosclerotic properties. This new mechanism of action of Sal B, in addition to its previously reported inhibition of LDL oxidation, may help explain its efficacy in the treatment of atherosclerosis.
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PMID:Salvianolic acid B attenuates cyclooxygenase-2 expression in vitro in LPS-treated human aortic smooth muscle cells and in vivo in the apolipoprotein-E-deficient mouse aorta. 1644 Mar 26

The anti-atherogenic effects of human apolipoprotein E3 (apoE3) have been partially attributed to its anti-proliferation properties. We studied if endogenously expressed apoE elicits isoform-dependent effects on cell proliferation. Rat F111 fibroblasts without native expression of apoE were used to establish cell lines with stable expression of the three human apoE isoforms. Cell growth curve studies showed that expression of apoE isoforms prolonged cell population doubling time in an isoform-dependent manner with apoE3 showing the most potent effect followed by apoE2 and apoE4 exhibiting comparable effects. Interestingly, saturation density of cell population was significantly reduced by the expression of apoE4 isofom. Further analyses revealed that all three apoE isoforms significantly lengthened G0/G1 phase (p < 0.05) of the cell cycle and were associated with the suppression of ERK1/2 activities. However, these changes were not sufficient to explain the isoform-dependent effects of apoE expression on cell population doubling time and saturation density.
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PMID:Inhibition of cell proliferation by apolipoprotein E isoform expression. 1678 Jul 88

Testicular receptor 4 (TR4) is an orphan member of the nuclear receptor superfamily. Despite the lack of identified ligands, its functional role has been demonstrated both in animals and cell cultures. However, it remains unclear how the biological activity of TR4 is regulated without specific ligands. In this study, we showed that in the absence of specific ligands the activity of TR4 could be modulated by mitogen-activated protein kinase (MAPK)-mediated phosphorylation of its activation function 1 (AF-1) domain. A mass spectrometry-based proteome analysis of TR4 expressed in insect cells revealed three phosphorylation sites in its AF-1 domain, specifically on Ser(19), Ser(55), and Ser(68). Site-directed mutagenesis studies demonstrated the functionality of phosphorylation on Ser(19) and Ser(68) but not Ser(55). We also demonstrated that MAPK-mediated phosphorylation of the AF-1 domain rendered TR4 a repressor, mediated through the preferential recruitment of corepressor RIP140. Dephosphorylation of its AF-1 made TR4 an activator due to its selective recruitment of coactivator, P300/cyclic AMP-responsive element binding protein-binding protein-associated factor (PCAF). The biological effects were validated by using the wild type TR4 and its constitutive negative (dephosphorylated) and constitutive positive (phosphorylated) mutants in the studies of regulation of its natural target gene, apoE. This study uncovered, for the first time, a ligand-independent mechanism underlying the biological activity of TR4 that was mediated by MAPK-mediated receptor phosphorylation of AF-1 domain.
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PMID:Modulation of testicular receptor 4 activity by mitogen-activated protein kinase-mediated phosphorylation. 1688 30

Serum osteoprotegerin (OPG) is significantly increased in diabetic patients, prompting expanded investigation of the correlation between OPG production/release and glycemic levels. Serum levels of OPG, but not of its cognate ligand receptor activator of nuclear factor-kappaB ligand (RANKL), were significantly increased in type 2 diabetes mellitus patients compared with healthy blood donors. Serum OPG was also significantly elevated in a subgroup of recently diagnosed diabetic patients (within 2 years). The relationship between serum OPG and diabetes mellitus onset was next investigated in apoE-null and littermate mice. Serum OPG increased early after diabetes induction in both mouse strains and showed a positive correlation with blood glucose levels and an inverse correlation with the levels of free (OPG-unbound) RANKL. The in vitro addition of tumor necrosis factor-alpha to human vascular endothelial cells, but not human peripheral blood mononuclear cells, markedly enhanced OPG release in culture. In contrast, high glucose concentrations did not modulate OPG release when used alone or in association with tumor necrosis factor-alpha. Moreover, the ability of soluble RANKL to activate the extracellular signal-regulated kinase/mitogen-activated protein kinase and endothelial nitric-oxide synthase pathways in endothelial cells was neutralized by preincubation with recombinant OPG. Altogether, these findings suggest that increased OPG production represents an early event in the natural history of diabetes mellitus, possibly contributing to disease-associated endothelial cell dysfunction.
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PMID:An increased osteoprotegerin serum release characterizes the early onset of diabetes mellitus and may contribute to endothelial cell dysfunction. 1714 84

The anti-atherogenic properties of human apoprotein E-associated lipoproteins have been partially attributed to its anti-inflammatory properties. We studied if endogenously expressed apoprotein E (apoE) elicits isoform-dependent effects on pro-inflammatory cytokine expression and secretion. Mouse J774A.1 peritoneal macrophages without native expression of apoE were used to establish cell lines with stable expression of the three human apoE isoforms, apoE2, apoE3 and apoE4. In the presence of lipopolysaccharide (LPS), expression and secretion of TNF-alpha and IL-6 in cells expressing different apoE isoforms were determined by RT-PCR, immunoblotting and ELISA assays. ApoE3-expressing cells have significantly lower expression and secretion levels of the two cytokines as compared to cells with apoE2 and apoE4 expression. Such observations were accompanied with the lowest ERK1/2 activity in apoE3-expressing cells. Further study shows that the apoE isoform-dependent variations of TNF-alpha and IL-6 expression/secretion in macrophages are diminished in the presence of ERK1/2 inhibitor U0126. In conclusion, apoE elicits isoform-dependent effects on macrophage TNF-alpha and IL-6 expression as well as secretion. The ERK1/2 signaling pathways are involved in mediating such apoE isoform-dependent effects.
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PMID:Apoprotein E isoform-dependent expression and secretion of pro-inflammatory cytokines TNF-alpha and IL-6 in macrophages. 1735 5

c-Jun is a transcription factor activated by phosphorylation by the stress-activated protein kinase/c-Jun N-terminal kinase pathway in response to extracellular signals and cytokines. We show that adenovirus-mediated gene transfer of the dominant negative form of c-Jun (dn-c-Jun) in C57BL/6 mice increased greatly apoE hepatic mRNA and plasma levels, increased plasma cholesterol, triglyceride, and very low density lipoprotein levels, and resulted in the accumulation of discoidal high density lipoprotein particles. A similar but more severe phenotype was generated by overexpression of the mouse apoE in C57BL/6 mice, suggesting that dyslipidemia induced by dn-c-Jun was the result of apoE overexpression. Unexpectedly, infection of apoE(-/-) mice with adenovirus expressing dn-c-Jun reduced plasma cholesterol by 70%, suggesting that dn-c-Jun affected other genes that control plasma cholesterol levels. To identify these genes, we performed whole genome expression analysis (34,000 genes) of isolated livers from two groups of five apoE(-/-) mice, infected with adenoviruses expressing either the dn-c-Jun or the green fluorescence protein. Bioinformatic analysis and Northern blotting validation revealed that dn-c-Jun increased 40-fold the apoE mRNA and reduced by 70% the Scd-1 (stearoyl-CoA-desaturase 1) mRNA. The involvement of Scd-1 in lowering plasma cholesterol was confirmed by restoration of high cholesterol levels of apoE(-/-) mice following coinfection with adenoviruses expressing dn-c-Jun and Scd-1. In conclusion, dn-c-Jun appears to trigger two opposing events in mice that affect plasma cholesterol and triglyceride levels as follows: one results in apoE overexpression and triggers dyslipidemia and the other results in inhibition of Scd-1 and offsets dyslipidemia.
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PMID:A dominant negative form of the transcription factor c-Jun affects genes that have opposing effects on lipid homeostasis in mice. 1745 67


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