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

The loss of neurons by programmed cell death is a normal feature of the nervous system during development and has recently been implicated as a major mechanism of cell death in neurodegenerative diseases. In some cases, programmed cell death is induced by the activation of membrane receptors and is referred to as activation-induced programmed cell death. Activation-induced programmed cell death has been previously described in cells from the immune system, in which the activation of receptors by receptor clustering leads to programmed cell death. To determine whether activation-induced programmed cell death occurs in neurons, Concanavalin A was used to cross-link membrane receptors on cortical neurons. Concanavalin A-induced neuronal death was dose dependent and effective at concentrations previously shown to induce activation-induced programmed cell death in lymphocytes. Programmed cell death was attenuated when Concanavalin A-specific binding to neurons was blocked with methyl alpha-D-mannopyranoside. Succinyl Concanavalin A, which bound to Concanavalin A receptors but was ineffective at cross-linking them, did not induce programmed cell death. Concanavalin A-induced neuronal death exhibited many of the hallmarks associated with programmed cell death, such as membrane blebbing, nuclear condensation and margination, and internucleosomal DNA cleavage. In addition, neurons exposed to Concanavalin A displayed a rapid, robust, and persistent increase in the immediate early gene protein c-Jun. A similar increase in c-Jun precedes programmed cell death induced by beta-amyloid in neurons, and under some conditions an increase in c-Jun has been shown to be required for programmed cell death to occur in neurons. Increased expression of c-jun and other immediate early genes has also been correlated with activation-induced programmed cell death in lymphocytes. These observations suggest that Concanavalin A induces activation-induced programmed cell death in neurons via signals produced from the cross-linking of receptors on neuronal membranes. These results also raise the possibility that beta-amyloid induces programmed cell death in a similar manner, by causing the cross-linking of receptors on neuronal membranes. This mechanism may be relevant to neuronal programmed cell death that occurs during development and neurodegeneration.
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PMID:Cross-linking of concanavalin A receptors on cortical neurons induces programmed cell death. 892 32

The biological effects of type IIA 14-kDa phospholipase A2 (sPLA2) on 1321N1 astrocytoma cells were studied. sPLA2 induced a release of [3H]arachidonic acid ([3H]AA) similar to that elicited by lysophosphatidic acid (LPA), a messenger acting via a G-protein-coupled receptor and a product of sPLA2 on lipid microvesicles. In contrast, no release of [1-14C]oleate could be detected in cells labeled with this fatty acid. As these findings pointed to a selective mechanism of [3H]AA release, it was hypothesized that sPLA2 could act by a signaling mechanism involving the activation of cytosolic PLA2 (cPLA2), i.e. the type of PLA2 involved in the release of [3H]AA elicited by agonists. In keeping with this view, stimulation of 1321N1 cells with sPLA2 elicited the decrease in electrophoretic mobility that is characteristic of the phosphorylation of cPLA2, as well as activation of p42 mitogen-activated protein (MAP) kinase, c-Jun kinase, and p38 MAP kinase. Incubation with sPLA2 of quiescent 1321N1 cells elicited a mitogenic response as judged from an increased incorporation of [3H]thymidine. Attempts to correlate the effect of extracellular PLA2 with the generation of LPA were negative. Incubation with pertussis toxin prior to the addition of either sPLA2 or LPA only showed abrogation of the response to LPA, thus suggesting the involvement of pertussis-sensitive Gi-proteins in the case of LPA. Treatments with inhibitors of the catalytic effect of sPLA2 such as p-bromophenacyl bromide and dithiothreitol did not prevent the effect on cPLA2 activation. In contrast, preincubation of 1321N1 cells with the antagonist of the sPLA2 receptor p-aminophenyl-alpha-D-mannopyranoside-bovine serum albumin, blocked cPLA2 activation with a EC50 similar to that described for the inhibition of binding of sPLA2 to its receptor. Moreover, treatment of 1321N1 cells with the MAP kinase kinase inhibitor PD-98059 inhibited the activation of both cPLA2 and p42 MAP kinase produced by sPLA2. In summary, these data indicate the existence in astrocytoma cells of a signaling pathway triggered by engagement of a sPLA2-binding structure, that produces the release of [3H]AA by activating the MAP kinase cascade and cPLA2, and leads to a mitogenic response after longer periods of incubation.
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PMID:Secretory phospholipase A2 activates the cascade of mitogen-activated protein kinases and cytosolic phospholipase A2 in the human astrocytoma cell line 1321N1. 941 22

Nitric oxide (NO*) expression by inducible nitric oxide synthase (iNOS) is an important host defense mechanism against Mycobacterium tuberculosis in mononuclear phagocytes. The objective of this investigation was to examine the role of mitogen-activated protein (MAP) kinase (MAPK) and nuclear factor kappaB (NF-kappaB) signaling pathways in the regulation of iNOS and NO* by a mycobacterial cell wall lipoglycan known as mannose-capped lipoarabinomannan (ManLAM). Specific pharmacologic inhibition of the extracellular-signal-regulated kinase (ERK) or NF-kappaB pathway revealed that both these signaling cascades were required in gamma interferon (IFN-gamma)-ManLAM-induced iNOS protein and NO2- expression in mouse macrophages. Transient cotransfection of dominant-negative protein mutants of the c-Jun NH2-terminal kinase (JNK) pathway revealed that the MAP kinase kinase 7 (MKK7)-JNK cascade also mediated IFN-gamma-ManLAM induction of iNOS promoter activity whereas MKK4 did not. Overexpression of null mutant IkappaBalpha, a potent inhibitor of NF-kappaB activation, confirmed that the IkappaBalpha kinase (IKK)-NF-kappaB signaling pathway enhanced IFN-gamma-ManLAM-induced iNOS promoter activity. By contrast, activated p38mapk inhibited iNOS induction. These results indicate that combined IFN-gamma and ManLAM stimulation induced iNOS and NO. expression and that MEK1-ERK, MKK7-JNK, IKK-NF-kappaB, and p38mapk signaling pathways play important regulatory roles.
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PMID:Induction of inducible nitric oxide synthase-NO* by lipoarabinomannan of Mycobacterium tuberculosis is mediated by MEK1-ERK, MKK7-JNK, and NF-kappaB signaling pathways. 1125 51

Renal cells in culture have low viability when exposed to hypertonicity. We developed cell lines of inner medullary collecting duct cells adapted to live at 600 and 900 mosmol/kgH(2)O. We studied the three modules of the mitogen-activated protein (MAP) kinase family in the adapted cells. These cells had no increase in either extracellular signal-regulated kinase, c-Jun NH(2)-terminal kinase, or p38 MAP kinase protein or basal activity. When acutely challenged with further increments in tonicity, they had blunted activation of these kinases, which was not due to enhanced phosphatase activity. In contrast, the cells adapted to the hypertonicity displayed a marked increment in Na-K-ATPase expression (5-fold) and ouabain-sensitive Na-K-ATPase activity (10-fold). The changes were reversible on return to isotonic conditions. Replacement of 300 mosmol/kgH(2)O of NaCl by urea in cells adapted to 600 mosmol/kgH(2)O resulted in marked decrement in Na-K-ATPase and failure to maintain the cell line. Replacement of NaCl for urea in cells adapted to 900 mosmol/kgH(2)O did not alter either Na-K-ATPase expression, or the viability of the cells. The in vivo modulation of Na-K-ATPase was studied in the renal papilla of water-deprived mice (urinary osmolality 2,900 mosmol/kgH(2)O), compared with that of mice drinking dextrose in water (550 mosmol/kgH(2)O). Increased water intake was associated with a ~30% decrement in Na-K-ATPase expression (P < 0.02, n = 6), suggesting that this enzyme is osmoregulated in vivo. We conclude that whereas MAP kinases play a role in the response to acute changes in tonicity, they are not central to the chronic adaptive response. Rather, in this setting there is upregulation of other osmoprotective proteins, among which Na-K-ATPase appears to be an important component of the adaptive process.
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PMID:Long-term adaptation of renal cells to hypertonicity: role of MAP kinases and Na-K-ATPase. 1129 18

The fruit juice of Morinda citrifolia (noni), a plant originally grown in the Hawaiian and Tahitian islands, has long been used by islanders to treat diseases, including cancer. Two novel glycosides, 6-O-(beta-D-glucopyranosyl)-1-O-octanoyl-beta-D-glucopyranose and asperulosidic acid, extracted from the juice of noni fruits, were used to examine their effects on 12-O-tedtradecanoylphorbol-13-acetate (TPA)- and epidermal growth factor (EGF)-induced AP-1 transactivation and cell transformation in mouse epidermal JB6 cells. The results indicated that both compounds were effective in suppressing TPA- or EGF-induced cell transformation and associated AP-1 activity. TPA- or EGF-induced phosphorylation of c-Jun, but not extracellular signal-regulated kinases or p38 kinases, was also blocked by the compounds, indicating that c-Jun N-terminal kinases were critical in mediating TPA- or EGF-induced AP-1 activity and subsequent cell transformation in JB6 cells.
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PMID:Two novel glycosides from the fruits of Morinda citrifolia (noni) inhibit AP-1 transactivation and cell transformation in the mouse epidermal JB6 cell line. 1147 11

Penta-O-galloyl-beta-D-glucose (5GG) inhibited the invasion of highly metastatic mouse melanoma B16F10 cells in vitro, as demonstrated by transwell assay. Its ability to diminish the activity of matrix metalloproteinase (MMP) was demonstrated by zymographic assay. Our data showed 5GG could diminish the activity of MMP-9 more than that of MMP-2. The effect on MMP-9 was elicited in a dose- and time-dependent manner, with IC50 of 15 microM. Next, we analyzed the amounts of MMP-9 and MMP-2 protein in conditioned media and in the cells. The data indicated MMP-9 proteins were also suppressed by 5GG in the same manner. In accordance with these data above, the results of reverse transcriptase polymerase chain reaction (RT-PCR) and Northern blot analysis showed a reduced level of MMP-9 mRNA. Furthermore, we studied transcription factor binding to MMP-2 and MMP-9 promoter regions by electrophoretic mobility shift assay (EMSA) in the nucleus. The results suggested that the transcription factor binding activities of Activator protein-1 (AP-1) and Sp-1 sites was mainly down-regulated by 5GG in the concentration range of 5-15 microM, but not that of nuclear factor kappaB (NF-kappaB), polioma enhancer activator 3 (PEA-3), and Activator protein-2 (AP-2) sites. The Western blot analysis of AP-1 nuclear protein showed a reduced level of c-Jun but not of c-Fos. In addition, the expression of Sp-1 and c-Jun protein was also suppressed. To elucidate whether the transcriptional activity of AP-1 or Sp-1 sites is more important, we transfected MMP-9/luciferase reporter vector, under MMP-9 promoter control, into the cells. We found that a decreased transcriptional activity of AP-1 sites is sufficient to reduce MMP-9 promoter activity. These results lead us to conclude that 5GG restricts the invasive ability of B16F10 mouse melanoma cells by reducing MMP-9 activity, by suppressing the transcriptional activity of AP-1 sites and the expression of c-Jun protein. The result may provide a potential mechanism for 5GG in cancer chemopreventive action.
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PMID:Penta-O-galloyl-beta-D-glucose inhibits the invasion of mouse melanoma by suppressing metalloproteinase-9 through down-regulation of activator protein-1. 1239 98

Rat neonatal ventricular myocytes exposed to simulated ischaemia and reperfusion (SI/R) were used as an in vitro model to delineate the role(s) of extracellular signal-regulated kinase (ERK), p38 and c-Jun NH(2)-terminal protein kinase (JNK), as well as PKB in apoptosis. Exposure of the myocytes to SI (simulated ischaemia - energy depletion induced by KCN and 2-deoxy- D-glucose) reduced cell viability, as measured by the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) assay, and stimulated apoptosis as evidenced by caspase-3 activation and poly(ADP-ribose) polymerase (PARP) cleavage. However, morphological evidence of increased apoptosis, detected by staining with Hoechst 33342, was only seen in response to reperfusion. This suggests that although ischaemic conditions are sufficient to induce cellular markers of apoptosis (PARP cleavage and caspase-3 activation), reperfusion is required to complete the apoptotic pathway in these cells. Furthermore, SI resulted in a rapid, strong, biphasic activation of p38 concomitant with a weak and transient activation of the two ERK isoenzymes, p42/p44-MAPK. Reperfusion for 5 minutes resulted in a strong phosphorylation of p42/p44-MAPK, while no additional p38 activation was seen at this stage. On the other hand, p46/p54-MAPK (JNK) was phosphorylated in response to 5 minutes of reperfusion only and not during SI alone. A peak of PKB/Akt (Ser(473)) activity was seen within 5 minutes of exposure to SI, whereas PKB/Akt (Thr(308)) phosphorylation remained at the baseline level. Both PKB/Akt phosphorylation sites (Ser(473) and Thr(308)) were phosphorylated after 5 minutes of reperfusion. Inhibition of PI-3-kinase activity, using wortmannin, decreased phosphorylation on both sites during SI. However, only SI/R-induced PKB/Akt phosphorylation on Thr(308) was reduced by wortmannin. Myocytes pre-treated with SB203580, a p38-inhibitor, displayed a significant increase in cell viability [63.67 +/- 1.85 to 84.33 +/- 4.8% (p < 0.05)] and attenuation of the apoptotic index during SI/R [22.6 +/- 2.94% to 9 +/- 0.43% (p < 0.001)], while SP600125, a specific JNK inhibitor, caused a significant increase in caspase-3 activation [1.66 +/- 0.03 fold to 2.56 +/- 0.27 fold (p < 0.001)] and apoptotic index [22.6 +/- 2.94% to 32.75 +/- 6.13% (p < 0.05)]. However, PD98059, an ERK inhibitor, failed to affect apoptosis during SI/R. Inhibition of PI-3-kinase prevented the increase in mitochondrial viability usually observed during reperfusion. Interestingly, wortmannin caused a significant increase in PARP cleavage during reperfusion, but had no effect on caspase-3 activation or the apoptotic index. Our results suggest that p38 has a pro-apoptotic role while JNK phosphorylation is protective in our cell model and that these kinases act via caspase-3 to prevent or promote cell survival in response to SI/R-induced injury.
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PMID:p38 and JNK have distinct regulatory functions on the development of apoptosis during simulated ischaemia and reperfusion in neonatal cardiomyocytes. 1530 13

Interferons (IFN)s are involved in numerous immune interactions during viral infections and contribute to both induction and regulation of innate and adaptive antiviral mechanisms. IFNs play a pivotal rule in the outcome of a viral infection, as demonstrated by the impaired resistance against different viruses in mice deficient for the receptors IFNAR-2 and IFNGR. During viral infections, IFNs are involved in numerous immune interactions as inducers, regulators, and effectors of both innate and adaptive antiviral mechanisms. IFN-alpha/beta is produced rapidly when viral factors, such as envelope glycoproteins, CpG DNA, or dsRNA, interact with cellular pattern-recognition receptors (PRRs), such as mannose receptors, toll-like receptors (TLRs), and cytosolic receptors. These host-virus interactions signal downstream to activate transcription factors needed to achieve expression from IFN-alpha/beta genes. These include IFN regulatory factor-3 (IRF-3), IRF-5, IRF-7, c-Jun/ATF-2, and NF-kappaB. In contrast, IFN-gamma is induced by receptor-mediated stimulation or in response to early produced cytokines, including interleukin-2 (IL-12), IL-18, and IFN-alpha/beta, or by stimulation through T cell receptors (TCRs) or natural killer (NK) cell receptors. IFNs signal through transmembrane receptors, activating mainly Jak-Stat pathways but also other signal transduction pathways. Cytokine and TCR-induced IFN-gamma expression uses distinct signal transduction pathways involving such transcription factors as NFAT, Stats and NF-kappaB. This results in induction and activation of numerous intrinsic antiviral factors, such as RNA-activated protein kinase (PKR), the 2-5A system, Mx proteins, and several apoptotic pathways. In addition, IFNs modulate distinct aspects of both innate and adaptive immunity. Thus, IFN-alpha/beta and IFN-gamma affect activities of macrophages, NK cells, dendritic cells (DC), and T cells by enhancing antigen presentation, cell trafficking, and cell differentiation and expression profiles, ultimately resulting in enhanced antiviral effector functions. This review focuses on the latest findings regarding induction and regulation of IFNs, primarily during the early phase of an antiviral immune response. Both cellular and molecular aspects are discussed from the perspective of host-virus interactions.
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PMID:Induction and regulation of IFNs during viral infections. 1532 Sep 58

Brain injury in hemolytic-uremic syndrome (HUS) may be enhanced by inflammatory cytokine up-regulation of endothelial cell sensitivity to shigatoxin (Stx). The present study investigated whether inflammatory cytokine up-regulation of Stx toxicity could be ameliorated by inhibiting candidate signal transduction pathways. Exposure of human brain endothelial cells (HBECs) to tumor necrosis factor (TNF) greatly increased Stx-1 and Stx-2 cytotoxicity; this was reduced by inhibition of p38 mitogen-activated protein kinase (MAPK), but not c-Jun kinase. SB203580, a specific inhibitor of p38 MAPK, reduced TNF-stimulated Stx cytotoxicity in HBECs, TNF-stimulated (125)Stx-1 binding to intact HBECs, the cellular content of Gb3 (galactose alpha 1,4, galactose ss 1,4, glucose-ceramide) (the Stx receptor), and TNF-stimulated Gb3 synthase and glucosylceramide synthase activities but did not affect lactosylceramide synthase activities or mRNA content. Thus, inhibition of p38 MAPK substantially reduces inflammatory cytokine up-regulation of Stx-receptor synthesis and cell-surface expression, thereby decreasing Stx cytotoxicity. Inhibition of p38 MAPK may be of therapeutic benefit in HUS.
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PMID:Inhibition of p38 mitogen-activated protein kinase ameliorates cytokine up-regulated shigatoxin-1 toxicity in human brain microvascular endothelial cells. 1563 6

Anthocyanins, present in various fruits and vegetables as natural colorant, have been well characterized to be involved in various bioactive properties and are wildly used for their antioxidant properties. Furthermore, recent studies have revealed pleiotropic anticancer and antiproliferative capabilities of anthocyanin. Berry extract contains high amounts of anthocyanins and is commonly used in diet or in some therapeutic applications. In this study, we first observed that cyanidin 3-rutinoside and cyanidin 3-glucoside (extracted from Morus alba L.) exerted a dose-dependent inhibitory effect on the migration and invasion, of highly metastatic A549 human lung carcinoma cells in absence of cytotoxicity. The results showed that cyanidin 3-glucoside and cyanidin 3-rutinoside treatments could decrease the expressions of matrix matalloprotinase-2 (MMP-2) and urokinase-plasminogen activator (u-PA) in a dose-dependent manner and enhance the expression of tissue inhibitor of matrix matalloprotinase-2 (TIMP-2) and plasminogen activator inhibitor (PAI). Further analysis with semi-quantitative RT-PCR showed that these alterations were all on the transcriptional level. Further, a treatment of cyanidin 3-rutinoside and cyanidin 3-glucoside also resulted in an inhibition on the activation of c-Jun and NF-kappaB. Together, these result suggested that anthocyanins could decrease the in vitro invasiveness of cancer cells and therefore, may be of great value in developing a potential cancer therapy.
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PMID:Mulberry anthocyanins, cyanidin 3-rutinoside and cyanidin 3-glucoside, exhibited an inhibitory effect on the migration and invasion of a human lung cancer cell line. 1597 9


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