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

(-)-Epigallocatechin gallate (EGCG) and theaflavins are believed to be key active components in tea for the chemoprevention against cancer. However, the molecular mechanisms by which EGCG and theaflavins block carcinogenesis are not clear. We have used the JB6 mouse epidermal cell line, a system that has been used extensively as an in vitro model for tumor promotion studies, to examine the anti-tumor promotion effects of EGCG and theaflavins at the molecular level. EGCG and theaflavins inhibited epidermal growth factor- or 12-O-tetradecanoylphorbol-13-acetate-induced cell transformation in a dose-dependent manner. At the dose range (5-20 microM) that inhibited cell transformation, EGCG and theaflavins also inhibited AP-1-dependent transcriptional activity and DNA binding activity. The inhibition of AP-1 activation occurs through the inhibition of a c-Jun NH2-terminal kinase-dependent, but not an extracellular signal-regulated protein kinase (Erk) 1-dependent or Erk2-dependent, pathway. Because the transcription factor AP-1 is important for tumor promoter-induced neoplastic transformation, the inhibitory effects on AP-1 activation by EGCG and theaflavins may further explain the anti-tumor promotion action of these tea constituents.
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PMID:Inhibition of tumor promoter-induced activator protein 1 activation and cell transformation by tea polyphenols, (-)-epigallocatechin gallate, and theaflavins. 933 Nov 5

Many natural products elicit diverse pharmacological effects. Using two classes of potential chemopreventive compounds, the phenolic compounds and the isothiocyanates, we review the potential utility of two signaling events, the mitogen-activated protein kinases (MAPKs) and the ICE/Ced-3 proteases (caspases) stimulated by these agents in mammalian cell lines. Studies with phenolic antioxidants (BHA, tBHQ), and natural products (flavonoids; EGCG, ECG, and isothiocyanates; PEITC, sulforaphane), provided important insights into the signaling pathways induced by these compounds. At low concentrations, these chemicals may activate the MAPK (ERK2, JNK1, p38) leading to gene expression of survival genes (c-Fos, c-Jun) and defensive genes (Phase II detoxifying enzymes; GST, QR) resulting in survival and protective mechanisms (homeostasis response). Increasing the concentrations of these compounds will additionally activate the caspase pathway, leading to apoptosis (potential cytotoxicity). Further increment to suprapharmacological concentrations will lead to nonspecific necrotic cell death. The wider and narrow concentration ranges between the activation of MAPK/gene induction and caspases/cell death exhibited by phenolic compounds and isothiocyanates, respectively, in mammalian cells, may reflect their respective therapeutic windows in vivo. Consequently, the studies of signaling pathways elicited by natural products will advance our understanding of their efficacy and safety, of which many may become important therapeutic drugs of the future.
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PMID:Signal transduction events elicited by natural products: role of MAPK and caspase pathways in homeostatic response and induction of apoptosis. 1072 49

The objective of the current study was to investigate the effect of resveratrol, a naturally occurring polyphenol with cancer chemopreventive properties, on polyamine metabolism in the human colonic adenocarcinoma cell line Caco-2. We demonstrated that inhibition of ornithine decarboxylase (ODC), the rate-limiting enzyme in polyamine biosynthesis, was due to attenuated ODC protein and mRNA levels (50-200 microM). The naturally occurring resveratrol analog piceatannol (100 microM) also diminished ODC activity, protein and mRNA levels, whereas the green tea polyphenol (-)-epigallocatechin gallate (EGCG; 100 microM) exerted only weak effects on ODC. The transcription factor c-Myc, a positive regulator of the odc gene was attenuated by resveratrol treatment and to a lesser extent by piceatannol and EGCG. S-Adenosylmethionine decarboxylase, an enzyme that synthesizes higher polyamines, was concomitantly inhibited by resveratrol and piceatannol treatment, whereas EGCG did not affect its activity. In addition resveratrol, piceatannol and EGCG enhanced spermidine/spermine N(1)-acetyltransferase activity, an enzyme that degrades polyamines in cooperation with polyamine oxidase. Intracellular levels of spermine and spermidine were not affected, whereas putrescine and N(8)-acetylspermidine concentrations increased after incubation with resveratrol. These events were paralleled by an increase of the activator protein-1 constituents c-Fos and c-Jun. Whereas DNA-binding activity of c-Jun remained unchanged, DNA-binding activity of c-Fos was significantly enhanced by resveratrol and piceatannol, but inhibited by EGCG. The data suggest that growth arrest by resveratrol is accompanied by inhibition of polyamine synthesis and increased polyamine catabolism. C-Fos seems to play a role in this context. Effects of piceatannol on polyamine synthesis were similar, but not as potent as those exerted by resveratrol.
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PMID:Resveratrol-induced modification of polyamine metabolism is accompanied by induction of c-Fos. 1266 6

It has been widely shown that many plant-derived compounds present significant anti-inflammatory effects. For this reason, they represent potential molecules for the development of new drugs, especially designed for the treatment and/or control of chronic inflammatory states such as rheumatism, asthma, inflammatory bowel diseases, atherosclerosis, etc. This review focuses on the naturally-occurring compounds with anti-inflammatory properties and attempts to correlate their actions with the modulation of cytokines and associated intracellular signalling pathways; it continues the review published in the November, 2003 issue of Planta Medica. Abbreviations. AP-1:activator protein-1 CCR1:chemokine receptor 1 CINC-1:cytokine-induced neutrophil chemoattractant 1 COX:cyclooxygenase EGCG:(-)-epigallocatechin gallate ELAM-1:endothelial-leukocyte adhesion molecule-1 ERK:extracellular signal-regulated kinase GRO:growth-related oncogene HUVEC:human umbilical vein endothelial cells ICAM-1:intercellular adhesion molecule-1 IFN:interferon IL:interleukin iNOS:inducible nitric oxide synthase IRA:the natural interleukin receptor activation JAK:janus kinase JNK:c-Jun NH2-terminal kinase LPS:lipopolysaccharide MAPK:mitogen-activated protein kinases MCP:monocyte chemotactic protein MHC:major histocompatibility complex MIP:macrophage inflammatory protein MMP:matrix metalloproteinases MPO:myeloperoxidase NF-kappaBnuclear factor kappa B NO:nitric oxide PAF:platelet aggregation factor PGEE:prostaglandin PK:protein kinase PMA/TPA:phorbol myristate acetate RANTES:regulated upon activation normal T-cell expressed and secreted TGF-beta:transforming growth factor-beta TNFalpha:tumour necrosis factor VCAM-1:vascular cell adhesion molecule-1
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PMID:Anti-inflammatory compounds of plant origin. Part II. modulation of pro-inflammatory cytokines, chemokines and adhesion molecules. 1499 84

In this study, we used rat aortic endothelial cells and human umbilical vein endothelial cells growing in collagen gel as a model system to study the tea catechin, (-)-epigallocatechin (EGCG), on the differential expression of transcription factors, Ets-1, c-Fos, and c-Jun during endothelial morphogenesis in vitro. Cells growing in collagen gel from 0 to 2 h remained spherical. After 6 h, the cells became elongated and underwent morphogenesis. At 24 h, cells started to organize to form capillary-like tubular structures. At 48 h, most cells in the gel formed a network of branching and tubular structures. Immunohistochemistry and immunofluorescence microscopy showed that the reaction products of Ets-1, c-Fos, and c-Jun presented predominantly in the nucleus. No reaction products appeared in the cells that were organized to form capillary-like tubular structures. After adding EGCG to the collagen gel, cells became elongated in the first 6 h and then remained quiescent. No tubular structure was formed. Western blotting showed that the levels of Ets-1, c-Fos, and c-Jun reached the highest levels at 12-24 h, decreasing to the basal level at 48 h. After adding EGCG to the collagen gel, levels were lower than for the non-EGCG-treated groups. These results indicated that the morphogenesis of endothelial cells in collagen gel was inhibited by EGCG through the down-regulation of Ets-1, c-Fos, and c-Jun.
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PMID:Effect of EGCG, a major component of green tea, on the expression of Ets-1, c-Fos, and c-Jun during angiogenesis in vitro. 1532 33

We reported recently that (-)epigallocatechin gallate and quercetin inhibited H2O2-induced apoptosis through modulation of the expression of apoptosis-related Bcl-2 and Bax in endothelial cells. This study attempted to identify possible regulatory sites and mechanisms of antiapoptotic flavonoids, focusing on ROS-mediated signaling in HUVEC. The effects of apigenin on the signaling pathway downstream were compared. Submillimolar H2O2 caused >30% cell killing with intracellular oxidant generation. H2O2-induced oxidant generation markedly decreased total intracellular glutathione (GSH) levels. Micromolar (-)epigallocatechin gallate and quercetin partially eliminated the dichlorodihydrofluorescein (DCF) and phospho-p53 staining, suggesting that these flavonoids inhibited the accumulation of intracellular oxidants and nuclear transactivation of p53 in H2O2-exposed cells. In contrast, cells treated with apigenin remained DCF and phospho-p53 staining positive in response to H2O2. (-)Epigallocatechin gallate significantly raised the total GSH level that had been depleted by H2O2. Caspase-3 activity was enhanced by H2O2, and this increase was inhibited by (-)epigallocatechin gallate and quercetin. Additionally, the upregulation of caspase-3 activation was reversed by these flavonoids at > or =10 micromol/L; these inhibitory effects were dose dependent. Western blot data revealed that H2O2 upregulated phosphorylation of c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK), which was rapidly reversed by quercetin within 30 min; H2O2 activation of c-Jun was downregulated. (-)Epigallocatechin gallate inhibited H2O2-induced phosphorylation of JNK and p38 MAPK after 60 min. These results reveal that quercetin blocks JNK- and p38 MAPK-related signaling triggered by the oxidant and may regulate expression of apoptotic downstream genes, preventing apoptosis and promoting cell survival. (-)Epigallocatechin gallate may function as an antiapoptotic agent through other antiapoptotic pathways.
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PMID:(-)Epigallocatechin gallate and quercetin enhance survival signaling in response to oxidant-induced human endothelial apoptosis. 1579 22

Curcumin, a phenolic compound isolated from the plant Curcuma longa (Linn), is ingested every day in the Indian subcontinent and is well reported to possess cancer-preventive activity. To achieve effective cancer prevention with curcumin, we need to find a new method to enhance the effects of curcumin in the diet. Based on our evidence that (-)-epicatechin (EC), an inert catechin, enhances the cancer-preventive activity of green tea catechins, we studied the enhancing effects of EC on inductions of growth inhibition and apoptosis in human lung cancer cell lines PC-9 and A549 with curcumin. The combination of curcumin with EC significantly increased the inhibition of cell growth compared with curcumin or EC alone. The combination similarly increased both apoptosis and expression of GADD153 and GADD45 genes, associated with their enhanced protein production. Knockdown of GADD153 or GADD45 by small interfering RNA abrogated the apoptosis induction and growth inhibition induced by the combination, indicating the crucial role of their upregulation. Treatments of PC-9 cells with c-Jun-NH(2)-kinase inhibitor SP600125, with p38 mitogen-activated protein kinase inhibitor SB202190 and with PD98059 (extracellular signal-regulated kinase 1/2 inhibitor) all increased the upregulation of GADD153 and GADD45 genes by the combination. Because EC was previously shown to enhance the incorporation of EGCG into PC-9 cells, we think that EC has similar effects on curcumin. This report is the first report on the enhancing effects of EC on curcumin, and the data suggest that EC plays a significant role in the enhancement of the cancer-preventive activity of curcumin in the diet.
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PMID:New role of (-)-epicatechin in enhancing the induction of growth inhibition and apoptosis in human lung cancer cells by curcumin. 2060 42

During the process of skin tumor promotion, expression of the cutaneous cancer stem cell (CSC) marker CD34(+) is required for stem cell activation and tumor formation. A previous study has shown that activation of protein kinase D1 (PKD1) is involved in epidermal tumor promotion; however, the signals that regulate CSCs in skin carcinogenesis have not been characterized. This study was designed to investigate the chemopreventive potential of peracetylated (-)-epigallocatechin-3-gallate (AcEGCG) on 7,12-dimethylbenz[a]-anthracene (DMBA)-initiated and 12-O-tetradecanoylphorbol-13-acetate (TPA)-promoted skin tumorigenesis in ICR mice and to elucidate the possible mechanisms involved in the inhibitory action of PKD1 on CSCs. We demonstrated that topical application of AcEGCG before TPA treatment can be more effective than EGCG in reducing DMBA/TPA-induced tumor incidence and multiplicity. Notably, AcEGCG not only inhibited the expression of p53, p21, c-Myc, cyclin B, p-CDK1 and Cdc25A but also restored the activation of extracellular signal-regulated kinase 1/2 (ERK1/2), which decreased DMBA/TPA-induced increases in tumor proliferation and mitotic index. To clarify the role of PKD1 in cell proliferation and tumorigenesis, we studied the expression and activation of PKD1 in CD34(+) skin stem cells and skin tumors. We found that PKD1 was strongly expressed in CD34(+) cells and that pretreatment with AcEGCG markedly inhibited PKD1 activation and CD34(+) expression. More importantly, pretreatment with AcEGCG remarkably suppressed nuclear factor-kappaB, cyclic adenosine 3',5'-monophosphate-responsive element-binding protein (CREB) and CCAAT-enhancer-binding protein (C/EBPs) activation by inhibiting the phosphorylation of c-Jun-N-terminal kinase 1/2, p38 and phosphatidylinositol 3-kinase (PI3K)/Akt and by attenuating downstream target gene expression, including inducible nitric oxide synthase, cyclooxygenase-2, ornithine decarboxylase and vascular endothelial growth factor. Moreover, this is the first study to demonstrate that AcEGCG is a CD34(+) and PKD1 inhibitor in the multistage mouse skin carcinogenesis model. Overall, our results powerfully suggest that AcEGCG could be developed into a novel chemopreventive agent and that PKD1 may be a preventive and therapeutic target for skin cancer in clinical settings.
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PMID:Peracetylated (-)-epigallocatechin-3-gallate (AcEGCG) potently prevents skin carcinogenesis by suppressing the PKD1-dependent signaling pathway in CD34+ skin stem cells and skin tumors. 2338 63

Leptin contributes to the pathogenesis of vascular repair and cardiovascular events. This study evaluated the molecular mechanism of EGCG in balloon injury-induced leptin expression. According to immunohistochemical and confocal analyses, leptin expression was increased and the aortic lumen exhibited narrowing after balloon injury. EGCG treatment attenuated leptin expression and diminished neointimal formation. The in vitro study showed that angiotensin II (Ang II) induced the migration and proliferation of cultured vascular smooth muscle cells (VSMCs), whereas treatment with EGCG, leptin siRNA, and c-Jun siRNA inhibited the migration and proliferation of VSMCs significantly. The EMSA shows that balloon injury increased AP-1-binding activity, and EGCG and c-Jun siRNA inhibited the AP-1-binding activity. Western blot and real-time RT-PCR analyses revealed similar results in intimal tissue samples. In summary, balloon injury induces leptin expression in the carotid artery of rats, and EGCG inhibits leptin expression through the JNK/AP-1 pathway and also attenuates neointimal formation.
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PMID:Molecular mechanism of (-)-epigallocatechin-3-gallate on balloon injury-induced neointimal formation and leptin expression. 2441 Jan 32