Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The induction of glutathione S-transferases by flavonoids is associated with cancer chemopreventive effects. We reported that 2'-amino-3'-methoxyflavone (PD98059), an MKK1 inhibitor, induces glutathione S-transferase A2 (rGSTA2). This report comparatively examines the role of CCAAT/enhancer-binding protein (C/EBP) and Nrf2 in the induction of rGSTA2 by PD98059. We first assessed whether the MKK1/ERK1/2 pathway regulated rGSTA2 induction. Northern and western blot analyses showed that PD98059 at the concentrations effective for the inhibition of MKK1 increased the rGSTA2 protein and mRNA levels in H4IIE cells. PD98059 also induced rGSTA2 in cells stably transfected with dominant-negative mutant of MKK1(-), which provided evidence that the inhibition of MKK1/ERK1/2 by PD98059 was not responsible for rGSTA2 induction. Gel shift assay and immunoblot analysis of subcellular fractions revealed that PD98059 caused nuclear translocation of C/EBP beta and increased C/EBP DNA binding, which was super-shifted with anti-C/EBP beta antibody. Nrf2 was not activated by PD98059. PD98059 increased the luciferase reporter gene activity in cells transfected with the C/EBP-containing -1.65 kb flanking region of the rGSTA2 gene. Deletion of the C/EBP-binding site or over-expression of dominant-negative mutant of C/EBP abolished the reporter gene activity. Flavone, a backbone structure of PD98059, also induced nuclear translocation of C/EBP beta and C/EBP-mediated rGSTA2 gene induction. Inhibition of phosphatidylinositol 3-kinase abolished C/EBP beta-mediated rGSTA2 induction by PD98059. These results provide evidence that PD98059 and flavone induce nuclear translocation of C/EBP beta and activate the C/EBP-binding site in the rGSTA2 gene, which constitutes the distinct pathway for the enzyme induction irrespective of the inhibition of MKK1/ERK activity.
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PMID:Activation of CCAAT/enhancer-binding protein beta by 2'-amino-3'-methoxyflavone (PD98059) leads to the induction of glutathione S-transferase A2. 1266 7

Mitogen-activated protein kinases (MAPKs) mediate signaling from the cell membrane to the nucleus following their phosphorylation at conserved threonine and tyrosine residues within their activation loops. We show that protein tyrosine phosphatase epsilon (PTP epsilon) inhibits ERK1 and ERK2 kinase activity and reduces their phosphorylation; in agreement, ERK phosphorylation is increased in fibroblasts and in mammary tumor cells from mice genetically lacking PTP epsilon. PTP epsilon inhibits events downstream of ERKs, such as transcriptional activation mediated by Elk1 or by the serum response element. PTP epsilon also inhibits transcriptional activation mediated by c-Jun and C/EBP binding protein (CHOP) but not that mediated by the unrelated NFkB, attesting that it is broadly active within the MAPK family but otherwise specific. The effect of PTP epsilon on ERKs is at least in part indirect because phosphorylation of the threonine residue in the ERK activation loop is reduced in the presence of PTP epsilon. Nonetheless, PTP epsilon is present in a molecular complex with ERK, providing PTP epsilon with opportunity to act on ERK proteins also directly. We conclude that PTP epsilon is a physiological inhibitor of ERK signaling. Slow induction of PTP epsilon and its lack of nuclear translocation following mitogenic stimulation suggest that PTP epsilon functions to prevent inappropriate activation and to terminate prolonged, rather than acute, activation of ERK in the cytosol.
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PMID:Protein tyrosine phosphatase epsilon inhibits signaling by mitogen-activated protein kinases. 1275 1

The chimeric MLL-EEN fusion protein is created as a result of chromosomal translocation t(11;19)(q23;p13). EEN, an Src homology 3 (SH3) domain-containing protein in the endophilin family, has been implicated in endocytosis, although little is known about its role in leukemogenesis mediated by the MLL-EEN fusion protein. In this study, we have identified and characterized EBP, a novel EEN binding protein that interacts with the SH3 domain of EEN through a proline-rich motif PPERP. EBP is a ubiquitous protein that is normally expressed in the cytoplasm but is recruited to the nucleus by MLL-EEN with a punctate localization pattern characteristic of the MLL chimeric proteins. EBP interacts simultaneously with EEN and Sos, a guanine-nucleotide exchange factor for Ras. Coexpressoin of EBP with EEN leads to suppression of Ras-induced cellular transformation and Ras-mediated activation of Elk-1. Taken together, our findings suggest a new mechanism for MLL-EEN-mediated leukemogenesis in which MLL-EEN interferes with the Ras-suppressing activities of EBP through direct interaction.
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PMID:Identification and characterization of EBP, a novel EEN binding protein that inhibits Ras signaling and is recruited into the nucleus by the MLL-EEN fusion protein. 1455 Nov 39

This study investigated the effects of cyclic stretching on adipocyte differentiation of mouse preadipocyte 3T3-L1 cells. Confluent 3T3-L1 cells were treated with dexamethasone, 3-isobutyl-1-methylxanthine and insulin for 45 hours (induction period), followed by incubation with insulin for 9 additional days (maturation period). A transient burst of CCAAT/enhancer-binding protein (C/EBP) beta and C/EBPdelta at an early stage (approximately 3 hours) and a delayed induction (approximately 45 hours) of C/EBPalpha and PPARgamma(2) were sequentially provoked during the induction period. Application of cyclic stretching during the entire induction period or only during the final 15 hours of the induction period significantly retarded the induction of glycerol-3-phosphate dehydrogenase (GPDH) activity and the accumulation of intracellular triglycerides by the end of the maturation period. Cyclic stretching for the entire induction period, as well as that applied during the final 15 hours of the induction period, significantly reduced the expression of PPARgamma(2) mRNA, whereas reduction in the expression of C/EBPdelta mRNA was only observed in response to stretching that had been applied during the entire induction period. The expression of C/EBPalpha and C/EBPbeta mRNA did not change in response to stretching. Stretching induced the phosphorylation of extracellular-signal-regulated protein kinases 1 and 2 (ERK1/2), which are members of the mitogen-activated-protein kinase (MAPK) family, during the induction period. PD98,059, a MAPK/ERK kinase inhibitor, reversed the stretch-induced reduction of PPARgamma(2) at both mRNA and protein levels achieved during the induction period. PD98,059 also restored GPDH activity and lipid droplet accumulation. Furthermore, the differentiation inhibited by the stretching was also restored by synthetic PPARgamma ligand. Collectively, these results suggest that the inhibition of adipocyte differentiation in response to stretching is mainly attributable to the reduced expression of PPARgamma(2), which is mediated by activation of the ERK/MAPK system.
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PMID:Inhibition of adipocyte differentiation by mechanical stretching through ERK-mediated downregulation of PPARgamma2. 1525 28

Genetic interventions that accelerate or retard aging in mice are crucial in advancing our knowledge over mammalian aging. Yet determining if a given intervention affects the aging process is not straightforward since, for instance, many disease-causing mutations may decrease life span without affecting aging. In this work, we employed the Gompertz model to determine whether several published interventions previously claimed to affect aging in mice do indeed alter the aging process. First, we constructed age-specific mortality tables for a number of mouse cohorts used in longevity experiments and calculated the rate at which mortality increases with age. Estimates of age-independent mortality were also calculated. We found no statistical evidence that GHRHR, IGF1R, INSR, PROP1, or TRX delay or that ATM + TERC, BubR1, klotho, LMNA, PRDX1, p53, WRN + TERC, or TOP3B accelerate mouse aging. Often, changes in the expression of these genes affected age-independent mortality and so they may prove useful to other aspects of medicine. We found statistical evidence that C/EBP, MSRA, SHC1, growth hormone, GHR, PIT1, and PolgA may influence aging in mice. These results were interpreted together with age-related physiological and pathological changes and provide novel insights regarding the role of several genes in the mammalian aging process.
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PMID:The influence of genes on the aging process of mice: a statistical assessment of the genetics of aging. 1546 29

Peroxisome proliferator-activated receptor gamma (PPARgamma) is a nuclear receptor regulating an array of diverse functions in a variety of cell types including regulation of genes associated with growth and differentiation. Its most notable function is to regulate development of adipose tissue, which involves coordinating expression of many hundreds of genes responsible for establishment of the mature adipocyte phenotype. Our recent studies have demonstrated a role for MEK/ERK signaling and CCAAT/enhancer binding proteins (C/EBP)beta in regulating expression of PPARgamma during adipogenesis. Furthermore, we have shown that cAMP-dependent signaling along with C/EBPbeta leads to the stimulation of PPARgamma activity by mechanisms that probably involve production of PPARgamma ligands. Additionally, we have recently demonstrated that phosphorylation of C/EBPbeta at a consensus ERK/GSK3 site is required for the PPARgamma-associated expression of adiponectin during the terminal stages of adipogenesis. GSK3beta also influences PPARgamma activity by regulating the turnover and subcellular localization of beta-catenin, a potent transcriptional activator of Wnt signaling. In fact, we have recently shown a crosstalk between PPARgamma and beta-catenin signaling. Specifically, activation of PPARgamma induces the degradation of beta-catenin during preadipocyte differentiation by mechanisms that require GSK3beta and the proteasome. In contrast, expression of a GSK3beta-phosphorylation-defective beta-catenin renders beta-catenin resistant to the degradatory action of PPARgamma. Interestingly, expression of the mutant beta-catenin blocks expression of adiponectin and C/EBPalpha in response to the activation of PPARgamma.
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PMID:Regulation of PPARgamma activity during adipogenesis. 1571 76

RTP801 is a newly discovered stress response gene that is induced by hypoxia and other cell stress signals. Here, we investigated the mechanism by which a DNA damaging agent, methyl methanesulfonate (MMS), induces RTP801 transcription. In HaCaT human keratinocytes, MMS was able to induce a rapid increase in the mRNA level of RTP801. Correspondingly, MMS treatment was capable of stimulating a 2.5 kb RTP801 promoter. Deletion studies with the promoter demonstrated a critical region between -1057 and -981 bp of the promoter that is responsive to MMS treatment. Point mutations of the consensus Elk-1 and C/EBP sites within this region were able to abrogate the stimulatory effect of MMS, indicating that Elk-1 and C/EBP are both involved in the transcriptional regulation of the RTP801 gene by MMS. Furthermore, a gel mobility shift assay revealed that MMS was able to initiate rapid formation of a protein complex that bound the C/EBP site of the promoter. In addition, an anti-C/EBPbetaantibody was capable of further shifting the bound protein complex. Therefore, these studies indicate that RTP801 is a transcriptional target of MMS in human keratinocytes and that C/EBP is implicated in transcriptional control of the gene.
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PMID:Induction of a cell stress response gene RTP801 by DNA damaging agent methyl methanesulfonate through CCAAT/enhancer binding protein. 1575 66

RTP801 is a newly discovered stress-response gene that is induced by hypoxia and other cell stress signals. Arsenic is a heavy metal that is linked to carcinogenesis in humans. Here, we investigated the mechanism by which arsenic induces RTP801 transcription. In HaCaT human keratinocytes, arsenite was able to induce a rapid rise in the RTP801 mRNA level. Correspondingly, arsenite treatment was capable of stimulating a 2.5 kb human RTP801 promoter. Such a stimulatory effect was inhibited by co-expression of superoxide dismutase or glutathione peroxidase, and was abrogated by N-acetylcysteine, implying that ROS (reactive oxygen species) were involved in transcriptional regulation of the RTP801 gene. A series of deletion studies with the promoter revealed a critical arsenic-responsive region between -1057 and -981 bp of the promoter. Point mutations of the putative Elk-1 site and the C/EBP (CCAAT/enhancer-binding protein) site within this region were able to reduce the stimulatory effect of arsenite, indicating that Elk-1 and C/EBP are involved in transcriptional regulation of the RTP801 gene by arsenite. Furthermore, a gel mobility-shift assay demonstrated that arsenite was able to mount the rapid formation of a protein complex that bound the arsenic-responsive region as well as the C/EBP-containing sequence. The arsenite stimulation on RTP801 transcription was partly mediated by the ERK (extracellular-signal-regulated kinase) pathway, since the effect of RTP801 was inhibited by a selective ERK inhibitor. In addition, overexpression of Elk-1 and C/EBPbeta was able to elevate the promoter activity. Therefore these studies indicate that RTP801 is a transcriptional target of arsenic in human keratinocytes, and that arsenic and ROS production are linked to Elk-1 and C/EBP in the transcriptional control.
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PMID:Arsenite induces a cell stress-response gene, RTP801, through reactive oxygen species and transcription factors Elk-1 and CCAAT/enhancer-binding protein. 1600 23

Interleukin-1beta (IL-1beta) is a major inducer of liver acute-phase protein expression in response to infection. Several transcription factors, including CCAAT/enhancer binding protein (C/EBP), are known mediators in this process, although the mechanisms by which they modulate IL-1beta's action are not completely understood. Activation of sphingomyelinase (SMase) and the subsequent generation of ceramide are early steps in the IL-1beta signaling cascade. In this study, we investigate the role of ceramide in the IL-1beta regulation of C/EBP in primary hepatocytes. The C/EBP DNA binding activity was found to increase in a dose-dependent manner after stimulation with IL-1beta and exogenous addition of C2-ceramide or treatment with SMase. These changes were accompanied by an increase in the nuclear content of C/EBPbeta. Both IL-1beta and ceramide led to extracellular signal-regulated kinase 1/2 (ERK1/2) activation as early as 15 min after treatment. Furthermore, the increase of cellular ceramide content resulted in increased phosphorylation of C/EBPbeta at serine 105 at later time points. Concurrently, the cytosolic levels of C/EBPbeta decreased, suggesting that IL-1beta and ceramide induced nuclear translocation of C/EBPbeta. Ceramide-induced C/EBPbeta phosphorylation, translocation, and DNA binding were suppressed by the addition of PD98059, an inhibitor of ERK1/2 phosphorylation. These results suggest that ceramide and ERK mediate a pathway in the IL-1beta signaling cascade, which results in rapid posttranslational activation of C/EBPbeta.
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PMID:Ceramide- and ERK-dependent pathway for the activation of CCAAT/enhancer binding protein by interleukin-1beta in hepatocytes. 1610 45

6-(Methylsulfinyl)hexyl isothiocyanate (6-MITC) is a chemopreventive compound occurring in Wasabi (Wasabia japonica (Miq.) Matsumura), which is a very popular pungent spice in Japan. We investigated the effects of 6-MITC on the expression of cyclooxygenase-2 (COX-2) in lipopolysaccharide (LPS)-activated murine macrophage RAW264 cells. Treatment with 6-MITC suppressed LPS-mediated induction of COX-2 protein in a dose-dependent manner. Transfections with various COX-2 promoter reporter constructs revealed that the inhibitory effects of 6-MITC on COX-2 gene expression were directed by the core promoter elements including nuclear factor kappaB (NF-kappaB), CCAAT/enhancer-binding protein (C/EBP) and cyclic AMP-response element (CRE) sites. Western blotting analysis showed that 6-MITC inhibited LPS-induced activation of MAPK (ERK, p38 kinase and JNK) and transcriptional factors (CREB, c-Jun and C/EBPdelta) binding the core elements of COX-2 promoter, substantiating the involvement of these signal transduction pathways in the regulation of COX-2 expression by 6-MITC. Moreover, Western blotting experiments with MAPK-specific inhibitors (U0126 for MEK1/2, SB203580 for p38 kinase and SP600125 for JNK) demonstrated that 6-MITC suppressed LPS-induced COX-2 expression by blocking the activation of JNK-mediated AP-1 and ERK/p38 kinase-mediated CREB or C/EBPdelta. Finally, the structure-activity study revealed that the inhibitory potency of methylsulfinyl isothiocyanates (MITCs) depended on the methyl chain length. These findings demonstrate for the first time that 6-MITC is an effective agent to attenuate COX-2 production, and enhance our understanding of the anti-inflammation properties of 6-MITC.
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PMID:Inhibition of lipopolysaccharide-induced cyclooxygenase-2 transcription by 6-(methylsulfinyl) hexyl isothiocyanate, a chemopreventive compound from Wasabia japonica (Miq.) Matsumura, in mouse macrophages. 1625 55


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