Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P05412 (c-Jun)
 11,453 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The cAMP-responsive element/activating transcription factor (CRE/ATF) element (also known as NF-ELAM1) of the endothelial leukocyte adhesion molecule-1 (ELAM-1) promoter is necessary for full cytokine responsiveness. It differs from a consensus cAMP-responsive element (CRE) by 1 nucleotide (G-->A conversion) and does not mediate transcriptional activation in response to cAMP. We reported previously that cAMP actually decreases ELAM-1 synthesis induced by tumor necrosis factor (TNF). We now show that cAMP decreases the ELAM-1 promoter response to TNF in transient transfection assays in bovine aortic endothelial cells and that cAMP-mediated inhibition maps to the CRE/ATF element. Electrophoretic mobility shift assays using the ELAM-1 CRE/ATF DNA sequence reveal three complexes. Antibody supershift assays suggest the slowest migrating form (complex 1) contains ATF2, the middle form (complex 2) contains ATF2 and c-Jun, and the fastest migrating form (complex 3) contains a CRE-binding protein. TNF increases c-Jun-containing complex 2 while diminishing complex 1, whereas cAMP decreases complex 2 and increases complex 1. Complex 3 is unchanged by either treatment, and the CRE-binding protein is not phosphorylated. Our data suggest that a change in the composition of the proteins binding to the CRE/ATF promoter element contributes to the competing effects of TNF and cAMP on ELAM-1 gene expression.
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PMID:cAMP and tumor necrosis factor competitively regulate transcriptional activation through and nuclear factor binding to the cAMP-responsive element/activating transcription factor element of the endothelial leukocyte adhesion molecule-1 (E-selectin) promoter. 751 52

Tumor necrosis factor (TNF) activates transcription of endothelial leukocyte adhesion molecule-1 (CD62E) in endothelial cells (ECs) through the binding to the gene promoter of the p50/p65 heterodimeric form of nuclear factor-kappa B (NF-kappa B) and of the N-terminal phosphorylated form of the ATF2/c-Jun transcription factor, which is phosphorylated by Jun N-terminal kinase (JNK). However, the intracellular signaling pathways that activate endothelial NF-kappa B and JNK in TNF-induced responses are unknown. In this study we have examined the role of a recently described TNF signaling pathway involving sphingomyelin activation to generate ceramide, a potential intracellular mediator. We find that concentrations of TNF that strongly activate NF-kappa B and JNK within 15 minutes do not produce either a measurable decline in sphingomyelin or a measurable generation of ceramide in cultured human umbilical vein ECs at any time examined. Stimulation of ECs with purified sphingomyelinase (SMase) enzyme causes a rapid 60% to 80% decrease in cellular sphingomyelin content and a large increase in ceramide. However, SMase treatment only minimally activates NF-kappa B, achieving levels that are insufficient to initiate gene transcription. Extracellular SMase does not have access to intracellular sphingomyelin, but treatment of ECs with membrane-permeant ceramide analogues still completely fails to activate NF-kappa B and only activates JNK at late times. Neither SMase nor ceramide analogues induce gene transcription or surface expression of endothelial leukocyte adhesion molecules that are readily induced by TNF. Strikingly, low concentrations of membrane-permeant ceramide cause programmed cell death in ECs, a finding not observed at any concentrations of TNF tested. We conclude that ceramide is not an important second messenger for TNF signaling of gene transcription in ECs but may be a second messenger for cell death in response to as-yet-unidentified signals.
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PMID:Ceramide is not a signal for tumor necrosis factor-induced gene expression but does cause programmed cell death in human vascular endothelial cells. 883 97

E-selectin, an adhesion molecule expressed on the surface of activated endothelial cells, is essential for leukocyte rolling on endothelium which leads to extravasation in the process of inflammation. Induction of E-selectin expression by proinflammatory stimuli such as TNF-alpha or LPS is reduced markedly in the presence of dexamethasone, a synthetic glucocorticoid and potent anti-inflammatory agent. We have investigated the molecular mechanism underlying dexamethasone-mediated E-selectin repression in porcine aortic endothelial cells. Reduced E-selectin protein expression is paralleled by a decrease in E-selectin mRNA and is based on changes in transcription rate. Analysis of the E-selectin promoter revealed that induction by proinflammatory stimuli as well as repression by dexamethasone are mediated by the same promoter region containing three closely spaced binding sites for nuclear factor (NF)-kappaB and an element, NF-ELAM-1 (endothelial leukocyte adhesion molecule-1), constitutively occupied by ATF and c-Jun. NF-ELAM-1 contributes to maximal promoter activity, but does not confer glucocorticoid inhibition, as demonstrated by site-directed mutagenesis. In contrast, transcription directed by the E-selectin NF-kappaB elements is reduced strongly in the presence of dexamethasone, thus identifying NF-kappaB as the primary target for glucocorticoid-mediated E-selectin repression.
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PMID:Glucocorticoids inhibit E-selectin expression by targeting NF-kappaB and not ATF/c-Jun. 910 51

Permanent or temporary disruption of cerebral blood flow rapidly depletes brain regions of their limited energy reserves (glycogen, glucose, oxygen, ATP) leading to an energy crisis. Tissue damage occurs due to the energy crisis. The central part of the damage, the ischaemic "core" region is surrounded by zones of the shell-like penumbra. Necrotic, as well as apoptotic cell death could be identified in the penumbra. Going away from the ischaemic core different neurochemical processes are occurring by space and time. "Immediate early response" genes (c-fos, fos-B, c-Jun, krox 20, 24) are activated, heatshock proteins (hsp 70, 72, HSF, HSE, HIF), cytokines (TNF-alpha, IL-1 beta), inflammatory factors (COX), adhesion and glial factors (ICAM-1, ELAM-1, P-selectin), vasoactive factors (IL-6, -10, PAF), reactive oxigen radicals and connected factors (O2, OH, NO, NOS, SOD) are produced within minutes and hours. Cell deaths, necrosis and apoptosis due to the activation of calpains, caspases and nucleases occur in days. In parallel, growth factors and plasticity proteins (BDNF, NGF, TGF-beta, VEGF, PDGF, GAP-43) are activated as a basis of functional rehabilitation.
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PMID:[Regulatory mechanisms in focal cerebral ischemia. New possibilities in neuroprotective therapy]. 1212 84

It has been widely shown that many plant-derived compounds present significant anti-inflammatory effects. For this reason, they represent potential molecules for the development of new drugs, especially designed for the treatment and/or control of chronic inflammatory states such as rheumatism, asthma, inflammatory bowel diseases, atherosclerosis, etc. This review focuses on the naturally-occurring compounds with anti-inflammatory properties and attempts to correlate their actions with the modulation of cytokines and associated intracellular signalling pathways; it continues the review published in the November, 2003 issue of Planta Medica. Abbreviations. AP-1:activator protein-1 CCR1:chemokine receptor 1 CINC-1:cytokine-induced neutrophil chemoattractant 1 COX:cyclooxygenase EGCG:(-)-epigallocatechin gallate ELAM-1:endothelial-leukocyte adhesion molecule-1 ERK:extracellular signal-regulated kinase GRO:growth-related oncogene HUVEC:human umbilical vein endothelial cells ICAM-1:intercellular adhesion molecule-1 IFN:interferon IL:interleukin iNOS:inducible nitric oxide synthase IRA:the natural interleukin receptor activation JAK:janus kinase JNK:c-Jun NH2-terminal kinase LPS:lipopolysaccharide MAPK:mitogen-activated protein kinases MCP:monocyte chemotactic protein MHC:major histocompatibility complex MIP:macrophage inflammatory protein MMP:matrix metalloproteinases MPO:myeloperoxidase NF-kappaBnuclear factor kappa B NO:nitric oxide PAF:platelet aggregation factor PGEE:prostaglandin PK:protein kinase PMA/TPA:phorbol myristate acetate RANTES:regulated upon activation normal T-cell expressed and secreted TGF-beta:transforming growth factor-beta TNFalpha:tumour necrosis factor VCAM-1:vascular cell adhesion molecule-1
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PMID:Anti-inflammatory compounds of plant origin. Part II. modulation of pro-inflammatory cytokines, chemokines and adhesion molecules. 1499 84

Drug carriers are generally introduced into the body intravenously and directly exposed to endothelial cells. Silica nanoparticles could be promising delivery vehicles for drug targeting or gene therapy. However, few studies have been undertaken to determine the biological behavior of silica nanoparticles on endothelial cells. Here we measured reactive oxygen species (ROS) generation, apoptosis and necrosis, proinflammatory and prothrombic properties and the levels of the apoptotic signaling proteins and the transcription factors in human umbilical vein endothelial cells (HUVECs) after exposure to silica nanoparticles of different concentrations (25, 50, 100, and 200 microg/mL) for 24h. The results showed that silica nanoparticles, ranging from 50 microg/mL to 200 microg/mL, markedly induced ROS production, mitochondrial depolarization and apoptosis in HUVECs. At the highest concentration, the necrotic rate, LDH leakage, the expression of CD54 and CD62E, and the release of TF, IL-6, IL-8 and MCP-1 were significantly increased. Silica nanoparticles also activated c-Jun N-terminal kinase (JNK), c-Jun, p53, caspase-3 and NF-kappaB, increased Bax expression and suppressed Bcl-2 protein. Moreover, inhibition of ROS attenuated silica nanoparticles-induced apoptosis and inflammation and the activation of JNK, c-Jun, p53 and NF-kappaB. In summary, our findings demonstrated that silica nanoparticles could induce dysfunction of endothelial cells through oxidative stress via JNK, p53 and NF-kappaB pathways, suggesting that exposure to silica nanoparticles may be a significant risk for the development of cardiovascular diseases such as atherosclerosis and thrombus.
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PMID:Endothelial cells dysfunction induced by silica nanoparticles through oxidative stress via JNK/P53 and NF-kappaB pathways. 2072 82