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)

Chronic infection with hepatitis B virus (HBV) is accompanied by an increasing risk of developing hepatocellular carcinoma. There are indications that the HBx protein of HBV is involved in the process of tumour formation. HBx also transactivates several transcription factor binding sites. Recently, we reported that HBx can use a tumour promotor pathway for transactivation. In particular, we found that transactivation of the binding motif for transcription factor AP-1 (JUN/FOS) by HBx is dependent on functional protein kinase C (PKC), as indicated by abolition of the transcriptional stimulation following downregulation or inhibition of the enzyme. Moreover, HBx activates PKC, probably via increasing the endogenous PKC activator sn-1,2-diacylglycerol (DAG). Here we extend these data and report on the time course of PKC activation. We found that activation of PKC by HBx is transient and differs from activation of PKC by the ras oncogene product or phorbol ester in that it does not lead to rapid downregulation of the enzyme subsequent to the activation. Moreover, we provide evidence that an increase in cellular DAG is observable not only as an early event in response to HBx but also in cell lines transformed after transfection with HBV DNA and stably expressing HBx. Besides its important role in the regulation of cellular genes, PKC is also the intracellular receptor for tumour-promoting agents and an activator of proto-oncogenes, suggesting that our observations might provide an explanation for the oncogenic properties of HBx.
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PMID:The hepatitis B virus transactivator HBx causes elevation of diacylglycerol and activation of protein kinase C. 821 Jul 15

The c-fos and c-jun proto-oncogenes encode components of the transcription factor AP-1. To determine whether transformation by the v-fos or v-jun oncogene results in alterations in the level or regulation of this factor, we have characterized AP-1 DNA-binding activity in nuclear extracts prepared from v-fos- and c-fos-transformed rat fibroblast cell lines and v-jun-transformed chicken embryo fibroblasts under various growth conditions. During proliferation, the level of AP-1 DNA-binding activity does not differ among the v-fos, c-fos, or v-jun-transformed cells and their normal progenitors, despite constitutive overexpression of the corresponding oncoproteins. Therefore, although necessary, it is not likely that an increase in DNA binding is sufficient for fos or jun transformation. Normal rat and chicken fibroblasts demonstrate very low levels of AP-1 DNA-binding activity when quiescent, and upon serum stimulation a biphasic increase is observed. A similar cyclical pattern is seen in v-fos-transformed cells, but in v-jun-transformed cells AP-1 DNA-binding activity does not fluctuate in response to serum stimulation, which suggests that this level of control may be exerted through the Jun component of the AP-1 complex.
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PMID:Transformation by the fos or jun oncogene does not increase AP-1 DNA-binding activity. 835 Apr 8

Halogenated aromatic hydrocarbons, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; dioxin), and polycyclic aromatic hydrocarbons, such as benzo[a]pyrene, are environmental contaminants that cause many apparently unrelated toxic effects. In a previous study, we have shown that treatment of mouse hepatoma cells with TCDD or B(a)P results in an increase in mRNA levels of the immediate-early protooncogenes c-fos, c-jun, junB, and junD, and the concomitant increase of the DNA-binding activity of the transcription factor AP-1, a dimer of FOS and JUN proteins. To analyze the mechanism of fos/jun activation by TCDD we have used electrophoretic mobility shift and transient expression assays of reporter gene constructs containing response elements for 12-O-tetradecanoyl-phorbol-13-acetate (TRE), serum (SRE), cAMP (CRE), and aromatic hydrocarbons (AhRE) from the fos and jun genes fused to the firefly luciferase gene under the control of the SV40 minimal promoter. In mouse hepatoma Hepa-1 cells, which have Ah receptor (AHR) and Ah receptor nuclear translocator (ARNT) proteins, inclusion of TRE, SRE, and the AhRE motifs from c-jun and junD, but not CRE or the AhREs from c-fos, fosB, and junB, causes a large TCDD-dependent increase in luciferase expression. In agreement with these results, c-jun and junD, but not c-fos, fosB, and junB AhREs, competed with a canonical Cyp1A1 AhRE for binding to the AHR ARNT heterodimeric complex. In African Green Monkey CV-1 cells, which lack AHR, expression plasmids with AhRE motifs require coexpression of AHR and ARNT for TCDD to stimulate luciferase expression. In contrast, SRE-containing expression plasmids respond equally well to TCDD whether or not AHR and ARNT are coexpressed. These results suggest that TCDD induces expression of the immediate-early response genes fos and jun by activation of possibly three separate signal transduction pathways, at least one of which does not require a functional Ah receptor complex.
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PMID:Dioxin induces transcription of fos and jun genes by Ah receptor-dependent and -independent pathways. 891 96

Cytokines, such as TNF alpha, modulate the behavior of many cells by regulating the expression of a wide array of genes. When a cytokine binds to its receptor on the cell surface, the receptor becomes activated and activates signal transduction cascades. These cascades typically involve a series of phosphorylation reactions that lead to sequential activation of various kinases. The targets of these kinases include DNA binding proteins that regulate the transcription of target genes. The activity of DNA binding proteins, such as c-Jun and NF-kappa B, titrates the transcriptional activity of cytokine-regulated genes. Both acute and chronic alcohol consumption of ethanol increase hepatic expression of TNF alpha. After acute ethanol consumption, this is associated with increased induction of several TNF-dependent regenerative events, including the activation of c-Jun and increased binding activity of NF-kappa B. However, chronic consumption of ethanol appears to impede TNF alpha signaling in the liver because it attenuates the increases in c-JUN activity and NF-kappa B binding, which normally follow partial hepatectomy. These results suggest that one mechanism by which ethanol influences liver cell behavior is by influencing local expression of TNF alpha and changing the activity of TNF-regulated transcription factors.
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PMID:Alcohol and cytokine-inducible transcription factors. 898 16

We have studied the role of Jun/stress-activated protein kinase (JNK/SAPK) pathway in DNA repair and cisplatin resistance in T98G glioblastoma cells. JUN/SAPK is activated by DNA damage and phosphorylates serines 63 and 73 in the N-terminal domain of c-Jun, which is known to increase its transactivation properties. We show that treatment of T98G glioblastoma cells with cisplatin but not the transplatin isomer activates JNK/SAPK about 10-fold. T98G cells, which are highly resistent to cisplatin (IC50 = 140 +/- 13 microM), modified to express a nonphosphorylatable dominant negative c-Jun (termed dnJun) exhibit decreased viability following treatment with cisplatin, but not transplatin, in proportion (rPearson = 0.98) to the level of dnJun expressed leading to a 7-fold decreased IC50. Similar effects are observed in U87 cells, PC-3 cells, and MCF-7 cells, as well as in T98G cells modified to express TAM-67, a known inhibitor of c-Jun function. In contrast, no sensitization effect was observed in cells modified to express wild-type c-Jun. Furthermore, through quantitative polymerase chain reaction-stop assays, we show that dnJun expressing cells were inhibited in repair of cisplatin adducts (p = 0.55), whereas repair is readily detectable (p = 0.003) in parental cells. These observations indicate that the JNK/SAPK pathway is activated by cisplatin-induced DNA damage and that this response is required for DNA repair and viability following cisplatin treatment. Regulation of DNA repair following genotoxic stress may be a normal physiological role of the JNK/SAPK pathway.
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PMID:The Jun kinase/stress-activated protein kinase pathway functions to regulate DNA repair and inhibition of the pathway sensitizes tumor cells to cisplatin. 916 25

The proto-oncogene c-jun, a member of the family of immediate-early genes, is transcriptionally induced in different cell types by a variety of stimuli, including mitogens, tumor promoters, growth factors. We show here that the protein kinase inhibitor staurosporine, which inhibits both the serine-threonine and tyrosine specific protein kinases, also causes differential regulation of the c-jun gene in endothelial cells. Increasing concentrations of staurosporine modulated the steady-state levels of c-jun mRNA in bovine aortic endothelial (BAE) cells in a multiphasic manner. The half-life of c-jun mRNA did not change significantly under these conditions, suggesting that the modulations in the mRNA levels were caused primarily by differential transcriptional activity of the gene. The expression of c-jun gene is believed to be regulated by its own product, the JUN protein, which constitutes a major component of the inducible transcription factor AP-1. In order to test whether the differential regulation of c-jun gene was caused by the differential activation (or inactivation) of the AP-1 transcription factor, the DNA-binding activity of this transcription factor in staurosporine-treated cells was measured. Gelshift analysis with a synthetic oligonucleotide probe showed modest effects of staurosporine on the DNA-binding activity of the transcription factor AP-1. The changes observed in the DNA-binding activity of AP-1 did not parallel the changes observed in the steady-state levels of c-jun mRNA. Similarly, the expression of an AP-1 dependent reporter gene construct was regulated in a fashion entirely different from the c-jun gene during the same protein kinase inhibitory conditions. These results suggest the existence of an alternative pathway that regulates the c-jun gene expression in endothelial cells independent of both the protein kinase and AP-1 transcription factor activation steps.
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PMID:Regulation of c-jun gene expression in endothelial cells by the protein kinase inhibitor staurosporine. 923 43

The major regulators of endometrial function are oestrogen and progesterone, which act through binding their nuclear receptors and by activating transcription of their target genes. Interactions between steroid receptors and transcription proteins, e.g. c-JUN/AP-1, can modulate steroid action at the transcriptional level. The 19-nortestosterone-derived progestin, levonorgestrel, is used for contraception, treatment of menorrhagia and for endometrial protection during hormone replacement therapy, but the signalling pathways of its action are totally undefined. We examined the effect of an intrauterine system, releasing 20 microg of levonorgestrel per 24 h (LNG-IUS), on immunoreactive oestrogen receptor, progesterone receptor, c-JUN and Ki-67 expression in 29 endometrial specimens, obtained from fertile women using the LNG-IUS for contraception. Moderate to strong immunostaining for oestrogen receptors was observed in the stromal cells in all specimens, in glandular epithelial cells in 26 cases and in flattened luminal epithelial cells in 17 specimens. Decidualized stromal cells showed no progesterone receptor immunoreactivity in 19 of the 29 specimens, and weak to moderate immunostaining in 10 cases. Luminal epithelial cells were negative for progesterone receptor in all samples. Intense nuclear staining for C-JUN was observed in epithelial cells in 26 and in decidualized stromal cells in all 29 of the samples. In 16 samples, Ki-67 immunoreactivity was evaluated as weak to moderate in decidualized stroma, and in 13 samples absent. Our data demonstrate that intrauterine release of LNG maintains constant expression of C-JUN and exerts progestational effects in the endometrium in the absence of progesterone receptors. In contrast, LNG-IUS inhibits several cellular responses to oestrogen despite the presence of endogenous oestrogen and oestrogen receptors. These data suggest that the progestational effects induced by progesterone and levonorgestrel are mediated through different signalling pathways.
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PMID:The effect of intrauterine levonorgestrel use on the expression of c-JUN, oestrogen receptors, progesterone receptors and Ki-67 in human endometrium. 987 60

The proto-oncogene c-jun is involved in cellular proliferation by interfering with signals that lead to cellular differentiation. Moreover the induction of metalloproteinase gene appears to utilise the c-jun oncogene as intracellular messenger. The aims of this study were to evaluate a) the expression of c-jun oncogene in pancreatic cancer b) its relation with tumor histological features. Surgical specimens of pancreatic cancer were collected from 22 patients radically operated upon, and from 11 submitted to palliation. As a control group, 5 specimens of normal pancreas and 5 specimens of chronic pancreatitis were studied. C-jun staining was graded as follows: (-) positive cells < 10%, (+) from 10 to 30%, (+2), from 30 to 60%, (+3) from 60 to 90%. Glucagon and somatostatin staining was graded counting the positive cells of total numer of Langherans islet cells counted. c-Jun expression (low: < 30% and high: > 30%) was related to stage, architectural and cytological grading, vascular, lymph nodal, perineural invasion. Normal pancreas and chronic pancreatitis tissues appear to express the c-jun protein in less than 10% of ductal cells. The percentage of tumor cells stained for c-jun is increased as compared to the control group in 28/33 cases: in 13 (46%) it ranges from 10 to 30%; in 10 (36%) from 30 to 60% and in 5 (18%) from 60 to 90%. The frequency of high or low c-jun expression is not different in relation to the histological features of tumor. Moreover, c-jun protein is present in 40% of cells of Langherans islets in normal pancreas, chronic pancreatitis and pancreatic cancer. The Langherans islet cells stained for c-jun exhibit also a positivity for glucagon. In conclusion; a) in pancreatic cancer, the expression of c-jun is increased in tumour cells in majority of cases as compared to the control group, b) a c-jun positivity is also found in alpha cells with a pattern not different from control group, but the relation between the alpha cells and c-jun production is unknown, c) c-jun expression does not vary in relation to histological findings.
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PMID:The expression of proto-oncogene c-jun in human pancreatic cancer. 1021 7

Type 2 diabetes is a polygenic and genetically heterogeneous disease . The age of onset of the disease is usually late and environmental factors may be required to induce the complete diabetic phenotype. Susceptibility genes for diabetes have not yet been identified. Islet-brain-1 (IB1, encoded by MAPK8IP1), a novel DNA-binding transactivator of the glucose transporter GLUT2 (encoded by SLC2A2), is the homologue of the c-Jun amino-terminal kinase-interacting protein-1 (JIP-1; refs 2-5). We evaluated the role of IBi in beta-cells by expression of a MAPK8IP1 antisense RNA in a stable insulinoma beta-cell line. A 38% decrease in IB1 protein content resulted in a 49% and a 41% reduction in SLC2A2 and INS (encoding insulin) mRNA expression, respectively. In addition, we detected MAPK8IP1 transcripts and IBi protein in human pancreatic islets. These data establish MAPK8IP1 as a candidate gene for human diabetes. Sibpair analyses performed on i49 multiplex French families with type 2 diabetes excluded MAPK8IP1 as a major diabetogenic locus. We did, however, identify in one family a missense mutation located in the coding region of MAPK8IP1 (559N) that segregated with diabetes. In vitro, this mutation was associated with an inability of IB1 to prevent apoptosis induced by MAPK/ERK kinase kinase 1 (MEKK1) and a reduced ability to counteract the inhibitory action of the activated c-JUN amino-terminal kinase (JNK) pathway on INS transcriptional activity. Identification of this novel non-maturity onset diabetes of the young (MODY) form of diabetes demonstrates that IB1 is a key regulator of 3-cell function.
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PMID:The gene MAPK8IP1, encoding islet-brain-1, is a candidate for type 2 diabetes. 1070 Jan 86

In previous studies it has been shown that neural cells undergoing programmed cell death display strongly positive cytoplasmic immunoreactivity to polyclonal antibodies directed against a c-Jun N-terminal peptide. It was later found that c-Jun-like immunoreactivity in apoptosis was due to cross-reactivity with proteins other than c-JUN: We have analysed the biochemical counterpart of this property in neuroblastoma cell lines treated to induce apoptosis. Using the c-Jun/sc-45 antibody, several bands with apparent molecular masses distinct from c-Jun were detected in extracts in parallel with both the degree of apoptosis and the appearance of the cytoplasmic signal after immunostaining. c-Jun/sc-45 immunostaining was prevented by caspase inhibitors and did not require de novo protein synthesis. One of the antigens recognized by the c-Jun/sc-45 antibody was identified as seryl-tRNA synthetase. We provide evidence that seryl-tRNA synthetase is a substrate of caspase-3 in vitro and that the digested form turns highly immunoreactive towards the antibody. A carboxy-terminus epitope of the protein that constitutes a consensus site for caspase-3 is involved in c-Jun/sc-45 recognition. This epitope shares some amino acids with the peptide used as the immunogen and this could explain the cross-reactivity observed. In conclusion, we demonstrate here that cytoplasmic c-Jun/sc-45-like immunoreactivity specific to apoptosis is due to post-translational changes which occur in seryl-tRNA synthetase and probably also in other proteins as a consequence of caspase mediated proteolysis.
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PMID:Antibodies against c-Jun N-terminal peptide cross-react with neo-epitopes emerging after caspase-mediated proteolysis during apoptosis. 1133 19


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