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)

Both retinoic acid (RA) treatment and dominant-negative c-Jun mutant expression effectively inhibit phorbol ester-induced AP-1 activity and induced neoplastic transformation in mouse epidermal JB6 cells. However, both reagents also target non-AP-1 molecules in addition. Because liganded retinoic acid receptors interact with and transactivate RA response elements (RAREs) on DNA, as well as interact with Jun protein to block AP-1 activity, the question arises as to which of these two activities of retinoids is responsible for antitumor-promoting activity. To address this question we generated JB6 promotion-sensitive (P+) cell lines that are stably transfected with a construct containing the collagenase promoter bearing one AP-1-binding site that drives a luciferase reporter gene. The stable collagenase-luciferase-transfected cell lines showed 1.5-3.5-fold enhanced AP-1 activity when treated with 12-0-tetradecanoyl-phorbol-13-acetate (TPA). Up to 90% of TPA-induced AP-1 activity was blocked by retinoids SR11238, SR11302, or trans-RA, but not by retinoid SR11235. Of these retinoids, only RA and SR11235 were able to transactivate RARE-dependent gene expression. Transrepression of TPA-induced AP-1 and transactivation of RARE by RA, SR11238, and SR11302 were concentration dependent at 10(-10) to 10(-6) M retinoid. When tested for activity in inhibiting tumor promoter-induced transformation in JB6 P+ cells, the retinoids specific for AP-1 transrepression were inhibitory, whereas SR11235, which only activated RARE, showed little effect. We thus conclude that the AP-1-blocking activity of retinoids is likely to be responsible for the antitumor-promoting activity. This result, together with the observation that dominant-negative Jun blocks transformation, argues for a requirement of induced AP-1 in the tumor promoter-induced transformation process.
Cancer Res 1996 Feb 01
PMID:Inhibition of tumor promoter-induced transformation by retinoids that transrepress AP-1 without transactivating retinoic acid response element. 856 58

Previous studies have shown that structurally diverse tumor promoters can modulate protein kinases involved in signal transduction. In this study, we show that palytoxin, a potent non-12-O-tetradecanoylphorbol-13-acetate (TPA)-type skin tumor promoter, induces a signaling pathway leading to the activation of the stress-activated protein kinases/c-Jun N-terminal kinases (JNK) in Swiss 3T3 fibroblasts. Treatment of cells with doses as low as 0.1 mN palytoxin results in significant activation of JNK. In contrast to epidermal growth factor, which induces a transient activation of JNK in Swiss 3T3 cells, palytoxin causes prolonged enzyme activation. Since stimulation of ion flux appears to play an important role in the mechanism of action of palytoxin in other systems, we investigated the role of sodium and calcium in the activation of JNK: (a) our results show that incubation of Swiss 3T3 cells in a sodium-free medium dramatically reduced the magnitude of JNK activation by palytoxin; and (b) we found that the sodium ionophore gramicidin activates JNK. Together, these results suggest that sodium influx, which is a hallmark of palytoxin action, may play a key role in the activation of JNK by palytoxin. Our results indicate that calcium influx is not necessary or sufficient for palytoxin-induced activation of JNK. In contrast to palytoxin, the TPA-type tumor promoter phorbol 12,13-dibutyrate and the non-TPA-type tumor promoters thapsigargin and okadaic acid do not appear to activate JNK in this system. In contrast to phorbol 12,13-dibutyrate, palytoxin does not activate the p42/p44 mitogen-activated protein kinases. Our results demonstrate that Swiss 3T3 fibroblasts, palytoxin can activate a protein kinase signaling pathway that is distinct from that activated by the prototypical phorbol ester tumor promoters and other potent skin tumor promoters.
Cancer Res 1996 Feb 01
PMID:Activation of stress-activator protein kinase/c-Jun N-terminal kinase by the non-TPA-type tumor promoter palytoxin. 856 84

Glutathione transferase P (GST-P) is specifically induced in rat liver and kidney by lead cation. The increase of GST-P mRNA after lead administration is blocked by actinomycin D, suggesting that GST-P production by lead is regulated at the transcriptional level. To further determine which part of the flanking region of the GST-P gene has the lead-responsive cis-element in vivo, we utilized transgenic rats with five different constructs having GST-P and/or chloramphenicol acetyl-transferase coding sequence. We studied the effect of lead on these transgenic rats and on transfected NRK (normal rat kidney) cells and found that GST-P induction by lead is indeed regulated at the transcriptional level and that the GST-P enhancer I (GPEI) enhancer is an essential cis-element required for the activation of the GST-P gene by lead. GPEI consists of two AP-1 (c-Jun/c-Fos heterodimer) site-like sequences that are palindromically arranged and can bind AP-1, c-jun mRNA in the liver increased after lead administration and GST-P, and c-Jun had patchy expression in the same hepatocytes 24 h after lead exposure. These results suggest that activation of the GST-P gene by lead is mediated in major part by enhancer GPEI and that AP-1 may be involved at least partially. GPEI has been shown to have essential sequence information for the trans-activation of the GST-P gene during chemical hepatocarcinogenesis of the rat (Morimura, S., Suzuki, T., Hochi, S., Yuki, A., Nomura, K., Kitagawa, T., Nagatsu, I., Imagawa, M., and Muramatsu, M. (1993) Proc. Natl. Acad. Sci. U.S.A. 90, 2065-2068; Suzuki, T., Imagawa, M., Hirabayashi, M., Yuki, A., Hisatake, K., Nomura, K., Kitagawa, T., and Muramatsu, M. (1995) Cancer Res. 55, 2651-2655). The present study establishes that the same enhancer element does operate in the activation of the GST-P gene by lead regardless of the trans-activators involved.
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PMID:Activation of glutathione transferase P gene by lead requires glutathione transferase P enhancer I. 857 62

Interleukin 1 (IL-1) and tumor necrosis factor alpha (TNFalpha) are known to induce production of reactive oxygen species (ROS), which have been suggested to act as second messengers. Here we demonstrate that ROS production by bovine chondrocytes upon cytokine stimulation induces c-jun expression. Since c-jun expression is regulated by its own gene product via phosphorylation by c-Jun NH2-terminal kinases (JNKs), we investigated if cytokines and ROS could modulate JNK activity in chondrocyte monolayer cultures. Treatment of bovine chondrocytes with both IL-1 and TNFalpha leads to rapid induction of JNK activity, stimulating JNK activity 7- and 20-fold, respectively. Importantly, the observation that antioxidant treatment antagonizes IL-1 and TNFalpha activation of JNK provides strong evidence that ROS can act as mediators of JNK activity. Moreover, potent activation of JNK is also observed by direct addition of the ROS hydrogen peroxide (H2O2) to the chondrocyte cultures. Nitric oxide (NO), a multifunctional ROS, also appears to simulate JNK, albeit to a lesser extent. These findings identify JNK as another molecular target for the actions of NO and H2O2. In addition, the inhibitory effect of diphenyleneiodonium on JNK activation implicates the involvement of flavonoid-containing enzymes in the ROS-mediated signaling process. Overstimulation of JNK activity by excessive production of ROS may, therefore, underlie pathological conditions such as arthritis and cancer.
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PMID:Reactive oxygen species mediate cytokine activation of c-Jun NH2-terminal kinases. 866 89

Photodynamic therapy (PDT) is currently under investigation in phase II and III clinical studies for the treatment of tumours in superficial localisations. Thus far, the underlying mechanisms of PDT regarding cellular responses and gene regulation are poorly understood. Photochemically generated singlet oxygen (1O2) is mainly responsible for cytotoxicity induced by PDT. If targeted cells are not disintegrated, photo-oxidative stress leads to transcription and translation of various stress response and cytokine genes. Tumour necrosis factor (TNF) alpha, interleukin (IL) 1 and IL-6 are strongly induced by photodynamic treatment, supporting inflammatory action and immunological anti-tumour responses. To investigate the first steps of gene activation, this study focused on the proto-oncogenes c-jun and c-fos, both coding for the transcription factor activator protein 1 (AP-1), which was found to mediate IL-6 gene expression. We here determine the effects of photodynamic treatment on transcriptional regulation and DNA binding of transcription factor AP-1 in order to understand the modulation of subsequent regulatory steps. Photodynamic treatment of epithelial HeLa cells was performed by incubation with Photofrin and illumination with 630 nm laser light in vitro. Expression of the c-jun and c-fos genes was determined by way of Northern blot analysis, and DNA-binding activity of the transcription factor AP-1 was evaluated by electrophoretic mobility shift assay (EMSA). Photofrin-mediated photosensitisation of HeLa cells resulted in a rapid and dose-dependent induction of both genes but preferential expression of c-jun. Compared with the transient expression of c-jun and c-fos by phorbol ester stimulation, photodynamic treatment led to a prolonged activation pattern of both immediate early genes. Furthermore, mRNA stability studies revealed an increased half-life of c-jun and c-fos transcripts resulting from photosensitisation. Although mRNA accumulation after PDT was stronger and more prolonged compared with phorbol ester stimulation, with regard to AP-1 DNA-binding activity, phorbol ester was more efficient. Surprisingly, in addition to the activation of AP-1 DNA-binding via PDT, photodynamic treatment can decrease AP-1 DNA-binding of other strong inducers, such as the protein kinase C-mediated pathway of phorbol esters and the antioxidant pyrrolidine dithiocarbamate (PDTC). This study demonstrates a strong induction of c-jun and c-fos expression by PDT, with prolonged kinetics and mRNA stabilisation as compared with activation by phorbol esters. Interestingly, this observation is not coincident with an overinduction of AP-1 DNA-binding, hence suggesting that post-translational modifications are dominant regulatory mechanisms after PDT that tightly control AP-1 activity in the nucleus thus limiting the risk of deregulated oncogene expression.
Br J Cancer 1996 Jul
PMID:Strong and prolonged induction of c-jun and c-fos proto-oncogenes by photodynamic therapy. 867 54

Apigenin, a low-toxic and non-mutagenic plant flavonoid, suppresses 12-O-tetradecanoyl-phorbol-13-acetate (TPA)-mediated tumour promotion of mouse skin. TPA has the ability to activate protein kinase C (PKC) and induce proto-oncogene expression. Our study shows that apigenin inhibits PKC by competing with ATP, and exhibits an IC50 value of 10 +/- 0.5 microM. Apigenin also reduces the level of TPA-stimulated phosphorylation of cellular proteins. Of the protein tyrosine kinases tested, the fibroblast growth factor (FGF) receptor was most strongly affected by apigenin (IC50 20 microM), and pp60v-src most weakly affected (IC50 > 200 microM). Treatment of NIH 3T3 cells with 100 ng/ml TPA and 10, 50 and 100 microM apigenin resulted in 50, 80 and 100% suppression of TPA-induced C-JUN expression, respectively. Treatment of TPA with 10 microM apigenin inhibited TPA-induced C-FOS expression. TPA-stimulated cell growth was suppressed by 25 microM apigenin. Our results provide some evidence for understanding apigenin's inhibitory effects of TPA-mediated tumour promotion.
Eur J Cancer 1996 Jan
PMID:Inhibitions of protein kinase C and proto-oncogene expressions in NIH 3T3 cells by apigenin. 869 23

We compared the ability of cellular and viral Jun (c-Jun and v-Jun) to transactivate target genes. c-Jun and v-Jun bind specifically to 12-O-tetradecanoylphorbol-13-acetate responsive elements [TREs, also called activator protein 1 (AP-1) motifs]. However, whereas c-Jun activates TRE-controlled promoters, v-Jun represses them. Cotransfection of the two Jun proteins reduces c-Jun-dependent transactivation. The expression of the endogenous c-jun gene, regulated through a promoter-proximal AP-1-binding site, is repressed in v-Jun-transformed chicken embryo fibroblasts. It is suggested that an M(r) 18,000 v-Jun peptide prominent in v-Jun-transformed cells acts as a transdominant-negative regulator of AP-1 activity and of c-jun expression. In contrast to the results with TRE sites, both v-Jun and c-Jun activate transcription through the human T-cell leukemia virus type I 21-bp repeat which contains a sequence homologous to the cyclic AMP responsive element. However, full-length Jun proteins bind to this site only with low affinity, and binding of the truncated v-Jun was barely detectable. These observations show that the oncogenic viral form of Jun differs from the cellular version in promoter preference and on certain promoters acts as an antagonist to c-Jun.
Cancer Res 1996 Sep 15
PMID:Differential and antagonistic effects of v-Jun and c-Jun. 879 97

The RRR-alpha-tocopheryl succinate form of vitamin E [vitamin E succinate (VES)] inhibits the proliferation of avian reticuloendotheliosis virus-transformed RECC-UTC4-1 (C4-1) lymphoblastoid cells in a dose-dependent manner, blocks the cells in the G2/M cell cycle phase, and induces the cells to undergo apoptosis. Apoptosis was documented by demonstrating changes that are characteristic of this type of cell death, including morphological analyses of chromatin condensation by 4',6-diamidine-2'-phenylindole dihydrochloride (DAPI) staining using scanning confocal and traditional fluorescent microscopy; flow cytometry analyses of propidium iodide-labeled DNA showing fragmented DNA as a pre-G1 peak; two-color flow cytometry analyses of intact cells labeled first by the TUNEL procedure (terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick-end-labeled DNA stained with fluorescein isothiocyanate-labeled avidin) and then by propidium iodide demonstrating fragmented DNA; and electrophoresis of DNA showing a DNA ladder created by internucleosomal DNA fragmentation. The percentage of apoptotic cells was determined by DAPI staining and showed 11%, 27%, and 49% of cells to be apoptotic after treatment with 10 micrograms/ml VES for one, two, and three days, respectively. Analyses of mRNA levels of genes that have been implicated in the apoptotic process, namely, bcl-2, c-myc, and c-jun, revealed no change in bcl-2, decreases in c-myc mRNA levels after 36 hours of treatment, and increases in c-jun mRNA levels within four hours after treatment. Western immunoblotting analyses of protein levels for the transcription factors c-Myc and c-Jun showed normal levels of c-Myc at early time points and decreased levels at 24 and 48 hours after treatment. c-Jun increased as early as 6 hours after treatment and returned to lower (yet still elevated over control) levels by 48 hours. To determine possible functional consequences of increased c-Jun expression, gel electrophoretic mobility assays were conducted that showed increased AP-1 binding at 24 and 48 hours after treatment. These data show that VES induces apoptosis in reticuloendotheliosis virus-transformed lymphoid cells and suggest that decreases of c-Myc protein and increases of c-Jun protein and DNA binding capacity may be playing a role in VES-mediated events leading to apoptosis in this cell type.
Nutr Cancer 1996
PMID:RRR-alpha-tocopheryl succinate induces apoptosis in avian retrovirus-transformed lymphoid cells. 883 58

Apoptotic cell death was induced in rat thymocytes on exposure to calcium ionophore A 23187 (100 micron(s)) for 24 h as observed from morphological changes and DNA fragmentation into oligonucleosomal ladder. The cell death was independent of de novo syntheses of protein. However, the involvement of c-Myc, c-Jun, poly ADPR polymerase and antioxidant enzymes CuZn SOD and catalase was observed.
Cancer Lett 1996 Oct 01
PMID:Calcium ionophore A 23187 induces apoptotic cell death in rat thymocytes. 891 72

c-Jun NH2-terminal protein kinase (JNK), a member of the mitogen-activated protein kinase family, is activated in response to many stressful stimuli including heat shock, UV irradiation, protein synthesis inhibitors, and inflammatory cytokines. In this study, we investigated whether JNK plays a role in the cellular response to different drugs commonly used in cancer chemotherapy. Treatment of human KB-3 carcinoma cells with Adriamycin resulted in a time- and dose-dependent activation of JNK of up to 40-fold. Treatment with vinblastine or etoposide (VP-16) also activated JNK, with maximum increases of 6.5- and 4.3-fold, respectively. Consistent with these findings, increased c-Jun phosphorylation was observed after drug treatment of cells. In contrast, none of the drugs significantly activated the extracellular response kinase/mitogen-activated protein kinase pathway. Since these drugs are transport substrates for the MDR1 gene product, P-glycoprotein, JNK was assayed in two multidrug-resistant (MDR) KB cell lines, KB-A1 and KB-V1, selected for resistance to Adriamycin and vinblastine, respectively. Relative to KB-3 cells, basal JNK activity was increased 7-fold in KB-A1 cells and 4-fold in KB-V1 cells, with no change in JNK protein expression, indicating that JNK is present in a more highly activated form in the MDR cell lines. Under conditions optimal for JNK activation, Adriamycin, vinblastine, and VP-16 all induced MDR1 mRNA expression in KB-3 cells. Our findings suggest that JNK activation is an important component of the cellular response to several structurally and functionally distinct anticancer drugs and may also play a role in the MDR phenotype.
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PMID:Role of the stress-activated/c-Jun NH2-terminal protein kinase pathway in the cellular response to adriamycin and other chemotherapeutic drugs. 894 82


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