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

Recent studies have demonstrated that stromal cell-derived factor-1alpha (SDF-1alpha)/CXCR4 interaction regulates multiple cell signal pathways and a variety of cellular functions such as cell migration, proliferation, survival and angiogenesis. In present study, we aimed to determine the effect of SDF-1alpha on endothelial progenitor cells (EPCs) apoptosis induced by serum deprivation and the implication of phosphoinositide 3-kinase (PI3K)/Akt and mitogen-activated protein kinases (MAPKs) signaling in this effect. EPCs were isolated and characterized. SDF-1alpha decreased EPCs apoptosis induced by serum deprivation in a dose-dependent manner and the inhibitory effect was CXCR4 dependent as confirmed by the total abolishment by AMD3100, a CXCR4-specific peptide antagonist. SDF-1alpha treatment also significant decreased caspase-3 expression and activity. The inhibitory effect of SDF-1alpha on EPCs apoptosis was nearly completely abolished by PI3K inhibitors (either Wortmannin or LY294002) and partially abolished by NOS inhibitor, N(G)-nitro-arginine methyl ester, whereas inhibitors of MAPKs had no significant effect on this inhibitory effect. The treatment of EPCs with SDF-1alpha resulted in time-dependent Akt, eNOS, extracellular-regulated kinase (ERK1/2), p38 MAPK and c-Jun N-terminal kinase (JNK) phosphorylations. These findings suggest that PI3K/Akt/eNOS activation, but not MAPKs activation, is required for the inhibitory effect of SDF-1alpha on EPCs apoptosis.
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PMID:SDF-1alpha/CXCR4 decreases endothelial progenitor cells apoptosis under serum deprivation by PI3K/Akt/eNOS pathway. 1838 92

Ginsenoside Rp1 (G-Rp1) is a ginseng saponin derivative with chemopreventive and anti-cancer activities. In this study, we examined the regulatory activity of G-Rp1 on the production of interleukin (IL)-1beta, a pro-inflammatory cytokine managing acute or chronic inflammatory diseases such as septic shock and rheumatoid arthritis, from lipopolysaccharide (LPS)-treated macrophage-like RAW264.7 cells. G-Rp1 dose-dependently inhibited IL-1beta production from LPS-treated RAW264.7 cells without altering cell viability. This compound suppressed both mRNA and protein levels of IL-1beta. In particular, this compound was found to down-regulate phosphorylation of the inhibitor of kappaB (IkappaB) kinase (IKK)/IkappaBalpha, and consequent activation of NF-kappaB, but not the activation of its upstream signaling enzymes such as mitogen-activated protein kinases (MAPK) and p85, a regulatory subunit of phosphoinositide 3-kinase (PI3K). Therefore, these results suggest that G-Rp1 may act as an inhibitor of IL-1beta production by inhibiting the NF-kappaB pathway.
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PMID:Ginsenoside Rp1, a ginsenoside derivative, blocks lipopolysaccharide-induced interleukin-1beta production via suppression of the NF-kappaB pathway. 1914 54

We recently reported that LY294002 (LY29) and LY303511 (LY30) sensitized tumor cells to drug-induced apoptosis independent of the phosphoinositide 3-kinase/Akt pathway. Here, we investigated the mechanism of LY30-induced sensitization of human neuroblastoma cells to TRAIL-mediated apoptosis. We provide evidence that LY30-induced increase in intracellular H(2)O(2) up-regulates the expression of TRAIL receptors (DR4 and DR5) in SHEP-1 cells by activating mitogen-activated protein kinases, resulting in a significant amplification of TRAIL-mediated caspase-8 processing and activity, cytosolic translocation of cytochrome c, and cell death. Involvement of the death receptors was further confirmed by the ability of blocking antibodies against DR4 and/or DR5 to inhibit LY30-induced TRAIL sensitization. Pharmacologic inhibition of c-Jun NH(2) terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) activation by SP600125 and PD98059, respectively, blocked LY30-induced increase in sensitization to TRAIL-mediated death. Finally, small interfering RNA-mediated gene silencing of JNK and ERK inhibited LY30-induced increase in surface expression of DR4 and DR5, respectively. These data show that JNK and ERK are two crucial players involved in H(2)O(2)-mediated increase in TRAIL sensitization of tumor cells upon exposure to LY30 and underscore a novel mode of action of this inactive analogue of LY29. Our findings could have implications for the use of LY30 and similar compounds for enhancing the apoptotic sensitivity of neuroblastoma cells that often become refractory to chemotherapy.
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PMID:LY303511 enhances TRAIL sensitivity of SHEP-1 neuroblastoma cells via hydrogen peroxide-mediated mitogen-activated protein kinase activation and up-regulation of death receptors. 1922 50

Ozone, one of the main components of photochemical smog, represents an important source of environmental oxidative stress to which the skin is exposed, especially during smoggy and ozone-alert days. However, very little is known about the effects of ozone exposure on human skin. Here, we used normal human epidermal keratinocytes (NHEKs) to determine the effects of attainable levels of ozone exposure on the family of cytochrome P450 (CYP) isoforms, which plays a determinant role in the biotransformation of many environmental pollutants. NHEK exposure to ozone (0.3 ppm) resulted in an increase in protein and messenger RNA (mRNA) expression of CYP1A1, CYP1A2, and CYP1B1. NHEK exposure to ozone also resulted in nuclear translocation of the aryl hydrocarbon receptor (AhR) and in phosphorylation of epidermal growth factor receptor (EGFR). The effect of ozone on events downstream of EGFR was an increased activation of phosphoinositide 3-kinase and phosphorylation of protein kinase B and mitogen-activated protein kinases. We found that AhR silencing by small interfering RNA abolished the capacity of these cells to increase the protein and mRNA expression of CYPs on ozone exposure. Thus, AhR signaling is an integral part of the induction of CYPs by ozone. These studies strongly suggest that there are toxicological consequences of ozone to human skin.
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PMID:Aryl hydrocarbon receptor is an ozone sensor in human skin. 1953 46

Humic acid, a group of polymer, resulting from the decomposition of organic matter has been implicated as a possible etiological factor for Black foot disease and cancer. However, the role of humic acid in carcinogenesis is not well clarified. In this study, we evaluated the enhancement effect of humic acid on the progression of A549 human lung cancer cells. Our findings showed that humic acid increased the migration, adhesion and invasion of A549 cells significantly after treatment at the concentration of 50 and 100 microg/ml for 24 and 48 h as compared with the untreated group. Results of zymography assay indicated that humic acid enhanced the activity of matrix metalloproteinase 9 (MMP-9). By western blotting analysis, humic acid increased the expression of phosphorylated focal adhesion kinase (FAK) and integrin alpha2 that may mediate cell motility and adhesion. Since the activation of signal pathways such as phosphoinositide 3-kinase/Akt (PI3K/Akt) and mitogen-activated protein kinases (MAPKs) may play a role in the cell invasion, we detected the expression of phosphorylated Akt and phosphorylated MAPKs including extracellular signal-regulated kinase (ERK), Jun N-terminus kinase (JNK), and p38. The result indicated that all kinases stated above were activated by humic acid in A549 cells. However, by adding an inhibitor respectively in the invasion assay, only Akt, ERK, and JNK pathways were found to be involved in the enhancing the invasion of A549 cells by humic acid. In addition, results of electrophoretic mobility shift assay (EMSA) demonstrated that humic acid increased nuclear extract binding to the DNA probe of activator protein 1 (AP-1) and nuclear factor kappaB (NFkappaB) respectively, implying that humic acid enhanced the progression of A549 lung cancer cells through activating multiple signaling pathways including ERK, JNK, and PI3K/Akt and increasing the transcription activation of AP-1 and NFkappaB.
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PMID:In vitro enhancement effect of humic acid on the progression of lung cancer cells. 1968 14

Lasonolide A, a novel polyketide-derived macrolide, was previously identified from an extract of the marine sponge Forcepia sp. in an assay for protein kinase C (PKC) inhibitors. Cytotoxicity testing and profiling of lasonolide A in the National Cancer Institute (NCI) 60 cell panel screen revealed that it was potent toward a broad range of cell lines and also suggested a unique mechanism of action. Contrary to expected results, we found lasonolide A to be a strong activator of PKC in Panc-1 pancreatic carcinoma cells. Downstream mitogen-activated protein kinases, ERK 1/2 and p38 were also rapidly phosphorylated in response to lasonolide A, as was Akt. Microscopy studies revealed that lasonolide A induced blebbing and contraction of the cells within minutes of exposure, and the eventual loss of adherence. However, membrane integrity was maintained and the effects were reversible if lasonolide A was washed from the cells after their loss of adherence. Pretreatment of cells with a myosin II inhibitor, blebbistatin, slowed the early onset, but did not prevent the morphological effects of lasonolide A. Cells stained for actin filaments showed some reduction in stress fiber structure after lasonolide A exposure; however, it did not affect the polymerization of purified actin in vitro. Bisindolemaleimide, a PKC inhibitor, and wortmannin, a phosphoinositide 3-kinase; inhibitor, did not reduce lasonolide A-induced contraction or blebbing or the activation of mitogen-activated protein kinases, although Akt phosphorylation was prevented by wortmannin pretreatment. Our results indicate that lasonolide A activates multiple signal transduction pathways and suggest that the origin is upstream of PKC.
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PMID:Early effects of lasonolide a on pancreatic cancer cells. 1969 35

Pseudomonas aeruginosa (PA) is an opportunistic pathogen that causes the relapse of illness in immunocompromised patients, leading to prolonged hospitalization, increased medical expense, and death. In this report, we show that PA invades natural killer (NK) cells and induces phagocytosis-induced cell death (PICD) of lymphocytes. In vivo tumor metastasis was augmented by PA infection, with a significant reduction in NK cell number. Adoptive transfer of NK cells mitigated PA-induced metastasis. Internalization of PA into NK cells was observed by transmission electron microscopy. In addition, PA invaded NK cells via phosphoinositide 3-kinase (PI3K) activation, and the phagocytic event led to caspase 9-dependent apoptosis of NK cells. PA-mediated NK cell apoptosis was dependent on activation of mitogen-activated protein (MAP) kinase and the generation of reactive oxygen species (ROS). These data suggest that the phagocytosis of PA by NK cells is a critical event that affects the relapse of diseases in immunocompromised patients, such as those with cancer, and provides important insights into the interactions between PA and NK cells.
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PMID:Pseudomonas aeruginosa eliminates natural killer cells via phagocytosis-induced apoptosis. 1971 21

Trefoil factor family 3 (TFF3) is secreted in saliva. The peptide improves the mechanical and chemical resistance of mucins, and it may act as a motility signal for oral keratinocytes during wound healing. This study aimed to identify novel functions of TFF3 in oral keratinocytes. To achieve this, we used phosphoprotein and messenger RNA (mRNA) arrays to compare TFF3-treated and untreated oral keratinocytes. Analysis of the phosphoprotein array indicated that TFF3 signals through the mitogen-activated protein kinases (MAPKs) c-Jun N-terminal kinase (JNK), p38, and extracellular signal-regulated kinase (ERK1/2), and through the phosphoinositide 3-kinase (PI3K)/protein kinase B (PKB) pathway. Microarray analysis of mRNA showed that TFF3 stimulation induced changes in the expression of genes functionally related to cell death/survival, cell growth and proliferation, and cell movement. The reverse transcription-polymerase chain reaction (RT-PCR) results indicated that the transcription of some immediate-early genes (IEGs) was downregulated, whereas the IEGs FBJ osteosarkoma oncogene (FOS) and C-MYC binding protein (MYCBP2) were transiently upregulated by TFF3 stimulation. Together, the results of the arrays indicate that TFF3 is a modifying factor in pathways regulating cell survival, cell growth and proliferation, and cell migration of oral keratinocytes. Trefoil factor family 3 may therefore promote oral wound healing and it should be considered for the treatment of oral ulcerating diseases, or of other diseases.
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PMID:Signal transduction and gene transcription induced by TFF3 in oral keratinocytes. 1975 46

Toll-like receptors (TLRs) are important sensors of foreign microbial components as well as products of damaged or inflamed self tissues. Upon sensing these molecules, TLRs initiate a series of downstream signaling events that drive cellular responses including the production of cytokines, chemokines, and other inflammatory mediators. This outcome results from the intracellular assembly of protein complexes that drive phosphorylation and other signaling cascades ultimately leading to chromatin remodeling and transcription factor activation. In addition to driving inflammatory responses, TLRs also regulate cell proliferation and survival which serves to expand useful immune cells and integrate inflammatory responses and tissue repair processes. In this context, central TLR signaling molecules, such as the mitogen-activated protein kinases (MAPK) and phosphoinositide 3-kinase (PI3K), play key roles. In addition, four major groups of transcription factors which are targets of TLR activation also control cell fate. This review focuses on the role of TLR signaling as it relates to cell proliferation and survival. This topic not only has important implications for understanding host defense and tissue repair, but also cancer which is often associated with conditions of chronic inflammation.
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PMID:Toll-like receptor signaling in cell proliferation and survival. 1977 7

TF (tissue factor) is the main trigger of the coagulation cascade; by binding Factor VIIa it activates Factor IX and Factor X, thereby resulting in fibrin formation. Various stimuli, such as cytokines, growth factors and biogenic amines, induce TF expression and activity in vascular cells. Downstream targets of these mediators include diverse signalling molecules such as MAPKs (mitogen-activated protein kinases), PI3K (phosphoinositide 3-kinase) and PKC (protein kinase C). In addition, TF can be detected in the bloodstream, known as circulating or blood-borne TF. Many cardiovascular risk factors, such as hypertension, diabetes, dyslipidaemia and smoking, are associated with increased expression of TF. Furthermore, in patients presenting with acute coronary syndromes, elevated levels of circulating TF are found. Apart from its role in thrombosis, TF has pro-atherogenic properties, as it is involved in neointima formation by inducing vascular smooth muscle cell migration. As inhibition of TF action appears to be an attractive target for the treatment of cardiovascular disease, therapeutic strategies are under investigation to specifically interfere with the action of TF or, alternatively, promote the effects of TFPI (TF pathway inhibitor).
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PMID:Tissue factor: beyond coagulation in the cardiovascular system. 1984 9


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