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)

The signal transduction pathways of mitogenic stimuli in intestinal epithelial cells are not clearly understood. We report here a possible signaling pathway of two closely related agonists, transforming growth factor-alpha (TGF alpha) and epidermal growth factor (EGF). Both increase thymidine incorporation in the intestinal epithelial cell (IEC) line IEC-6. This increase is dose dependent and inhibited by the tyrosine kinase inhibitors genistein and tyrphostin. The addition of either TGF alpha or EGF to IEC-6 cells also stimulates the activities of the two forms of mitogen-activated protein kinase, p42erk2 MAPK and p44erk1 MAPK, as evidenced by increased incorporation of radiolabeled phosphate in myelin basic protein. The main difference between the MAPK activity levels induced by the two agonists is in the intensity of the response. Maximum TGF alpha-induced stimulation of p42erk2 MAPK activity is 9-fold at 2 ng/ml, while maximum EGF stimulation is only 4.5-fold at 25 ng/ml. These doses correlated closely with the dose required for maximum thymidine incorporation. The activity of the 90-kDa ribosomal S6 kinase, a downstream substrate for activated MAPK, is also enhanced as evidenced by increased incorporation of radiolabeled phosphate in the rsk kinase substrate peptide in IEC-6 cells following stimulation with either TGF alpha or EGF. This increase correlates closely with the stimulus-induced increase in MAPK activity with respect to dose, but the time of increased activity is more prolonged, especially after EGF stimulation. TGF alpha induced the synthesis of both c-Fos and c-Myc, two nuclear substrates for MAPK, and increased c-fos and c-myc message levels as well. However, c-Jun protein and c-jun mRNA were not induced. The increase in IEC-6 cell proliferation in response to TGF alpha and EGF stimulation may then be due, in part, to an increase in immediate early gene expression as a direct result of MAPK and RSK activation.
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PMID:Transforming growth factor-alpha and epidermal growth factor activate mitogen-activated protein kinase and its substrates in intestinal epithelial cells. 756 87

Sphingosylphosphocholine (SPC) is the deacylated derivative of sphingomyelin known to accumulate in neuropathic Niemann-Pick disease type A. SPC is a potent mitogen that increases intracellular free Ca2+ and free arachidonate through pathways that are only partly protein kinase C-dependent. Here we show that SPC increased specific DNA-binding activity of transcription activator AP-1 in electrophoretic mobility-shift assays. Increased DNA-binding activity of AP-1 was detected after only 1-3 min, was maximal after 6 hr, and remained elevated at 12-24 hr. c-Fos was found to be a component of the AP-1 complex. Northern hybridization revealed an increase in c-fos transcripts after 30 min. Since the increase in AP-1 binding activity preceded the increase in c-fos mRNA, posttranslational modifications may be important in mediating the early SPC-induced increases in AP-1 DNA-binding activity. Western analysis detected increases in nuclear c-Jun and c-Fos proteins following SPC treatment. SPC also transactivated a reporter gene construct through the AP-1 recognition site, indicating that SPC can regulate the expression of target genes. Thus, SPC-induced cell proliferation may result from activation of AP-1, linking signal transduction by SPC to gene expression. Since the expression of many proteins with diverse functions is known to be regulated by AP-1, SPC-induced activation of AP-1 may contribute to the pathophysiology of Niemann-Pick disease.
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PMID:Sphingosylphosphocholine, a signaling molecule which accumulates in Niemann-Pick disease type A, stimulates DNA-binding activity of the transcription activator protein AP-1. 759 47

Haloperidol has been shown to induce rapid and transient expression of c-fos messenger RNA and Fos protein in striatal neurons via dopamine D2 receptors. Regulation of the c-fos gene by cyclic AMP and Ca2+ has been shown to be dependent on a DNA regulatory element within its promoter that binds the constitutively expressed transcription factor cyclic AMP response element binding protein. Cyclic AMP response element binding protein binds to an oligonucleotide containing the calcium/cyclic AMP response element of the c-fos promoter sequence in striatal cell extracts; the amount of binding is not regulated by haloperidol treatment. We have previously shown that haloperidol induces cyclic AMP response element binding protein phosphorylation in the striatum. Here we show by intrastriatal injection of antisense oligonucleotides that haloperidol-induced Fos expression is dependent on cyclic AMP response element binding protein. Intrastriatal injections of phosphorothioate oligonucleotides, in antisense orientation to cyclic AMP response element binding protein messenger RNA, reduce levels of cyclic AMP response element binding protein and completely prevent haloperidol-mediated induction of Fos. Oligonucleotides in sense orientation have no such effect. We observed a markedly different time course of the Fos protein inhibition by cyclic AMP response element binding protein antisense oligonucleotides compared to c-fos antisense oligonucleotides. This most likely reflects the different half-lives of c-fos and cyclic AMP response element binding protein messenger RNA and proteins. Neither cyclic AMP response element binding protein nor c-fos antisense oligonucleotide injection reduced c-Jun immunostaining in the striatum. We conclude that haloperidol induces Fos via transcription factor cyclic AMP response element binding protein.
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PMID:Haloperidol-induced Fos expression in striatum is dependent upon transcription factor cyclic AMP response element binding protein. 761 61

Induction of c-fos protooncogene expression following exposure of mammalian skin to UV irradiation suggests an involvement in UV-induced alterations of epidermal cell proliferation and viability. In the present study we have investigated whether topically administered c-fos antisense oligodeoxynucleotides (ODNs) inhibit c-fos activation in the UV-exposed rat skin and thereby modulate the delayed increase in cellular proliferative activity. The accumulation of c-Fos immunolabeled nuclei in the epidermis was almost completely blocked 18 h post-irradiation by topical treatment with the c-fos antisense ODN. The co-expression of c-Jun was not affected and a random sequence control ODN was ineffective. Epicutaneous application of fluorescein-labeled ODNs revealed penetration into the underlying epidermis. The appearance of nuclear immunoreactivity for proliferating cell nuclear antigen (PCNA) 18 h after UV exposure was significantly suppressed in the epidermis treated with c-fos antisense ODNs. In vitro PCNA is involved in both DNA repair synthesis and DNA replication, and the expression of PCNA mRNA is increased after UV irradiation. Thus, it may be speculated that UV-induced c-Fos transcription factor may be linked to repair of photodamaged DNA and/or cell cycle progression by trans-activating PCNA gene expression.
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PMID:Inhibition of c-Fos expression in the UV-irradiated epidermis by topical application of antisense oligodeoxynucleotides suppresses activation of proliferating cell nuclear antigen. 763 14

Facial motoneurons respond to peripheral transection of the facial nerve with a number of molecular changes. In order to obtain insight into the transcriptional mechanisms underlying the changes induced by axotomy, the expression of a number of immediate early genes was investigated after facial nerve lesion in the rat. Some immediate early genes (such as c-fos, c-jun or jun B) are known to encode transcription factors that bind to DNA at sites that regulate gene expression and they could therefore contribute to long-term changes in motoneurons. Northern blot analysis of RNA extracted from the facial nucleus from postoperative intervals covering hours and days revealed that axotomy results in a unique pattern of immediate early gene induction in the facial nucleus. c-Jun, jun B and 12-O-tetradecanoylphorbol-13-acetate-induced sequence (TIS) 11 messenger RNA, also present in low amounts in the unoperated nucleus, were strongly induced in a long-term fashion after nerve injury. Increased levels of these messenger RNAs were first detectable at 5 h, reaching a maximum (300-500% compared to control) within 24 h followed by a gradual decline during the following week. Elevated levels were maintained at least up to eleven days compared to the unoperated side. On the other hand, c-fos messenger RNA was neither expressed in the unoperated nucleus, nor was c-fos messenger RNA induced by axotomy at any of the time-points studied. Another member of the TIS family of immediate early genes TIS 7 (PC4), however, was detectable at low levels in normal facial nucleus, but its expression was unaffected by lesion. The three axotomy-induced messenger RNAs, c-jun, jun B and TIS 11, were all localized in the facial motoneurons by in situ hybridization histochemistry indicating that their induction occurs as part of the retrograde reaction of the motoneurons in response to lesion. These data suggest that c-jun, jun B and TIS 11 may play a role in triggering the regeneration programme of motoneurons.
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PMID:Differential expression of immediate early genes after transection of the facial nerve. 768 1

The pharmacological potency of angiotensin-converting enzyme (ACE) inhibitors (lisinopril and enalaprilat) on the transcription of low density lipoprotein receptor and 3-hydroxy-3-methylglutaryl-CoA reductase genes was examined in human vascular smooth muscle cells and compared with the action of Ca(2+)-channel blockers (manidipine, verapamil, and diltiazem). Analogous to Ca(2+)-channel blockers, nanomolar concentrations of enalaprilat or lisinopril stimulated the synthesis of low density lipoprotein receptor mRNA and amplified the transcription induced by recombinant platelet-derived growth factor BB. In contrast to Ca(2+)-channel blockers, ACE inhibitors did not alter the transcription of the 3-hydroxy-3-methylglutaryl-CoA reductase gene. Platelet-derived growth factor BB stimulated the translocation of delta and epsilon isoforms of protein kinase C. Similar to Ca(2+)-channel blockers, ACE inhibitors reduced the translocation of delta and epsilon isoforms of protein kinase C. Furthermore, ACE inhibitors and Ca(2+)-channel blockers inhibited platelet-derived growth factor BB-induced transcription of c-fos and c-jun genes. The findings suggest that increased de novo synthesis of mRNA low density lipoprotein receptor apparently involves the participation of delta and epsilon isoforms of protein kinase C and transcription factors c-Fos and c-Jun.
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PMID:Transcriptional activation of low density lipoprotein receptor gene by angiotensin-converting enzyme inhibitors and Ca(2+)-channel blockers involves protein kinase C isoforms. 768 21

The expression of the protooncogenes, c-fos, jun B, c-jun, and jun D was investigated in a rat focal cerebral ischemia model by Northern analysis and in situ hybridization. Severe ischemia (reduction of regional blood flow by 88-92%) in this model is confined to cerebral cortex irrigated by the right middle cerebral artery. Ischemia for 30 minutes, which caused only slight cortical damage (infarct size, < 10 mm3), induced both jun B and c-fos mRNAs exclusively in the right cerebral cortex. Ischemia for 90 minutes, which led to large cortical infarction (infarct size, > 140 mm3), also induced the expression of these two genes in the right cerebral cortex as well as the ipsilateral hippocampus. The latter sustained very mild ischemia (reduction of regional blood flow by 10-20%). The coinduction of jun B and c-fos expression occurred immediately after reperfusion and peaked at 60 minutes after reperfusion. The expression of c-jun was enhanced in a similar pattern, but at a much lower magnitude. In contrast, no change in jun D expression was observed. Nuclear run-on assays indicated that the increase in c-fos, jun B, and c-jun mRNA levels was due to the increase of transcription rate in these genes. Mobility shift assays showed a basal DNA binding activity of transcription factor AP-1 in the right cerebral cortex. Ischemia for 30 or 90 minutes followed by reperfusion for 4 hours resulted in a four- to sixfold increase of AP-1 binding activity. The enhanced DNA binding activity persisted for as long as 24 hours.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Expression of c-fos and c-jun family genes after focal cerebral ischemia. 849 19

Glucocorticosteroids have a wide variety of effects which result in the long-term dampening of inflammatory responses. An important site of steroid action may be on the control of the activator protein-1 (AP-1) binding to deoxyribonucleic acid (DNA). AP-1 is a proinflammatory transcription factor composed of a heterodimer of Fos and Jun proto-oncogenes, which can be induced by phorbol esters and various cytokines. We have examined the hypothesis that dexamethasone may inhibit inflammation via an effect on AP-1 activation in human lung tissue. The effect of dexamethasone on the phorbol ester and cytokine activation of AP-1 and its monomers was examined in human lung tissue obtained from transplantation donors. AP-1 activation was measured by its ability to bind DNA, its localization in the nucleus by Western blotting, and the levels of fos and jun messenger ribonucleic acids (mRNAs) using Northern blotting. The phorbol ester, phorbol myristate acetate (PMA), caused a significant 2-3 fold increase in AP-1 DNA binding, which was sustained for 24 h and completely attenuated by co-incubation with dexamethasone. Dexamethasone alone caused a 40% decrease in AP-1 DNA binding. Dexamethasone modulated the expression of both c-jun and c-fos mRNA and produced long-term (24 h) 40% reduction in both mRNAs when compared to control tissues. PMA induced a rapid and prolonged increase in c-Fos and c-Jun nuclear localization, which was not attenuated by co-incubation with dexamethasone.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of dexamethasone on cytokine and phorbol ester stimulated c-Fos and c-Jun DNA binding and gene expression in human lung. 771 92

Human papillomavirus (HPV) type 16 and 18 viral genomes are frequently detected in cervical and penile cancer biopsies. Although this strongly suggests a prominent role for HPV infection in the development of genital cancer, other genetic or environmental factors are also involved. Genital cancer is postulated to result from loss of cellular control functions, which leads to an unregulated expression of HPV oncogenic proteins. In our study, we determined the trans-activating properties of nuclear proto-oncogene proteins c-Fos, c-Jun and c-Myc on P97 enhancer/promoter activity of HPV16. Using a CAT-reporter construct containing the HPV16 enhancer/promoter element, we investigated the trans-activating effects of c-Fos, c-Jun, c-Myc, and E2 in cervical HT-3 cells. c-Fos and c-Jun overexpression resulted in a 3.3- and 3.1-fold up-regulation of CAT activity. Only 2-fold induction was determined by co-transfection with c-myc and the viral transcription factor E2. Based on these findings, we investigated the expression of HPV DNA (16 and 18) as well as nuclear proto-oncogenes (c-fos, c-jun and c-myc) in nine cervical cancers by in situ hybridisation. In six out of nine carcinomas, HPV16 and/or HPV18 DNA was detectable. All tumours showed an intense and homogeneous expression of c-fos and c-jun mRNA, while the signal for c-myc was detectable only in four specimens. These data suggest that deregulation of nuclear proto-oncogene expression may contribute to an overexpression of HPV-derived oncogenic proteins (E6 and E7), which is generally hypothesised to be an important step in the malignant transformation of HPV-associated tumours.
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PMID:Nuclear proto-oncogene products transactivate the human papillomavirus type 16 promoter. 773 93

Primary mouse brain astrocytes were stimulated with phorbol 12-myristate 13-acetate (PMA), serum, forskolin and ionophore A23187, in order to investigate the effect of distinct signalling pathways on the expression of the nerve growth factor (NGF) gene and of proto-oncogenes encoding transcription factors of the Fos and Jun families. PMA, and to a lesser extent serum, induced a marked accumulation of NGF transcripts, in agreement with published observations [Brain Res., 570 (1992) 316-322]. The effect of A23187 was less pronounced and that of forskolin barely detectable. No relationship was observed between the expression of NGF gene and that of c-fos, fos-B, fra-1, jun-B proto-oncogenes. In contrast, changes in the levels of NGF transcripts were associated with corresponding modifications of the levels of c-jun transcripts, a fact which suggests that the c-Jun protein exerts a regulatory role on the expression of the NGF gene. In these cells, however, the regulation of NGF synthesis appears complex, since a pretreatment with forskolin or ionophore A23187 interfered with the promoting effect elicited by PMA or serum in inducing an early decline of the levels of NGF transcripts. This phenomenon was accompanied by a corresponding decrease in the amounts of cell-secreted NGF in cells treated with forskolin and PMA. A23187 had a much more striking effect on the production of mature NGF since this compound maintained the level of cell-secreted NGF to basal values, irrespective of the presence of PMA. A similar inhibitory effect was observed with thapsigargin, another compound able to increase the cytosolic concentration of calcium.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Interactions between second messenger pathways influence NGF synthesis in mouse primary astrocytes. 774 33


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