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)

CEA functions as an intercellular adhesion molecule and is up-regulated in a wide variety of human cancers, including colon, breast and lung. Its over-expression inhibits cellular differentiation, blocks cell polarization, distorts tissue architecture, and inhibits anoikis of many different cell types. Here we report results concerning the molecular mechanism involved in these biological effects, where relatively rapid molecular changes not requiring alterations in gene expression were emphasized. Confocal microscopy experiments showed that antibody-mediated clustering of a deletion mutant of CEA (DeltaNCEA), normally incapable of self binding and clustering, led to the co-localization of integrin alpha5beta1 with patches of DeltaNCEA on the cell surface. Activation of alpha5, as defined by an anti-alpha5 mAb-sensitive increase in cell adhesion to immobilized fibronectin, and an increased binding of soluble fibronectin to cells, was also observed. This was accompanied by the recruitment of integrin-linked kinase (ILK), protein kinase B (PKB/Akt), and the mitogen-activated protein kinase (MAPK) to membrane microdomains and the phosphorylation of Akt and MAPK. Inhibition of PI3-K and ILK, but not MAPK, prevented the alpha5beta1 integrin activation. Conversely, anti-alpha5 antibody inhibited the PI3-K-mediated activation of Akt, implying the involvement of outside-in and inside-out signaling in integrin activation. Therefore we propose that CEA-mediated signaling involves clustering of CEA and co-clustering and activation of the alpha5beta1 and associated specific signaling elements on the internal surfaces of membrane microdomains. These changes may represent a molecular mechanism for the biological effects of CEA.
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PMID:A co-clustering model involving alpha5beta1 integrin for the biological effects of GPI-anchored human carcinoembryonic antigen (CEA). 1728 76

Tumour necrosis factor (TNF) is a pro-inflammatory cytokine, whose primary targets include vascular endothelial cells. TNF-mediated adhesion molecule expression has been shown to play a central role in endothelial cells inflammatory responses and disorders such as atherosclerosis. However it is not fully understand how the TNF receptor subtypes, namely TNFR1 and TNFR2, regulate inflammatory responses in endothelial cells. The aim of this study was to elucidate the kinase signalling pathways that TNF receptors activate, and determine the pathways responsible for downstream expression of adhesion molecules, intracellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in human endothelial cells. Using human umbilical vein endothelial cells (HUVEC), we demonstrated that TNF activates a range of mitogen-activated protein kinases (MAPKs), including the extracellular-regulated kinase (ERK) pathway and the p38MAPK and c-Jun N-terminal kinase (JNK) stress kinase pathways. Human endothelial cells express both TNF receptor subtypes at low levels, however using TNFR-specific agonistic agents, we uncovered that TNF acts through its TNFR1 receptor subtype to activate NF-kappaB transcriptional pathways. Further investigation revealed that ICAM-1 and VCAM-1 mRNA and protein are induced by TNFR1 (but not TNFR2) in a wholly NF-kappaB-dependent manner. These findings reveal for the first time that TNF stimulation of adhesion molecules ICAM-1 and VCAM-1 in human endothelial cells occurs through the TNFR1 subtype and is mediated by the NF-kappaB pathway, but not the ERK, p38MAPK or JNK kinase pathways.
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PMID:TNFR1-induced NF-kappaB, but not ERK, p38MAPK or JNK activation, mediates TNF-induced ICAM-1 and VCAM-1 expression on endothelial cells. 1729 86

Smad2 participates in the TGF-beta signaling pathway, where it cooperates with transcription factors to regulate expression of defined genes. The purpose of this study was to investigate the expression pattern of phosphorylated Smad2 (pSmad2) in association with clinicopathological parameters and biological markers of proliferation and invasion. Immunohistochemistry was applied on paraffin-embedded sections from 164 patients with invasive breast carcinomas to detect the expression of the proteins pSmad2, ER, PR, Ki67, topoisomerase IIa, ERK2, catenin-p120, MMP-14 and TIMP-2. pSmad2 protein was detected in the nuclei of the malignant cells (68.1%) and in the tumor fibroblasts (55.2%). Nuclear pSmad2 was inversely correlated with histological grade and LN (p=0.047 and p=0.05) as well as with Ki67 and topoIIa (p=0.003 and p=0.021, respectively). There was also an inverse relation between nuclear pSmad2 and normal immunoexpression of the adhesion molecule catenin-p120 (p=0.028). Both nuclear and stromal pSmad2 were positively correlated with ERK2 of tumor fibroblasts (p=0.008 and p=0.0001, respectively), while stromal pSmad2 was furthermore related to stromal MMP-14 and tumor TIMP-2 (p=0.006 and p=0.022, respectively). Patients with high expression of cancerous pSmad2 tended to have a better prognosis, although statistic significance was never reached. pSmad2 was found to play a dual role, according to its distribution. Nuclear localization was thus found to be related to a less aggressive tumor phenotype, whereas stromal location was associated with an invasive phenotype.
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PMID:Effect of the different phosphorylated Smad2 protein localizations on the invasive breast carcinoma phenotype. 1729 76

The recent molecular characterization and sequencing of equine P-selectin (ePsel), and its glycoprotein ligand, P-selectin glycoprotein ligand-1 (PSGL-1), have provided the tools for further investigation into their role in leukocyte trafficking. Here, we report the generation of a genetically engineered chimeric protein (ePsel-IgG) in which the equine P-selectin lectin and epithelial growth factor (EGF) domains were covalently linked to the equine IgG1 heavy chain constant region. The soluble ePsel-IgG was observed to bind to equine monocytes by confocal microscopy and flow cytometry. Furthermore, equine monocytes bound to immobilized ePsel-IgG in a time course and dose dependent manner. Not only did ePsel-IgG act as an adhesion molecule, it was also found to activate ERK1/2 kinase and induce IL-8 mRNA expression in equine monocytes. That all of the aforementioned ePsel-IgG-induced cell binding and cell signaling were abolished by the addition of EDTA, suggested that ePsel-IgG chimera mediated events occurred via the P-selectin ligand, PSGL-1. We were able to demonstrate that 78% of equine monocytes cross-reacted with anti-human HECA-452 antibody, which recognizes the sialy-Lewis X (sLex) epitope, a well-known carbohydrate binding site on human PSGL-1. Pre-incubation of equine PBMC with neuraminidase or O-sialoglycoprotein endopeptidase (OSGP) reduced ePsel-IgG monocyte binding to 36% or 60%, respectively. Taken together, these data suggest that there might be two ligand recognition sites on P-selectin, one of which recognizes sLex and another which recognizes P-selectin ligand core protein. The ePsel-IgG chimera can be a useful as a reagent for further studies on the role of equine P-selectin and signal transduction in inflammatory events in horse.
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PMID:Cloning and functional characterization of recombinant equine P-selectin. 1730 78

Activation of eosinophils by microbe-derived molecules via Toll-like receptors (TLR) potentially provides the link between microbe-induced innate immune responses and the exacerbation of allergic inflammation. We investigated the expression of TLRs and the effect of their ligands on human eosinophils. Expression of TLR1-9 was detected by Western blot and flow cytometry. Adhesion molecules, cytokines, superoxides, and eosinophlilic cationic protein (ECP) were assessed by flow cytometry, enzyme-linked immunosorbent assay, chemiluminescent method, and fluorescence immunoassay, respectively. Human eosinophils differentially expressed TLR1, -2, -4, -5, -6, -7, and -9. Peptidoglycan (PGN) (TLR2 ligand), flagellin (TLR5 ligand), and Imiquimod R837 (TLR7 ligand) could significantly upregulate cell surface expression of intercellular adhesion molecule (ICAM)-1 and CD18, and induce the release of IL-1beta, IL-6, IL-8, growth-related oncogene (GRO)-alpha, and superoxides of eosinophils. Only PGN could induce the degranulation for ECP release. However, ds poly I-C (TLR3 ligand), LPS (TLR4 ligand), ssRNA (TLR8 ligand), and CpG-DNA (TLR9 ligand) were much less effective or inactive. PGN, flagellin, and R837 could activate both nuclear factor (NF)-kappaB and extracellular signal-regulated protein kinase (ERK). PGN could activate phosphatidylinositol 3-kinase (PI3K)-Akt, and R837 both PI3K-Akt and p38 mitogen-activated protein kinase (MAPK). The induction of the release of IL-1beta, IL-6, IL-8, GRO-alpha, superoxides, and ECP by PGN, flagellin, and R837 was found to be differentially regulated by NF-kappaB, ERK, PI3K-Akt, and p38 MAPK. The above results therefore support that microbial infection may lead to the exacerbation of allergic inflammation.
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PMID:Intracellular signaling mechanisms regulating toll-like receptor-mediated activation of eosinophils. 1733 40

E-selectin is a major adhesion molecule expressed by endothelial cells (ECs), which are exposed to shear stress and neighboring smooth muscle cells (SMCs). We investigated the mechanisms underlying the modulation of EC E-selectin expression by SMCs and shear stress. SMC coculture induced rapid and sustained increases in expression of E-selectin and phosphorylation of interleukin-1 (IL-1) receptor-associated kinase glycoprotein-130, as well as the downstream mitogen-activated protein kinases (MAPKs) and Akt. By using specific inhibitors, dominant-negative mutants, and small interfering RNA, we demonstrated that activations of c-Jun-NH(2)-terminal kinase (JNK) and p38 of the MAPK pathways are critical for the coculture-induced E-selectin expression. Gel shifting and chromatin immunoprecipitation assays showed that SMC coculture increased the nuclear factor-kappaB (NF-kappaB)-promoter binding activity in ECs; inhibition of NF-kappaB activation by p65-antisense, lactacystin, and N-acetyl-cysteine blocked the coculture-induced E-selectin promoter activity. Protein arrays and blocking assays using neutralizing antibodies demonstrated that IL-1beta and IL-6 produced by EC/SMC cocultures are major contributors to the coculture induction of EC signaling and E-selectin expression. Preshearing of ECs at 12 dynes/cm(2) inhibited the coculture-induced EC signaling and E-selectin expression. Our findings have elucidated the molecular mechanisms underlying the SMC induction of EC E-selectin expression and the shear stress protection against this SMC induction.
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PMID:Mechanisms of induction of endothelial cell E-selectin expression by smooth muscle cells and its inhibition by shear stress. 1737 46

We investigated the regulatory role of glutathione in tumor necrosis factor-alpha (TNF-alpha)-induced vascular endothelial dysfunction as evaluated by using vascular endothelial adhesion molecule expression and monocyte-endothelial monolayer binding. Since TNF-alpha induces various biological effects on vascular cells, TNF-alpha dosage could be a determinant factor directing vascular cells into different biological fates. Based on the adhesion molecule expression patterns responding to different TNF-alpha concentrations, we adopted the lower TNF-alpha (0.2 ng/ml) to rule out the possible involvement of other TNF-alpha-induced biological effects. Inhibition of glutathione synthesis by l-buthionine-(S,R)-sulfoximine (BSO) resulted in down-regulations of the TNF-alpha-induced adhesion molecule expression and monocyte-endothelial monolayer binding. BSO attenuated the TNF-alpha-induced nuclear factor-kappaB (NF-kappaB) activation, however, with no detectable effect on AP-1 and its related mitogen-activated protein kinases (MAPKs). Deletion of an AP-1 binding site in intercellular adhesion molecule-1 (ICAM-1) promoter totally abolished its constitutive promoter activity and its responsiveness to TNF-alpha. Inhibition of ERK, JNK, or NF-kappaB attenuates TNF-alpha-induced ICAM-1 promoter activation and monocyte-endothelial monolayer binding. Our study indicates that TNF-alpha induces adhesion molecule expression and monocyte-endothelial monolayer binding mainly via activation of NF-kappaB in a glutathione-sensitive manner. We also demonstrated that intracellular glutathione does not modulate the activation of MAPKs and/or their downstream AP-1 induced by lower TNF-alpha. Although AP-1 activation by the lower TNF-alpha was not detected in our systems, we could not rule out the possible involvement of transiently activated MAPKs/AP-1 in the regulation of TNF-alpha-induced adhesion molecule expression.
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PMID:Glutathione regulation of redox-sensitive signals in tumor necrosis factor-alpha-induced vascular endothelial dysfunction. 1746 21

Crohn's disease and ulcerative colitis are two idiopathic inflammatory bowel disorders. In this paper we discuss the current diagnostic approach, their pathology, natural course, and common complications, the assessment of disease activity, extraintestinal manifestations, and medical and surgical management, and provide diagnostic and therapeutic algorithms. We critically review the evidence for established (5-aminosalicylic acid compounds, corticosteroids, immunomodulators, calcineurin inhibitors) and emerging novel therapies--including biological therapies--directed at cytokines (eg, infliximab, adalimumab, certolizumab pegol) and receptors (eg, visilizumab, abatacept) involved in T-cell activation, selective adhesion molecule blockers (eg, natalizumab, MLN-02, alicaforsen), anti-inflammatory cytokines (eg, interleukin 10), modulation of the intestinal flora (eg, antibiotics, prebiotics, probiotics), leucocyte apheresis and many more monoclonal antibodies, small molecules, recombinant growth factors, and MAP kinase inhibitors targeting various inflammatory cells and pathways. Finally, we summarise the practical aspects of standard therapies including dosing, precautions, and side-effects.
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PMID:Inflammatory bowel disease: clinical aspects and established and evolving therapies. 1766 78

In end-stage renal disease (ESRD) endothelium may represent a key target for the action of circulating elements, such as modified erythrocytes (RBC) and/or plasmatic factors, that may facilitate inflammation and the vasculopathy associated with uremia. We have previously demonstrated that phosphatidylserine (PS) exposure on the surface of RBC from ESRD patients increases RBC-human umbilical vein endothelial cell (HUVEC) interactions and causes decreased nitric oxide (NO) production. We postulated that, besides the pro-inflammatory effects due to decreased NO bio-availability, enhanced ESRD-RBC-HUVEC interactions might directly stimulate pro-inflammatory pathways leading to increased vascular adhesion molecule expression. ESRD-RBC-endothelial cell interactions induced a time-dependent up-regulation of VCAM-1 and ICAM-1 (measured by Western blot (WB) and real-time PCR), associated with mitogen-activated protein kinase (MAPK) activation and impairment of the Akt/endothelial nitric oxide synthase (eNOS) signaling cascade, measured by WB. In reconstitution experiments, normal RBC incubated with uremic plasma showed increased PS exposure and significantly increased VCAM-1 and ICAM-1 mRNA levels when incubated on HUVEC. Interestingly, ESRD-RBC induced increased expression of adhesion molecules was prevented by Annexin-V (AnV, able to mask PS on RBC surface), anti-integrin-alpha(v)beta3, anti-thrombospondin-1 (TSP-1), and PD98059 (a selective inhibitor of MAPK phosphorylation). Moreover, AnV reversed the ESRD-RBC effects on MAPK and Akt/eNOS signaling pathways. Our data demonstrate that, possibly via a direct interaction with the endothelial thrombospondin-(alpha(v)beta3) integrin complex, ESRD-RBC-HUVEC adhesion induces a vascular inflammatory phenotype. Thus, intervention targeting ESRD-RBC increased adhesion to endothelium and/or MAPK and Akt/eNOS pathways may have the potential to prevent vascular lesions under uremic conditions.
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PMID:Mechanisms of uremic erythrocyte-induced adhesion of human monocytes to cultured endothelial cells. 1751 66

We demonstrate that mitogen-activated protein kinase-activated kinase-2 (MK2) is essential for localized Th2-type inflammation and development of experimental asthma. MK2 deficiency does not affect systemic Th2 immunity, but reduces endothelial permeability, as well as adhesion molecule and chemokine expression. NF-kappaB regulates transcription of adhesion molecules and chemokines. We show that MK2 and its substrate HSP27 are essential for sustained NF-kappaB activation. MK2 and HSP27 prevent nuclear retention of p38 by sequestering it in the cytosol. As a result, MK2 precludes excessive phosphorylation of MSK1. By reducing MSK1 activity, MK2 prevents p65 NF-kappaB hyperphosphorylation and excessive IkappaBalpha transcription. IkappaBalpha mediates nuclear export of p65. By reducing IkappaBalpha level, MK2 prevents premature export of NF-kappaB from the nucleus. Thus, the MK2-HSP27 pathway regulates the NF-kappaB transcriptional output by switching the activation pattern from high level, but short lasting, to moderate-level, but long lasting. This pattern of activation is essential for many NF-kappaB-regulated genes and development of inflammation. Thus, the MK2-HSP27 pathway is an excellent target for therapeutic control of localized inflammatory diseases.
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PMID:MK2 controls the level of negative feedback in the NF-kappaB pathway and is essential for vascular permeability and airway inflammation. 1757 78


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