Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

CD4 T-lymphocytes, which orchestrate immune responses, receive a cognitive signal when clonally distributed receptors are occupied by MHC class II bound peptides on antigen-presenting cells. The latter provide costimulatory or accessory signals through macromolecules such as B7.1 and B7.2 which interact with coreceptors on T-cells to regulate outcomes in terms of T-cell activation or specific non-responsiveness. Complementary studies at the chemical level have implicated Schiff base formation between specialised carbonyls and amines, constitutively expressed on antigen-presenting cell and T-cell surfaces, as an essential element in specific T-cell activation. The small xenobiotic Schiff base forming molecule tucaresol, which substitutes for the physiological donor of carbonyl groups to provide a costimulatory signal to CD4 T-helper lymphocytes (Th-cells), has been developed for testing as an immunopotentiatory drug. Tucaresol, which is orally bioavailable and systemically active, enhances CD4 Th-cell and CD8 cytotoxic T-cell responses in vivo and selectively favours a Th1-type profile of cytokine production. In murine models of virus infection and syngeneic tumour growth it has substantial therapeutic activity. Schiff base formation by tucaresol on T-cell surface amines provides a costimulatory signal to the T-cell through a mechanism that activates clofilium-sensitive K+ and Na+ transport. The signalling pathway utilised by tucaresol converges with T-cell receptor signalling at the level of MAP kinase, promoting the tyrosyl phosphorylation of ERK2 by MEK (mitogen-activated protein kinase kinase). The Schiff base forming class of immunopotentiatory drug provides the first orally active, mechanism-based immunopotentiatory agents for therapeutic testing. Tucaresol is currently undergoing pilot phase I/II clinical trials as an immunopotentiator in chronic hepatitis B virus infection, HIV infection and malignant melanoma.
 ...
PMID:Schiff base forming drugs: mechanisms of immune potentiation and therapeutic potential. 889 54

The gene encoding manganese superoxide dismutase (MnSOD) from Drosophila melanogaster has been isolated and its expression has been studied. In contrast to several mammalian MnSOD genes, the Drosophila gene contains a single intron and is transcribed into a single 0.8-kb transcript. Whole-mount in situ hybridization reveals extensive transcript accumulation in ovarian nurse cells and a heavy maternal contribution to the early embryo. Larval imaginal discs are enriched with MnSOD transcripts relative to other larval tissues, further suggesting a possible relationship between high MnSOD expression and mitotic activity. The 5'-upstream region contains several well-known regulatory elements including metal response, antioxidant response, and xenobiotic response elements (MRE, ARE, and XRE, respectively), sites for activator protein-1 (AP-1), nuclear factor-kappaB (NF-kappaB), adenosine 3',5'-cyclic monophosphate regulator binding element factor (CREB), as well as classic TATA and CAAT boxes. That MnSOD expression in Drosophila is regulated in part by the transcription factor AP-1 via the MAP kinase signal transduction pathway is suggested by experiments which show that a hypomorphic mutation of the MAP kinase-encoding rolled gene substantially reduces levels of MnSOD transcripts and correlates with reduced resistance to oxidative stress in rolled mutants.
 ...
PMID:The manganese superoxide dismutase gene of Drosophila: structure, expression, and evidence for regulation by MAP kinase. 915 Apr 26

Monofunctional alkylating agents like methyl methanesulfonate (MMS) and N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) are potent inducers of cellular stress leading to chromosomal aberrations, point mutations, and cell killing. We show that these agents induce a specific cellular stress response program which includes the activation of Jun N-terminal kinases/stress-activated protein kinases (JNK/SAPKs), p38 mitogen-activated protein kinase, and the upstream kinase SEK1/MKK4 and which depends on the reaction mechanism of the alkylating agent in question. Similar to another inducer of cellular stress, UV irradiation, damage of nuclear DNA by alkylation is not involved in the MMS-induced response. However, in contrast to UV and other inducers of the JNK/SAPKs and p38 pathways, activation of growth factor and G-protein-coupled receptors does not play a role in the MMS response. We identified the intracellular glutathione (GSH) level as critical for JNK/SAPK activation by MMS: enhancing the GSH level by pretreatment of the cells with GSH or N-acetylcysteine inhibits, whereas depletion of the cellular GSH pool causes hyperinduction of JNK/SAPK activity by MMS. In light of the JNK/SAPK-dependent induction of c-jun and c-fos transcription, and the Jun/Fos-induced transcription of xenobiotic-metabolizing enzymes, these data provide a potential critical role of JNK/SAPK and p38 in the induction of a cellular defense program against cytotoxic xenobiotics such as MMS.
 ...
PMID:The level of intracellular glutathione is a key regulator for the induction of stress-activated signal transduction pathways including Jun N-terminal protein kinases and p38 kinase by alkylating agents. 923 35

In the present study, we studied the signal transduction mechanism that is involved in the expression of c-Jun protein evident after exposure of rat liver epithelial RL34 cells to the major end product of oxidized fatty acid metabolism, 4-hydroxy-2-nonenal (HNE). HNE treatment of the cells resulted in depletion of intracellular glutathione (GSH) and in the formation of protein-bound HNE in plasma membrane. In addition, HNE strongly induced intracellular peroxide production, suggesting that HNE exerted oxidative stress on the cells. Potent expression of c-Jun occurred within 30 min of HNE treatment, which was accompanied by a time-dependent increase in activator protein-1 (AP-1) DNA binding activity. We found that HNE caused an immediate increase in tyrosine phosphorylation in RL34 cells. In addition, HNE strongly induced phosphorylation of c-Jun N-terminal kinases (JNK) and p38 mitogen-activated protein kinases and also moderately induced phosphorylation of extracellular signal-regulated kinases. The phosphorylation of JNK was accompanied by a rapid and transient increase in JNK and p38 activities, whereas changes in the activity of extracellular signal-regulated kinase were scarcely observed. GSH depletion by L-buthionine-S, R-sulfoximine, a specific inhibitor of GSH biosynthesis, only slightly enhanced peroxide production and JNK activation, suggesting that HNE exerted these effects independent of GSH depletion. This and the findings that (i) HNE strongly induced intracellular peroxide production, (ii) HNE-induced JNK activation was inhibited by pretreatment of the cells with a thiol antioxidant, N-acetylcysteine, and (iii) H2O2 significantly activated JNK support the hypothesis that pro-oxidants play a crucial role in the HNE-induced activation of stress signaling pathways. In addition, we found that, among the inhibitors of tyrosine kinases, cyclooxygenase, and Ca2+ influx, only quercetin exerted a significant inhibitory effect on HNE-induced JNK activation. In light of the JNK-dependent induction of c-jun transcription and the AP-1-induced transcription of xenobiotic-metabolizing enzymes, these data may show a potential critical role for JNK in the induction of a cellular defense program against toxic products generated from lipid peroxidation.
 ...
PMID:Activation of stress signaling pathways by the end product of lipid peroxidation. 4-hydroxy-2-nonenal is a potential inducer of intracellular peroxide production. 989 Sep 86

The arylhydrocarbon receptor (AhR) is the receptor for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds. Although a physiological ligand for the AhR has yet to be identified, and the precise physiological roles of the AhR are unknown, it may play important roles not only in the regulation of xenobiotic metabolism but also in the maintenance of homeostatic functions. We have previously reported that the level of AhR protein decreased with ongoing adipose differentiation in 3T3-L1 cells. Studies using a TCDD-resistant clone of 3T3-L1 cells suggested that the AhR may be involved in the negative regulation of adipose differentiation. To confirm this hypothesis, 3T3-L1 fibroblast cells were stably transfected with a vector expressing high levels of full-length sense AhR mRNA, antisense AhR mRNA or a control vector. Comparison of the differentiation potency of these clones with that of control cells showed that overexpression of the AhR suppressed morphological differentiation, as well as induction of adipocyte-related genes, whereas decreased expression of the AhR induced much greater morphological differentiation and expression of adipocyte-related genes. Activation of PPARgamma2 with ligands such as troglitazone, ciglitazone and indomethacin restored the ability of the AhR-overexpressing cells to differentiate. The cells overexpressing the AhR exhibited the higher p42/p44 MAP kinase activity compared with the control cells. Treatment with PD98059 or U0126 also abrogated the inhibitory action of the AhR on adipogenesis. We also present data showing that activation of the AhR slowed clonal expansion. During clonal expansion, the AhR inhibited the pRB phosphorylation and the downregulation of p107 expression. Taken together, these results strongly suggest that AhR is a negative regulator of adipose differentiation in 3T3 L1 cells.
 ...
PMID:Arylhydrocarbon receptor (AhR) is involved in negative regulation of adipose differentiation in 3T3-L1 cells: AhR inhibits adipose differentiation independently of dioxin. 1168 14

Cellular responses to xenobiotic-induced stress can signal proliferation, differentiation, homeostasis, apoptosis, or necrosis. To better understand the underlying molecular mechanisms after exposure to xenobiotics or drugs, we studied the signal transduction pathways, the mitogen-activated protein kinase (MAPK), and the basic leucine zipper transcription factor Nrf2, activated by different agents in the induction of Phase II drug metabolizing enzymes (DMEs). The MAPKs, characterized as proline-directed serine/threonine kinases, are essential components of signaling pathways that convert various extracellular signals into intracellular responses through serial phosphorylation cascades. Once activated, MAPKs can phosphorylate many transcription factors, such as c-Jun, ATF-2, and ultimately lead to changes in gene expression. Two classes of Phase II gene inducers, which are also cancer chemopreventive agents, were studied: (1) the phenolic antioxidants, namely butylated hydroxyanisole (BHA) and its active de-methylated metabolite t-butylhydroquinone (tBHQ), and phenolic flavonoids such as green tea polyphenols (GTP) and (-)-epigallocatechin-3-gallate (EGCG); and (2) the naturally occurring isothiocyanates, namely phenethyl isothiocyanate (PEITC), and sulforaphane. BHA and tBHQ are both well-known phenolic antioxidants used as food preservatives, and strongly activate c-Jun N-terminal kinase 1 (JNK1), extracellular signal-regulated protein kinase 2 (ERK2), or p38, in a time- and dose-dependent fashion. Free radical scavengers N-acetyl-L-cysteine (NAC), or glutathione (GSH), inhibited ERK2 activation and, to a much lesser extent, JNK1 activation by BHA/tBHQ, implicating the role of oxidative stress. Under conditions where MAPKs were activated, BHA or GTP also activated ARE/EpRE (antioxidant/electrophile response element), with the induction of Phase II genes such as NQO. Transfection studies with various cDNAs encoding wild-type or dominant-negative mutants of MAPKs and/or transcription factor Nrf2, substantially modulated ARE-mediated luciferase reporter activity in the presence or absence of phenolic compounds. Other phytochemicals including PEITC, and sulforaphane, also differentially regulated the activities of MAPKs, Nrf2, and ARE-mediated luciferase reporter gene activity and Phase II enzyme induction. A model is proposed where these xenobiotics (BHA, tBHQ, GTP, EGCG, PEITC, sulforaphane) activate the MAPK pathway via an electrophilic-mediated stress response, leading to the transcription activation of Nrf2/Maf heterodimers on ARE/EpRE enhancers, with the subsequent induction of cellular defense/detoxifying genes including Phase II DMEs, which may protect the cells against toxic environmental insults and thereby enhance cell survival. The studies of these signaling pathways may yield insights into the fate of cells upon exposure to xenobiotics.
 ...
PMID:Induction of xenobiotic enzymes by the MAP kinase pathway and the antioxidant or electrophile response element (ARE/EpRE). 1176 69

The orphan nuclear hormone receptor SHP has been proposed to have a key role in the negative feedback regulation of bile acid production. Consistent with this, mice lacking the SHP gene exhibit mild defects in bile acid homeostasis and fail to repress cholesterol 7-alpha-hydroxylase expression in response to a specific agonist for the bile acid receptor FXR. However, this repression is retained in SHP null mice fed bile acids, demonstrating the existence of compensatory repression pathways of bile acid signaling. We provide evidence for two such pathways, based on activation of the xenobiotic receptor PXR or the c-Jun N-terminal kinase JNK. We conclude that redundant mechanisms regulate this critical aspect of cholesterol homeostasis.
 ...
PMID:Redundant pathways for negative feedback regulation of bile acid production. 1206 85

Diesel exhaust particles (DEP) induce a proinflammatory response in human bronchial epithelial cells (16HBE) characterized by the release of proinflammatory cytokines after activation of transduction pathways involving MAPK and the transcription factor NF-kappaB. Because cellular effects induced by DEP are prevented by antioxidants, they could be mediated by reactive oxygen species (ROS). Using fluorescent probes, we detected ROS production in bronchial and nasal epithelial cells exposed to native DEP, organic extracts of DEP (OE-DEP), or several polyaromatic hydrocarbons. Carbon black particles mimicking the inorganic part of DEP did not increase ROS production. DEP and OE-DEP also induced the expression of genes for phase I [cytochrome P-450 1A1 (CYP1A1)] and phase II [NADPH quinone oxidoreductase-1 (NQO-1)] xenobiotic metabolization enzymes, suggesting that DEP-adsorbed organic compounds become bioavailable, activate transcription, and are metabolized since the CYP1A1 enzymatic activity is increased. Because NQO-1 gene induction is reduced by antioxidants, it could be related to the ROS generated by DEP, most likely through the activation of the stress-sensitive Nrf2 transcription factor. Indeed, DEP induced the translocation of Nrf2 to the nucleus and increased protein nuclear binding to the antioxidant responsive element. In conclusion, we show that DEP-organic compounds generate an oxidative stress, activate the Nrf2 transcription factor, and increase the expression of genes for phase I and II metabolization enzymes.
 ...
PMID:Involvement of reactive oxygen species in the metabolic pathways triggered by diesel exhaust particles in human airway epithelial cells. 1273 81

Induction of drug-metabolizing microsomal cytochromes p450 (p450s) results in a striking proliferation of the smooth endoplasmic reticulum (ER). Overexpression of P450s in yeast and cultured cells produces a similar response. The signals mediating this process are not known but probably involve signal transduction pathways involved in the unfolded protein response (UPR) or the ER overload response (EOR). We have examined the temporal response of specific genes in these pathways and genes globally to overexpression of p450 in cultured cells. Activity of NFkappaB, an EOR component, was substantially increased by overexpression of full-length p450 2C2 or a chimera with the 28-amino acid signal anchor sequence of p450 2C2 in HepG2 cells, and the activation correlated temporally with the accumulation of p450 in the cells. In the UPR pathway, activation of the transcription factor XBP1 by IRE1 also correlated with the accumulation of p450 in the cells, and in contrast, maximum activation of the BiP/grp78 promoter preceded the accumulation. Differential effects of expression of p450 on apoptosis were observed in nonhepatic COS1 and hepatic HepG2 cells. In COS1 cells, apoptosis was induced, and this correlated with sustained activation of the pro-apoptotic JNK pathway, induction of CHOP, and an absence of the increased NFkappaB activity. In HepG2 cells, JNK was only transiently activated, and CHOP expression was not induced. As assessed by DNA microarray analysis, up-regulation of signaling genes was predominant including those involved in anti-apoptosis and ER stress. These results suggest that both the EOR and UPR pathways are involved in the cellular response to induction of p450 expression and that in hepatic cells genes are also induced to block apoptosis, which may be a physiologically relevant response to prevent cell death during xenobiotic induced expression of p450 in the liver.
 ...
PMID:Gene expression changes associated with the endoplasmic reticulum stress response induced by microsomal cytochrome p450 overproduction. 1471 36

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that plays a role as an intracellular mediator of the xenobiotic signaling pathway. AhR contains signals for both nuclear localization and nuclear export (NES). The objective of this study was to demonstrate how AhR intracellular distribution was regulated physiologically in cells. We found that cell density, but not the cell cycle, influenced the subcellular distribution of AhR in a keratinocyte cell line, HaCaT: AhR was predominantly nuclear at sparse cell densities, both nuclear and cytoplasmic at subconfluence, and predominantly cytoplasmic at confluence. Stable transfectants of HaCaT carrying a reporter gene fused with xenobiotic responsive element showed an association between xenobiotic responsive element-mediated transcription and AhR relocalization. Leptomycin B promoted nuclear accumulation of AhR irrespective of cell density, suggesting that this alteration may be because of a change of the regulation of the nuclear export of AhR. We found that Ser-68 in the NES of AhR was phosphorylated after nuclear accumulation of activated AhR and the nuclear export of a chimeric GST-AhR-GFP fusion protein was suppressed by substitution of a serine residue (Ser-68) to aspartic acid, which mimics the negative charge of phosphorylation. This novel cell density-dependent AhR relocalization was affected by exposure to SB203580, okadaic acid, and low Ca(2+) concentrations. These findings strongly suggest that cell density regulates the intracellular localization and function of AhR, because of modulation of nuclear export activity. The p38 MAPK-mediated phosphorylation of the NES and its dephosphorylation, regulated by cell-cell contact signals, may have pivotal roles in the novel AhR relocalization.
 ...
PMID:Cell density regulates intracellular localization of aryl hydrocarbon receptor. 1498 36


1 2 3 4 5 6 7 8 9 10 Next >>