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)

We have previously identified a novel xenobiotic responsive element, which has been termed the antioxidant responsive element (ARE), in the 5'-flanking region of the rat quinone reductase gene (Favreau, L. V., and Pickett, C. B. (1991) J. Biol. Chem. 266, 4556-4561). This element is responsible for basal level expression of the gene as well as transcriptional activation by phenolic antioxidants and metabolizable planar aromatic compounds. In this communication, we demonstrate that hydrogen peroxide can act as an inducer through the ARE sequence, a phenomenon recently demonstrated for the glutathione S-transferase Ya subunit gene (Rushmore, T. H., Morton, M. R., and Pickett, C. B. (1991) J. Biol. Chem. 266, 11632-11639). To further characterize the quinone reductase ARE, we demonstrate by DNase I footprinting that in crude Hep G2 nuclear extracts a trans-acting factor exists which interacts with a region of DNA found within the 31-nucleotide ARE sequence. Furthermore, electrophoretic mobility shift assays demonstrate the presence of a specific DNA-protein complex which can be competed only by double-stranded oligonucleotides containing the ARE sequences from the quinone reductase and glutathione S-transferase Ya subunit genes. Methylation interference and protection assays indicate that several guanine residues found in the sequence GTGACTTGGC are involved in the binding of the nuclear factor(s) to the DNA. Although electrophoretic mobility shift assays indicate that the rat quinone reductase ARE does not contain a high affinity recognition site for in vitro translated c-Jun and c-Fos, 12-O-tetradecanoylphorbol 13-acetate can act as an inducer through the ARE sequence in Hep G2 cells.
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PMID:Transcriptional regulation of the rat NAD(P)H:quinone reductase gene. Characterization of a DNA-protein interaction at the antioxidant responsive element and induction by 12-O-tetradecanoylphorbol 13-acetate. 839 48

Benzene toxicity towards lymphocytes is thought to be mediated by metabolites of benzene including benzoquinone (BQ). NAD(P)H:quinone reductase (QR) is known to protect against BQ toxicity. The expression of the QR gene is regulated by the transcription factor AP-1. We had previously found that aspirin-like drugs (ALD) induce AP-1 in human T lymphocytes. It was therefore hypothesized that ALD would protect lymphocytes against BQ toxicity by inducing QR. Molt-4 cells (M4), a human T lymphocyte cell line, were incubated with different concentrations of two ALD, flurbiprofen and sodium diclofenac, and then exposed to BQ. Toxicity was measured by viability (trypan blue exclusion). Both drugs protected the cells against BQ cytotoxicity in a dose-dependent manner, e.g., sodium diclofenac at 15 microM reduced the fraction of BQ-treated dead cells by 70%. ALDs induced QR activity in the M4 cells in the same range of concentrations that protected the cells against BQ toxicity. The protective effect of ALD was significantly reduced by dicoumarol, a QR-specific inhibitor. Since human T cells and T cell lines do not metabolize arachidonic acid, our data suggest that ALD can protect human T lymphocytes against a metabolite of benzene by induction of QR activity.
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PMID:Aspirin-like drugs can protect human T lymphocytes against benzoquinone cytotoxicity: evidence for a NAD(P)H:quinone reductase-dependent mechanism. 857 25

Benzyl isothiocyanate (BIT), a microconstituent found in cruciferous vegetables, is known to be a potent inducer of the detoxification enzyme, NAD(P)H: quinone reductase (QR). QR catalyzes a two-electron transfer to a wide variety of redox-cycling species, including quinones, transforming them into dihydrodiols, thereby preventing the mutation of DNA and reducing cancer risk. The upstream signaling mechanisms that lead to the induction of QR remain unclear. The 5' promoter region of the human QR gene contains the cis-acting AP-1 and NFkappaB transcription factor binding sites. When HT29 human colon cells were exposed to 25microM benzyl isothiocyanate, AP-1 binding increased, beginning at 3 hours and increasing until 16 hours. NFkappaB binding also increased, reaching a maximum at around 6 hours. We also found that c-Jun N-terminal kinase (JNK), which phosphorylates c-Jun, a component of AP-1, was activated 9-fold over controls, beginning at 60 minutes. The temporal sequence of these events supports the idea that JNK is involved in the induction of QR and that this is an initial event preceding an increase in transcription factor binding and subsequent QR activity.
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PMID:Temporal effects of the detoxification enzyme inducer, benzyl isothiocyanate: activation of c-Jun N-terminal kinase prior to the transcription factors AP-1 and NFkappaB. 1009 25

A variety of environmental stresses stimulate the mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEKK) > stress-activated protein kinase (SAPK)-ERK kinase (SEK) > SAPK/c-Jun NH(2)-terminal kinase (JNK) stress-activated protein kinase cascade and coordinately activate the transcription factor NFkappaB. Mechanisms of stress activation upstream of MEKK1 have not been precisely determined. Redox mechanisms involving sulfhydryls are likely because N-acetyl-cysteine at millimolar concentrations blocks stress signals. Because intracellular sulfhydryl concentrations can be regulated through redox cycling involving reactive quinones (1), we tested the ability of quinone reductase inhibitors to alter stress signaling. Several quinone reductases are inhibited by dicoumarol, a coumarin derivative. Dicoumarol prevented SAPK activation in vivo by chemical cell stressors and also prevented SAPK activation induced by expression of the tumor necrosis factor alpha (TNFalpha) receptor-associated protein TRAF2 but not by expression of truncated active MEKK1. Other coumarin derivatives failed to block SAPK activation, but other inhibitors of quinone reductases, particularly menadione, similarly blocked SAPK activation. Cells deficient in a major quinone reductase, NQO1, displayed hypersensitivity to dicoumarol stress inhibition, whereas SAPK in cells reconstituted with the NQO1 gene displayed relative dicoumarol resistance. Consistent with the proposed role of overlapping upstream signaling cascades in activation of NFkappaB, dicoumarol also blocked NFkappaB activation in primary macrophages stimulated with either lipopolysaccharide or TNFalpha. In addition, dicoumarol strongly potentiated TNFalpha-induced apoptosis in HeLa cells, probably by blocking the anti-apoptotic effect of NFkappaB. The ability of dicoumarol to simultaneously inhibit SAPK and NFkappaB activation and to potentiate apoptotic cell death suggests that SAPK is not an obligate participant in apoptosis. Dicoumarol, currently in clinical use as an oral anticoagulant, represents a potential therapeutic inhibitor of the SAPK and NFkappaB response.
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PMID:Quinone reductase inhibitors block SAPK/JNK and NFkappaB pathways and potentiate apoptosis. 1053 5

High concentrations of non steroidal antiinflammatory drugs (NSAIDs) exert preventive effects against carcinogenesis. Their molecular mechanism of action remains to be elucidated. Based on previous reports with salicylate, we have made the hypothesis that various NSAIDs can activate the mitogen-activated protein kinases (MAPK). Moreover, we tested the idea that NSAIDs act by increasing the effects of oxidative stress. We report that in human colorectal carcinoma cells NSAIDs stimulated the three families of MAPK, extracellular regulated kinases, c-Jun N-terminal kinases, p38 MAPK and that this stimulation is prevented by N-acetyl cysteine. In cultured astrocytes, a biological system less sensitive to oxidative stress, we show that a short treatment by NSAIDs strongly activated the three MAP kinases in the presence of H(2)O(2). A 25 microM H(2)O(2), unable to stimulate by itself the MAP kinases, promote an almost complete activation of MAP kinases in the presence of NSAIDs. The activation of MAP kinases by H(2)O(2) and NSAIDs was suppressed by quinone reductase inhibitors, suggesting that "redox cycling" was involved in the activation mechanisms of MAP kinases by H(2)O(2) and NSAIDs. The mobility on SDS-PAGE of the apoptosis signal-regulating kinase, which activates C-Jun N-terminal kinases and p38 MAPK cascades, was reduced by H(2)O(2) and NSAIDs, suggesting, that H(2)O(2) and NSAIDs activated apoptosis signal-regulating kinase by increasing its state of phosphorylation. In conclusion, we demonstrate that various NSAIDs can activate the three families of MAP kinases and that this activation depends on the presence of reactive oxygenated species. These results give a new insight into the mechanism of the action of NSAIDs.
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PMID:Role of redox status on the activation of mitogen-activated protein kinase cascades by NSAIDs. 1184 90

1,8-Diaza-anthracene-tetraones are novel intermediates in the synthesis of the antifolate antibiotic diazaquinomycin A that was found before to have potent antitumor activity. Three of them (CV65, CV66, and CV70) were found to inhibit growth of a panel of several human tumor cell lines. The IC50s ranged from 0.05 to 1.5 microM and are comparable with that of doxorubicin. Among the three drugs, CV70 showed the highest cytotoxic activity. The growth-inhibitory action of these compounds was unrelated to the p53 status of the cells. At micromolar concentrations, all three compounds induced apoptosis, CV70 being the most proapoptotic. The incubation of HeLa cells with CV65, CV66, and CV70, at concentrations between 10 and 20 microM, inhibited the activation of c-Jun NH2-terminal kinase by various stimuli and prevented growth factor-induced extracellular signal-regulated kinase (ERK) 5 activation. At least one drug, CV65, also inhibited p38. This was surprising because proapoptotic antitumor drugs activate stress signaling pathways. Activation of ERK1/ 2 by growth factors or phorbol esters was unaffected by preincubation of cells with CV compounds. In vitro, CV compounds inhibit the enzyme quinone reductase but not c-Jun NH2-terminal kinase or ERK5. Because doxorubicin also inhibits quinone reductase, we conclude that the inhibitory effect of CV compounds on stress signaling kinases is not a direct effect on the kinases and is likely attributable to upstream elements of the activation cascades.
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PMID:Mitogen-activated protein kinase routes as targets in the action of diaza-anthracene compounds with a potent growth-inhibitory effect on cancer cells. 1249 14