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)

Twenty-four base pairs of the human antioxidant response element (hARE) are required for high basal transcription of the NAD(P)H:quinone oxidoreductase1 (NQO1) gene and its induction in response to xenobiotics and antioxidants. hARE is a unique cis-element that contains one perfect and one imperfect AP1 element arranged as inverse repeats separated by 3 bp, followed by a "GC" box. We report here that Jun, Fos, Fra, and Nrf nuclear transcription factors bind to the hARE. Overexpression of cDNA derived combinations of the nuclear proteins Jun and Fos or Jun and Fra1 repressed hARE-mediated chloramphenicol acetyltransferase (CAT) gene expression in transfected human hepatoblastoma (Hep-G2) cells. Further experiments suggested that this repression was due to overexpression of c-Fos and Fra1, but not due to Jun proteins. The Jun (c-Jun, Jun-B, and Jun-D) proteins in all the possible combinations were more or less ineffective in repression or upregulation of hARE-mediated gene expression. Interestingly, overexpression of Nrf1 and Nrf2 individually in Hep-G2 and monkey kidney (COS1) cells significantly increased CAT gene expression from reporter plasmid hARE-thymidine kinase-CAT in transfected cells that were inducible by beta-naphthoflavone and teri-butyl hydroquinone. These results indicated that hARE-mediated expression of the NQO1 gene and its induction by xenobiotics and antioxidants are mediated by Nrf1 and Nrf2. The hARE-mediated basal expression, however, is repressed by overexpression of c-Fos and Fra1.
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PMID:Nrf1 and Nrf2 positively and c-Fos and Fra1 negatively regulate the human antioxidant response element-mediated expression of NAD(P)H:quinone oxidoreductase1 gene. 896 64

Xenobiotics and antioxidants induce expression of detoxifying enzymes including NAD(P)H: quinone oxidoreductase (NQO1), NRH:quinone oxidoreductase (NQO2), and glutathione S-transferase Ya (GST Ya), presumably to provide protection to cells against electrophilic and oxidative stress. Antioxidant response elements (AREs) have been found in the promoter regions of the various detoxifying enzyme genes. An ARE is required for basal expression and induction of the various detoxifying enzyme genes in response to xenobiotics and antioxidants. In this study, we demonstrated that exposure of cells to xenobiotics [e.g. beta-naphthoflavone (beta-NF)] and antioxidants [e.g. tert-butyl hydroquinone (t-BHQ)] also induced the expression of the proto-oncogene c-jun. The induction of c-jun gene expression followed kinetics similar to the induction of NQO1 and NQO2 genes with respect to the level and time of exposure. Sequence analysis of the c-jun gene promoter revealed the presence of an ARE between nucleotides -538 and -514. The c-jun ARE was highly homologous to the AREs from genes encoding NQO1, NQO2, and GST Ya. Constructs containing the c-jun ARE and 1.7 and 4.5 kb of the c-jun promoter ligated to the chloramphenicol acetyltransferase (CAT) gene, upon transfection in human hepatoblastoma (Hep-G2) cells, expressed the CAT gene, which was inducible with beta-NF and t-BHQ. Band shift assays indicated binding of two specific nuclear protein complexes with the c-jun gene ARE. The faster running c-jun gene ARE-nuclear protein complex was specifically competed out by unlabeled NQO1 and GST Ya gene AREs. These results suggest that c-jun gene expression is coordinately induced and regulated with detoxifying enzyme genes in response to xenobiotics and antioxidants. The results also suggest involvement of an ARE-mediated mechanism of induction of c-jun gene expression. However, a comparison of fold induction of endogenous c-jun gene and transfected c-jun promoter/ARE-CAT constructs indicated involvement of another ARE upstream of the 4.5-kb promoter and/or additional mechanisms such as stabilization of c-Jun RNA in response to exposure to xenobiotics and antioxidants.
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PMID:Coordinated induction of the c-jun gene with genes encoding quinone oxidoreductases in response to xenobiotics and antioxidants. 1041 96

Parthenolide, a sesquiterpene lactone, shows antitumor activity in vitro, which correlates with its ability to inhibit the DNA binding of the antiapoptotic transcription factor nuclear factor kappaB (NF-kappaB) and activation of the c-Jun NH(2)-terminal kinase. In this study, we investigated the chemosensitizing activity of parthenolide in vitro as well as in MDA-MB-231 cell-derived xenograft metastasis model of breast cancer. HBL-100 and MDA-MB-231 cells were used to measure the antitumor and chemosensitizing activity of parthenolide in vitro. Parthenolide was effective either alone or in combination with docetaxel in reducing colony formation, inducing apoptosis and reducing the expression of prometastatic genes IL-8 and the antiapoptotic gene GADD45beta1 in vitro. In an adjuvant setting, animals treated with parthenolide and docetaxel combination showed significantly enhanced survival compared with untreated animals or animals treated with either drug. The enhanced survival in the combination arm was associated with reduced lung metastases. In addition, nuclear NF-kappaB levels were lower in residual tumors and lung metastasis of animals treated with parthenolide, docetaxel, or both. In the established orthotopic model, there was a trend toward slower growth in the parthenolide-treated animals but no statistically significant findings were seen. These results for the first time reveal the significant in vivo chemosensitizing properties of parthenolide in the metastatic breast cancer setting and support the contention that metastases are very reliant on activation of NF-kappaB.
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PMID:The sesquiterpene lactone parthenolide in combination with docetaxel reduces metastasis and improves survival in a xenograft model of breast cancer. 1595 58

Gadolinium (Gd) compounds have important applications as MRI contrast and potential anticancer agents. The present study investigated the mechanisms of the proapoptotic effect of gadolinium chloride (GdCl(3)) on hepatoblastoma cell line (Hep G2) tumor cells. The experimental results indicated that GdCl(3) induced apoptosis of Hep G2 at high concentration and with long time incubation; however, unlike the actions on normal cell lines, GdCl(3) did not cause any oxidative stress on tumor cells. Cytochrome c (Cyt c) and apoptosis inducing factor release, Bax translocation, collapse of mitochondria membrane potential, caspase 3 and 8 activation, and Bid cleavage were observed along with a sustained activation of extracellular signal-regulated kinase (ERK) and c-Jun NH2 terminal kinase (JNK). Addition of ERK and JNK inhibitor attenuated the effect of GdCl(3) induced apoptosis and Cyt c release. All the results suggested a novel mechanism that GdCl(3) induced Hep G2 cell death through intrinsic and external death pathways without significant elevation of reactive oxygen species generation. The present work provided new insight to understand the mechanisms of the biological effects of GdCl(3) and implications for the development of anticancer Gd agents.
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PMID:GdCl3 induced Hep G2 cell death through mitochondrial and external death pathways without significant elevation of ROS generation. 2312 26

Furazolidone (FZD), a synthetic nitrofuran with a broad spectrum of antimicrobial actions, is known to induce genotoxicity and potential carcinogenicity in several types of cells, but little is known about its p38 mitogen-activation protein kinase (p38 MAPK) and c-Jun N-terminal protein kinase (JNK) pathways in human hepatoblastoma cell line (HepG2). Given the previously described essential roles of p38 MAPK and JNK pathways in HepG2 cells, we undertook the present study to investigate the roles of p38 MAPK and JNK pathways in cell cycle arrest of HepG2 cells stimulated with FZD. Here we reported that FZD could obviously induce S phase cell cycle arrest, suppress cell growth, increase the activity of phosphorylated p38 (p-p38), and decrease the activity of phosphorylated JNK (p-JNK) in HepG2 cells. Simultaneously, inhibition of p38 MAPK pathway could significantly reduce FZD-stimulated S phase cell cycle arrest, active cell growth, decrease the activity of p-p38, and increase the activity of p-JNK. To the opposite, inhibition of JNK pathway could significantly increase FZD-stimulated S phase cell cycle arrest, suppress cell growth, decrease the activity of p-JNK, and increase the activity of p-p38. These results demonstrate that JNK and p38 MAPK pathways have opposite roles in FZD-stimulated S phase cell cycle arrest of HepG2 cells. FZD induces S phase cell cycle arrest and suppresses cell proliferation of HepG2 cells via activating the pathway from p38 to p-p38 and inhibiting the pathway from JNK to p-JNK.
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PMID:Opposite effects of JNK and p38 MAPK signaling pathways on furazolidone-stimulated S phase cell cycle arrest of human hepatoblastoma cell line. 2366 Mar 33