Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P05412 (c-Jun)
 11,453 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Retinoic acid inhibits the enzyme collagenase by forming an inactive complex between the liganded nuclear retinoic acid receptors and c-Jun, a protein that is itself an activator of the collagenase gene.
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PMID:The molecular basis of the inhibition of collagenase by vitamin A. 133 26

The proto-oncogene c-jun, a major component of transcription factor AP-1, is expressed at very low levels in undifferentiated embryonal carcinoma (EC) end embryonic stem (ES) cells. Retinoic acid (RA) induced differentiation causes a strong increase in the levels of c-jun mRNA. In this paper we report the cloning and characterization of the mouse c-jun promoter. Our results show that RA treatment causes a strong enhancement in c-jun promoter activity, an effect probably mediated by the RA-receptor beta (RAR beta). Sequences located between -329 and -293 are responsible for the observed RA effect, and bind at least five different protein complexes, of which three are decreased upon RA treatment. These protein binding sites do not resemble RA-responsive elements (RARE's) found in the promoters of retinoic acid receptor beta (RAR beta) and laminin B1. Furthermore, we could not detect a direct interaction of RAR alpha and RAR beta to these sequences, indicating that RA-induced c-jun expression is an indirect effect of RAR action.
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PMID:Transcriptional control of c-jun by retinoic acid. 185 Dec 95

Retinoic acid receptors (RARs) regulate gene expression either by directly binding to the RAR-responsive elements or by antagonizing the action of c-Jun/c-Fos (AP1). AP1 is involved in the expression of metalloproteases, cytokines and other factors which play critical roles in the turnover of extracellular matrix, inflammation and hyperproliferation in diseases such as psoriasis, rheumatoid arthritis and in tumor metastases. We demonstrate here that synthetic retinoids inhibit 12-O-tetradecanoylphorbol-14-acetate-induced transcription from the stromelysin AP1 motif through RAR alpha, -beta, and -gamma. Interestingly, these diaryl acetylenic retinoids, which are potent agonists only for RAR beta and RAR gamma, but not for RAR alpha, in transactivation assays, are able to inhibit AP1-dependent gene expression through RAR alpha. Thus these analogs can differentially affect the transactivation and AP1 antagonistic functions of RAR alpha. These results demonstrate that the transactivation and AP1 antagonistic functions are separable, and it should be possible to develop retinoids that are completely specific for AP1 antagonism through all RARs. Furthermore, using an RAR-selective ligand, we also demonstrate the separation of ligand binding and AP1 antagonism functions of RARs.
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PMID:Separation of transactivation and AP1 antagonism functions of retinoic acid receptor alpha. 782 31

Retinoic acid has been identified as a key morphogen governing pattern formation in the developing cartilaginous skeleton. Retinoids have also been implicated in the premature closure of the cartilage growth plate following vitamin A intoxication or administration of retinoids for dermatologic conditions. Previous studies of the mechanism of action of retinoids in non-chondrogenic cells have concluded that retinoic acid is a negative regulator of AP-1 responsive metalloprotease genes. We show that inhibition of expression of the cartilage phenotype by retinoic acid in epiphyseal chondrocytes is associated with positive regulation of AP-1 responsive metalloprotease genes, as well as induction of gene expression for the two components of the transcription factor AP-1, c-fos and c-jun. Despite the similar effects of TGF-beta 1 on expression of cartilage matrix proteins and metalloproteases in this culture system, no appreciable changes in the expression of TGF-beta isoforms were evident in response to retinoic acid treatment. The present investigation demonstrates that regulation of AP-1 responsive genes by retinoic acid can be either positive or negative, depending on the target cell type, and illuminates new mechanisms by which retinoic acid and other retinoids may exert control during development and growth of the limb.
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PMID:Inhibition of the chondrocyte phenotype by retinoic acid involves upregulation of metalloprotease genes independent of TGF-beta. 816 72

Retinoic acid (RA) induces differentiation of B16 mouse melanoma cells, which is accompanied by an increase in protein kinase Calpha (PKCalpha) as well as a selective enrichment of nuclear PKCalpha. We report here that RA also increases AP-1 activity in these cells. Transient transfection of B16 cells with luciferase reporter gene constructs indicated that RA induced a concentration-dependent increase in AP-1 activity. Acute treatment (2 h) of B16 cells with phorbol dibutyrate (PDB) increased AP-1 activity by 10-fold. RA treatment did not change the expression of Jun family members; however, it decreased the expression of c-Fos. In contrast acute PDB treatment induced c-Fos expression, while having little effect on c-Jun. Five DNA-protein complexes were formed with nuclear extracts from B16 cells and an oligonucleotide containing an AP-1 consensus sequence. Several complexes were decreased in cells treated with RA. Conversely, certain complexes were increased in cells acutely treated with PDB. The slowest migrating complexes were shown to contain Fos family members. Down-regulation of PKC inhibited both the acute PDB-induced and the RA-induced increase in AP-1 activity. The selective PKC enzyme inhibitor, bisindolylmaleimide, reduced PDB-stimulated AP-1 activity, but enhanced RA-induced AP-1 activity. These results together with our previous studies suggest the intriguing possibility that PKC protein, but not enzyme activity, may be required for RA-induced AP-1 activity.
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PMID:Characterization of retinoic acid-induced AP-1 activity in B16 mouse melanoma cells. 913 41

Retinoic acid induces P19 mouse embryonal carcinoma cells to differentiate to endoderm and increases expression of the heterotrimeric G-protein subunits Galpha12 and Galpha13. Retinoic acid was found to induce differentiation and sustained activation of c-Jun amino-terminal kinase, but not of ERK1,2 or of p38 mitogen-activated protein kinases. Much like retinoic acid, expression of constitutively active forms of Galpha12 and Galpha13 induced differentiation and constitutive activation of c-Jun amino-terminal kinase. Expression of the dominant negative form of c-Jun amino-terminal kinase 1 blocked both the activation of c-Jun amino-terminal kinase and the induction of endodermal differentiation in the presence of retinoic acid. These data implicate c-Jun amino-terminal kinase as a downstream element of activation of Galpha12 or Galpha13 obligate for retinoic acid-induced differentiation.
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PMID:c-Jun amino-terminal kinase is regulated by Galpha12/Galpha13 and obligate for differentiation of P19 embryonal carcinoma cells by retinoic acid. 930 8

Chronic ethanol intake may interfere with retinoid signal transduction by inhibiting retinoic acid synthesis and by enhancing activator protein-1 (AP-1) (c-Jun and c-Fos) expression, thereby contributing to malignant transformation. To determine the effect of ethanol on hepatic retinoid levels, retinoic acid receptors (RARs) and AP-1 (c-Jun and c-Fos) gene expression, chronic ethanol (36% of total calorie intake) pair-feeding was conducted on rats for a 1-month period. Retinoic acid, retinol, and retinyl ester concentrations in both liver and plasma were examined by using high-performance liquid chromatography (HPLC). Both retinoic acid receptor (alpha, beta, gamma) and AP-1 (c-Jun and c-Fos) expression in the rat liver were examined by using Western blot analysis. Treatment with high-dose ethanol led to a significant reduction of retinoic acid concentration in both the liver and the plasma (11- and 8.5-fold reduction, respectively), as compared with animals pair-fed an isocaloric control diet containing the same amount of vitamin A. Similar to the retinoic acid reductions, both retinol and retinyl palmitate levels in the livers of the alcohol-fed group decreased significantly, but in smaller fold reduction (6.5- and 2.6-fold reduction, respectively). Ethanol did not modulate the expression of RARalpha, -beta, and -gamma genes in the liver. However, chronic alcohol feeding enhanced AP-1 (c-Jun and c-Fos) expression by 7- to 8-fold, as compared with the control group. These data suggest that functional downregulation of RARs by inhibiting biosynthesis of retinoic acid and up-regulation of AP-1 gene expression may be important mechanisms for causing malignant transformation by ethanol.
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PMID:Chronic alcohol intake reduces retinoic acid concentration and enhances AP-1 (c-Jun and c-Fos) expression in rat liver. 973 67

There remains a remarkable discordance between the results of observational epidemiological studies and intervention trials using beta-carotene as a potential chemopreventive agent. One question that needs to be examined is whether the adverse outcomes of human beta-carotene trials are related to the large doses of beta-carotene that were administered. In the present study, ferrets were given a physiological (low) dose or a pharmacological (high) dose of beta-carotene supplementation (0.43 mg versus 2.4 mg/kg body wt/day, which is equivalent to 6 mg versus 30 mg/day in humans) and exposed to cigarette smoke for 6 months. We investigated the effects of these doses of beta-carotene on retinoid concentrations, expression of retinoic acid receptors (RARs), activator protein 1 (AP-1; c-Jun and c-Fos), cyclin D1, proliferating cellular nuclear antigen (PCNA), and histopathological changes in the lungs of both normal and cigarette smoke-exposed ferrets. Thirty-six male ferrets were treated in six groups-control, smoke-exposed (SM), low-dose beta-carotene (LBC), high-dose beta-carotene (HBC), low-dose beta-carotene plus smoke exposure (LBC+SM) or high-dose beta-carotene plus smoke exposure (HBC+SM)-for 6 months. Retinoic acid concentration and RAR beta gene expression, but not expression of RAR alpha and RAR gamma, was reduced in the lung tissue of HBC+SM, HBC, SM and LBC+SM ferrets, but not in that of LBC ferrets, as compared with the control group. Expression of AP-1 and PCNA was greater in HBC+SM, HBC, SM and LBC+SM ferrets, but not in the LBC ferrets, as compared with the control group. Increased amounts of cyclin D1 and keratinized squamous metaplasia were observed in the lung tissue of HBC+SM, HBC and SM groups but not in that of the LBC+SM, LBC or control groups. These data suggest that, in contrast with a pharmacological dose of beta-carotene, a physiological dose of beta-carotene in smoke-exposed ferrets has no potentially detrimental effects and may afford weak protection against lung damage induced by cigarette smoke.
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PMID:Effects of physiological versus pharmacological beta-carotene supplementation on cell proliferation and histopathological changes in the lungs of cigarette smoke-exposed ferrets. 1113 14

Retinoic acid (RA), a potent teratogen, produces a characteristic set of embryonic cardiovascular malformations similar to those observed in neural crest ablated avians. While the effects of RA on neural crest are well described, the molecular mechanism(s) of RA action on these cells is less clear. The present study examines the relationship between RA and mitogen-activated protein kinase signaling in neural crest cells and demonstrates that c-Jun N-terminal kinase (JNK) activation is severely repressed by RA. RA suppressed migration and proliferation of primary cultures of mouse neural crest cells treated in vitro as well as from animals treated in vivo. On Western blots, JNK activation/phosphorylation in neural crest cultures was reduced, while neither extracellular signal-regulated kinase (ERK) nor p38 pathways were affected. Both the dose-dependent stimulation of neural crest outgrowth and JNK phosphorylation by platelet-derived growth factor AA, which promotes outgrowth but not proliferation of neural crest cultures, were completely abrogated by RA. To establish the relevance of the JNK signaling pathway to cardiac neural crest migration, dominant negative adenoviral constructs were used to inhibit upstream activation of JNK or c-Jun downstream responses. Both adenoviral constructs markedly reduced neural crest cell outgrowth, while a dominant negative inhibitor of the p38 pathway had no effect. These data demonstrate that the JNK signaling pathway and c-Jun activation are critical for cardiac neural crest outgrowth and are potential targets for the action of RA.
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PMID:Retinoic acid inhibits cardiac neural crest migration by blocking c-Jun N-terminal kinase activation. 1140 97

Retinoic acid (RA) supplementation suppresses ethanol-enhanced hepatocyte hyperproliferation in rats; however, little is known about the mechanism(s). Here, we investigated whether RA affects the protein kinase signaling pathways in the liver tissues of rats fed with a high dose of ethanol for a prolonged period of time (6 months). Results show that there were greater levels of phosphorylated Jun N-terminal kinase (JNK) and phosphorylated c-Jun protein, but not total JNK protein, in livers of ethanol-fed rats vs those of controls. Moreover, ethanol feeding to rats increased the levels of phosphorylated mitogen-activated protein kinase kinase-4 (MKK-4) and decreased the levels of mitogen-activated kinase phosphatase-1 (MKP-1) in liver tissue. However, hepatic levels of phosphorylated-p38 protein and total-p38 protein were not altered by the ethanol treatment. In contrast, all-trans-RA supplementation at two doses in ethanol-fed rats greatly attenuated the ethanol-induced hepatic phosphorylation of MKK-4, phosphorylated-JNK and c-Jun proteins. The level of MKP-1 was increased in ethanol-fed rats supplemented with all-trans-RA. Further, ethanol-induced hepatocyte hyperproliferation, measured by immunostaining for proliferating cell nuclear antigen, were markedly decreased by all-trans-RA supplementation. Interestingly, hepatic apoptosis in the liver of ethanol-fed rats after 6 months of treatment decreased significantly. This decrease of hepatic apoptosis in ethanol-fed rats was prevented by all-trans-RA supplementation in a dose-dependent manner. The results from these studies indicate that restoration of RA homeostasis is critical for the regulation of JNK-dependent signaling pathway and apoptosis in the liver of ethanol-fed rats.
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PMID:Retinoic acid inhibits hepatic Jun N-terminal kinase-dependent signaling pathway in ethanol-fed rats. 1189 82


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