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)

Fibrolamellar carcinomas (FLC) are a rare type of primary hepatocellular carcinoma found in younger individuals. FLC are known to have relatively few consistent chromosomal alterations, although a gain of chromosome 1q has been reported. The gene expression of 4 FLC (2 primary FLC and 2 metastatic deposits) were studied using Affymetrix DNA microarray technology (Santa Clara, CA). Selected genes were confirmed by real-time polymerase chain reaction. Relatively few genes were significantly overexpressed-447 genes, case 1; 1298 genes, case 2-corresponding to approximately 0.8% and 2.3%, respectively, of the 56000 transcripts present in the arrays. Of these, 155 genes were overexpressed simultaneously by both tumors. The number of significantly overexpressed genes more than doubled in the 2 metastatic deposits (2777 and 2855 genes compared with 1298 in the primary tumor). Proteins involved in the RAS, MAPK, PIK3, and xenobiotic degradation pathways were commonly overexpressed. Because chromosome 1q is thought to contain an important oncogene, additional attention was focused on this region. Of 114 total genes found overexpressed in common among all primary and metastatic tumors, 11 of 114 genes were located on chromosome 1q: ARF1, CD46, CNIH4, ENSA, FH, NICE-3, PSMB4, RGS2, RGS5, TIMM17A, and UFC1. Primary FLC show overexpression of genes involved in the RAS, MAPK, PIK3, and xenobiotic degradation pathways. Eleven common genes were consistently overexpressed on chromosome 1q among all tumors and metastases and warrant further study as potential oncogenes.
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PMID:Fibrolamellar carcinomas show overexpression of genes in the RAS, MAPK, PIK3, and xenobiotic degradation pathways. 1736 6

4-Methoxyequilenin (4-MeOEN) is an O-methylated metabolite in equine estrogen metabolism. O-methylation of catechol estrogens is considered as a protective mechanism; however, comparison of the properties of 4-MeOEN with estradiol (E(2)) in human breast cancer cells showed that 4-MeOEN is a proliferative, estrogenic agent that may contribute to carcinogenesis. 4-MeOEN results from O-methylation of 4-hydroxyequilenin, a major catechol metabolite of the equine estrogens present in hormone replacement therapeutics, which causes DNA damage via quinone formation, raising the possibility of synergistic hormonal and chemical carcinogenesis. 4-MeOEN induced cell proliferation with nanomolar potency and induced estrogen response element (ERE)-mediated gene transcription of an ERE-luciferase reporter and the endogenous estrogen-responsive genes pS2 and TGF-alpha. These estrogenic actions were blocked by the antiestrogen ICI 182,780. In the standard radioligand estrogen receptor (ER) binding assay, 4-MeOEN showed very weak binding. To test for alternate ligand-ER-independent mechanisms, the possibility of aryl hydrocarbon receptor (AhR) binding and ER-AhR cross talk was examined using a xenobiotic response element-luciferase reporter and using AhR small interfering RNA silencing in the ERE-luciferase reporter assay. The results negated the possibility of AhR-mediated estrogenic activity. Comparison of gene transcription time course, ER degradation, and rapid activation of MAPK/ERK in MCF-7 cells demonstrated that the actions of 4-MeOEN mirrored those of E(2) with potency for classical and nonclassical estrogenic pathways bracketing that of E(2). Methylation of 4-OHEN may not represent a detoxification pathway because 4-MeOEN is a full, potent estrogen agonist.
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PMID:Activation of estrogen receptor-mediated gene transcription by the equine estrogen metabolite, 4-methoxyequilenin, in human breast cancer cells. 1758 65

Insulin-like growth factor type I receptor (IGF-IR) is frequently overexpressed in human hepatocellular carcinoma cells (HCC), and this overexpression has been correlated with increased tumor growth. The protective response of HCC to reactive oxygen species (ROS) produced by chemotherapeutic agents is mediated with the induction of phase II detoxifying genes including glutathione transferase (GST). To understand the roles of IGF-IR overexpression in HCC in terms of its detoxifying effect on ROS and conferred resistance to chemotherapy, we analyzed whether IGF-IR overexpressions affect IGF-1-inducible GST expression. GSTalpha was induced by exposure to IGF-1 in IGF-IR cells but not in cells expressing normal levels of IGF-IR. Furthermore, IGF-IR-overexpressed HCCs (IR-HCC) are more resistant to doxorubicin than control HCC cells, which was associated with the increased GST induction by IGF-1. Molecular analyses using GSTA2 promoter supported the involvement of xenobiotic response element (XRE) in GSTalpha induction. IGF-1 caused the nuclear translocation of CCAAT/enhancer-binding protein beta (C/EBPbeta), which might be responsible for XRE activation. In addition, IGF-1 increased the activities of phosphatidylinositol 3-kinase (PI3-kinase) and extracellular signal-regulated kinase in IR-HCCs. Moreover, the inhibition of PI3-kinase completely abolished the nuclear translocation of C/EBPbeta and the up-regulation of GSTalpha protein in IR-HCC treated with IGF-1. However, specific inhibitors against extracellular signal-regulated kinase, c-Jun N-terminal kinase, or p38 kinase did not alter IGF-1-inducible GSTalpha expression. These results provide evidence that one of the pathological consequences of IGF-IR overexpression in HCCs is the potentiation of GSTalpha inducibility by IGF-1. Moreover, this potentiation of GST may be associated with decreased susceptibility to chemotherapeutic agents such as doxorubicin.
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PMID:Induction of glutathione transferase in insulin-like growth factor type I receptor-overexpressed hepatoma cells. 1761 45

CD4+ T lymphocytes, which orchestrate immune responses, receive a cognitive signal when clonally distributed receptors are occupied by peptides bound to major histocompatibility complex (MHC) class II molecules on antigen-presenting cells. The latter cells 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 nonresponsiveness. Complementary studies of the interactions between antigen-presenting cells and T helper cells at the chemical level have implicated Schiff base formation between specialised carbonyls and amines, constitutively expressed on the surfaces of antigen-presenting cells and T cells, as an essential element in specific T cell activation. Small Schiff base-forming molecules can substitute for the natural donor of carbonyl groups and provide a costimulatory signal to the T cell. From this class of Schiff base-forming costimulatory molecules, the small xenobiotic substituted benzaldehyde, tucaresol, has been selected for development and testing as an immunopotentiatory drug. Tucaresol, which is orally bioavailable and systemically active, enhances CD4+ T helper cell and CD8+ cytotoxic T cell responses in vivo, and selectively favours a T helper 1 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 pathway utilised by tucaresol converges with T cell receptor signalling at the level of mitogen-activated protein (MAP) kinase, promoting the activation of MAP kinase kinase (MEK) and consequential tyrosyl phosphorylation of ERK2. Tucaresol is the first orally active, mechanism-based immunopotentiatory drug available for therapeutic testing. It is currently undergoing phase I/II clinical trials in chronic hepatitis B virus infection, HIV infection and malignant melanoma.
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PMID:[Not Available]. 1803 Oct 95

Exposure to toxic polycyclic aromatic hydrocarbons raises a number of toxic and carcinogenic responses in experimental animals and humans mediated for the most part by the aryl hydrocarbon -- or dioxin -- receptor (AHR). The AHR is a ligand-activated transcription factor whose central role in the induction of drug-metabolizing enzymes has long been recognized. For quite some time now, it has become clear that the AHR also functions in pathways outside of its role in detoxification and that perturbation of these pathways by xenobiotic ligands may be an important part of the toxicity of these compounds. AHR activation by some of its ligands participates among others in pathways critical to cell cycle regulation, mitogen-activated protein kinase cascades, immediate-early gene induction, cross-talk within the RB/E2F axis and mobilization of crucial calcium stores. Ultimately, the effect of a particular AHR ligand may depend as much on the adaptive interactions that it established with pathways and proteins expressed in a specific cell or tissue as on the toxic responses that it raises.
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PMID:The aryl hydrocarbon receptor cross-talks with multiple signal transduction pathways. 1881 53

Aldose reductase (AR) is a multi-functional AKR (AKR1B1) that catalyzes the reduction of a wide range of endogenous and xenobiotic aldehydes and their glutathione conjugates with high efficiency. Previous studies from our laboratory show that AR protects against myocardial ischemia-reperfusion injury, however, the mechanisms by which it confers cardioprotection remain unknown. Because AR metabolizes aldehydes generated from lipid peroxidation, we tested the hypothesis that it protects against ischemic injury by preventing ER stress induced by excessive accumulation of aldehyde-modified proteins in the ischemic heart. In cell culture experiments, exposure to model lipid peroxidation aldehydes-4-hydroxy-trans-2-nonenal (HNE), 1-palmitoyl-2-oxovaleroyl phosphatidylcholine (POVPC) or acrolein led to an increase in the phosphorylation of ER stress markers PERK and eIF2-alpha and an increase in ATF3. The reduced metabolite of POVPC 1-palmitoyl-2-hydroxyvaleroyl phosphatidylcholine (PHVPC) was unable to stimulate JNK phosphorylation. No increase in phospho-eIF2-alpha, ATF3 or phospho-PERK was observed in cells treated with the reduced HNE metabolite 1,4-dihydroxynonenol (DHN). Lysates prepared from isolated perfused mouse hearts subjected to 15 min of global ischemia followed by 30 min of reperfusion ex vivo showed greater phosphorylation of PERK and eIF2-alpha than hearts subjected to aerobic perfusion alone. Ischemia-induced increases in phospho-PERK and phospho-eIF2-alpha were diminished in the hearts of cardiomyocyte-specific transgenic mice overexpressing the AR transgene. These observations support the notion that by removing aldehydic products of lipid peroxidation, AR decreases ischemia-reperfusion injury by diminishing ER stress.
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PMID:Aldose reductase decreases endoplasmic reticulum stress in ischemic hearts. 1904 36

Mutated K-ras is frequently found in human malignancies and plays a key role in many signal transduction processes resulting in an altered gene and/or protein expression pattern. Proteins controlled by a constitutive activated mitogen-activated protein kinase pathway are primarily related to alterations in the mitochondrial and nuclear compartments. Therefore, different K-Ras mutants and respective control cells were subjected to two-dimensional gel electrophoresis using basic pH gradients. This approach led to the identification of differentially expressed proteins, such as members of the heterogeneous ribonucleoprotein family, and enzymes involved in cellular detoxification as well as in oxidative stress. Increased expression of these enzymes was paralleled by an elevated tolerance of K-ras mutants against the cytotoxic potential of hydrogen peroxide and formaldehyde as well as an altered redox status based on enhanced intracellular glutathione (GSH) levels indicating an improved detoxification potential of defined K-ras transfectants, whereas down-regulation by RNA interference of candidate proteins reversed the tolerance against these compounds. This hypothesis is supported by an up-regulated expression of a key enzyme of the pentose phosphate pathway resulting in an increased production of NADPH required for anabolic processes as well as the rebuilding of oxidized GSH. Both the enhanced resistance against xenobiotic compounds as well as an altered oxidative pathway might confer growth advantages for tumor cells carrying dominant-positive K-ras mutations such as in lung or pancreatic adenocarcinoma.
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PMID:Altered detoxification status and increased resistance to oxidative stress by K-ras transformation. 1907 74

The aryl hydrocarbon receptor (AHR) has long been recognized as a ligand-activated transcription factor responsible for the induction of drug-metabolizing enzymes. Its role in the combinatorial matrix of cell functions was established long before the first report of an AHR cDNA sequence was published. It is only recently that other functions of this protein have begun to be recognized, and it is now clear that the AHR also functions in pathways outside of its well-characterized role in xenobiotic enzyme induction. Perturbation of these pathways by xenobiotic ligands may ultimately explain much of the toxicity of these compounds. This chapter focuses on the interactions of the AHR in pathways critical to cell cycle regulation, mitogen-activated protein kinase cascades, differentiation and apoptosis. Ultimately, the effect of a particular AHR ligand on the biology of the organism will depend on the milieu of critical pathways and proteins expressed in specific cells and tissues with which the AHR itself interacts.
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PMID:The aryl hydrocarbon receptor at the crossroads of multiple signaling pathways. 1915 64

Signaling through the Ha-Ras/ mitogen-activated protein kinase cascade and through the Wnt/ beta-catenin signaling pathway has been implicated in various developmental processes as well as in carcinogenesis of different organs by regulating cell growth and differentiation. In particular, both pathways have been reported to play an important role in embryonic liver development as well as in liver regeneration after partial hepatectomy. More recently, there is accumulating evidence for a role of Ras- and beta catenin-dependent signal transduction in the regulation of zone-specific gene expression in healthy adult liver. An antagonistic interplay of both pathways was proposed: beta-catenin was established to function as a decisive regulator of 'perivenous' gene expression in hepatocytes neighboring branches of the central vein, whereas the Ras pathway was linked to transcription of 'periportal' genes. Xenobiotic-metabolizing enzymes constitute one of the largest functionally related groups of zonated genes with predominantly perivenous expression of the most abundant enzymes of xenobiotic metabolism. In this review, the current knowledge regarding the role of Ras and beta catenin signaling in the regulation of expression of xenobiotic-metabolizing enzymes from the cytochrome P450 superfamily will be summarized including both in vitro and in vivo observations.
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PMID:Regulation of cytochrome P450 expression by Ras- and beta-catenin-dependent signaling. 1927 49

JNK signaling functions to induce defense mechanisms that protect organisms against acute oxidative and xenobiotic insults. Using Drosophila as a model system, we investigated the role of autophagy as such a JNK-regulated protective mechanism. We show that oxidative stress can induce autophagy in the intestinal epithelium by a mechanism that requires JNK signaling. Consistently, artificial activation of JNK in the gut gives rise to an autophagy phenotype. JNK signaling can induce the expression of several autophagy-related (ATG) genes, and the integrity of these genes is required for the stress protective function of the JNK pathway. In contrast to autophagy induced by oxidative stress, non-stress related autophagy, as it occurs for example in starving adipose or intestinal tissue, or during metamorphosis, proceeds independently of JNK signaling. Autophagy thus emerges as a multifunctional process that organisms employ in a variety of different situations using separate regulatory mechanisms.
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PMID:JNK protects Drosophila from oxidative stress by trancriptionally activating autophagy. 1954 Mar 38


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