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)

(-)-Epigallocatechin-3-gallate (EGCG) is an important bioactive constituent of green tea that efficiently reduces epidermal cancer cell proliferation. This inhibition is associated with a reduction in activator protein 1 (AP1) transcription factor level and activity. However, its effects on AP1 function in normal epidermal cells have not been extensively explored. Our present studies show that EGCG regulates normal keratinocyte function. To understand the mechanism of action, we examined the effects of EGCG on AP1 factor activity, MAPK signal transduction, and expression of the AP1 factor-regulated human involucrin (hINV) gene. EGCG increases hINV promoter activity in a concentration-dependent manner that requires the presence of an intact hINV promoter AP1 factor binding site. This response appears to be physiologic, as endogenous hINV gene expression is also increased. Fra-1, Fra-2, FosB, JunB, JunD, c-Jun, and c-Fos levels are increased by EGCG treatment, as is AP1 factor binding to hINV promoter AP1 site. Gel mobility shift studies show that this complex contains Fra-1 and JunD. Signal transduction analysis indicates that the EGCG response requires Ras, MEKK1, MEK3, and p38 kinases. Kinase assays and inhibitor studies suggest that p38delta is the p38 isoform responsible for the regulation. These changes are also associated with a cessation of cell proliferation and enhanced cornified envelope formation. These studies show that in normal human keratinocytes EGCG markedly increases, via a MAPK signaling mechanism, AP1 factor-associated responses.
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PMID:Green tea polyphenol stimulates a Ras, MEKK1, MEK3, and p38 cascade to increase activator protein 1 factor-dependent involucrin gene expression in normal human keratinocytes. 1169 15

Smad7 transcription is known to be regulated by TGF-beta to form a negative-feedback loop of TGF-beta-mediated biological responses. In this study, we sought to determine whether other signaling cascades, especially mitogen-activated protein (MAP) kinases, might be involved in the transcriptional regulation of Smad7. Hyperosmolarity (500 mOsm/kg H(2)O) or anisomycin (10 microg/ml) potentiated TGF-beta-induced increases of Smad7 mRNA abundance in normal rat kidney fibroblasts. SB203580 (10 microM) treatment had no effect on basal and TGF-beta-induced Smad7 mRNA abundance, and the overexpression of kinase-negative ATF2 had no effect on Smad7 promoter activity. On the other hand, overexpression of dominant-negative JNK and dominant-negative c-Jun significantly attenuated the TGF-beta-induced increases of Smad7 mRNA abundance and promoter activity, respectively. Mutations of the AP-1 element near the Smad-binding element in the rat Smad7 promoter also completely abolished TGF-beta-induced Smad7 promoter activity. These results suggested that the JNK cascade, not p38 kinase, cooperated with the Smad signaling to induce Smad7 transcription through the AP-1 element. Serum treatment (10%) attenuated the TGF-beta-induced Smad7 mRNA increase, and PD98059 (30 microM) treatment increased the basal and TGF-beta-induced Smad7 promoter activity. Gel shift analysis revealed that serum treatment decreased the amount of nuclear Smad complex that PD98059 treatment was shown to restore. These results indicated that ERK activation negatively regulated Smad7 transcription possibly by inhibiting translocation of Smad complex to nuclei. In conclusion, JNK cascade and ERK cascade are important positive and negative regulators of Smad7 transcription, respectively.
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PMID:Involvement of MAP kinase cascades in Smad7 transcriptional regulation. 1171 83

Adenovirus gene therapy is a promising tool in the clinical treatment of many genetic and acquired diseases. However, it has also caused pathogenic effects in organs such as the liver. The redox-sensitive transcription factors AP-1 and NF-kappaB have been implicated in these effects. To study the mechanisms of adenovirus-mediated AP-1 and NF-kappaB activation and the possible involvement of oxidative stress in adenovirus transduction, rats were injected with either replication-defective recombinant adenovirus with DNA containing the cytomegalovirus promoter region only (AdCMV), adenovirus containing human manganese-containing superoxide dismutase (MnSOD) cDNA (AdMnSOD), or vehicle. Compared to vehicle and AdCMV transduction, MnSOD gene transfer yielded a fivefold increase in liver MnSOD activity 7 days postinjection. Gel shift assay showed that AdCMV transduction induced DNA binding activity for AP-1 but not NF-kappaB. MnSOD overexpression abolished this activation. Western blotting analysis of c-Fos and c-Jun suggested that up-regulation of c-fos and c-jun gene expression does not directly contribute to the induction of AP-1 activation. Glutathione/glutathione disulfide ratios were decreased by adenovirus transduction and restored by MnSOD overexpression. The AP-1 binding activity that was induced by AdCMV was decreased by immunoprecipitation of Ref-1 protein. Ref-1 involvement was confirmed by restoration of AP-1 binding activity after the immunoprecipitated Ref-1 protein had been added back. AP-1 DNA binding activity was also elevated in control and AdMnSOD-injected rats after addition of the immunoprecipitated Ref-1 protein. These data indicate that cellular transduction by recombinant adenovirus stimulates AP-1 DNA binding activity. Furthermore, our results suggest that MnSOD overexpression decreases AP-1 DNA binding activity by regulating intracellular redox status, with the possible involvement of Ref-1 in this redox-sensitive pathway.
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PMID:Redox regulation of adenovirus-induced AP-1 activation by overexpression of manganese-containing superoxide dismutase. 1173

The FSH receptor (FSHR) is selectively expressed in the granulosa and Sertoli cells in a development-dependent manner. Little is known regarding how the regulatory factors balance expression of this gene in ovarian cycles or spermatogenic stages. We have used the ovine FSHR promoter as a model system and identified a third regulatory element (RE-3) located at -197 to -171 of the strongest promoter. Gel mobility shift and antibody supershift assays demonstrated that nuclear factors c-Fos/c-Jun, steroidogenic factor-1 (SF-1), upstream stimulatory factor-1/2 (USF-1/2), and chicken ovalbumin upstream promoter transcription factor-1/2 (COUP-TFI/II) potentially bound to RE-3. We have also extended our previous observations by showing that a sequence containing an E-box was not only bound by USF proteins but also recognized by COUP-TF orphan receptors. Functional studies demonstrated that USF-1/2, c-Fos/c-Jun, and SF-1 were activators, whereas COUP-TFs were repressors. Our studies indicated that RE-3 mediated SF-1 activation as well as phorbol 12-myristate 13-acetate stimulation, whereas COUP-TFs inhibited AP-1, USFs, and SF-1 activation. We also demonstrated that both COUP-TF-binding sites in the core promoter were required for the bipartite elements to oppose their competitor binding. These data suggest a mechanism by which positive and negative regulators compete for the common regulatory elements, providing antagonistic pathways that might govern the expression of FSHR in gonadal cells.
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PMID:Orphan receptor chicken ovalbumin upstream promoter transcription factors inhibit steroid factor-1, upstream stimulatory factor, and activator protein-1 activation of ovine follicle-stimulating hormone receptor expression via composite cis-elements. 1202 Oct 44

c-Jun has a variety of functions including proliferation, differentiation and death. c-Jun is specifically phosphorylated by c-Jun N-terminal kinase (JNK) which is regulated by Ras-MEKK1-MKK4/7 pathway. Previous studies showed that c-Jun protein plays a positive role in cell proliferation of normal hepatocytes and was detected in hepatocellular carcinoma (HCC) tissues. However, the function of c-Jun in HCC cells has not been examined. The aim of this study was to investigate whether the MEKK1-JNK signaling pathway and c-Jun may be involved in the survival and proliferation of HCC. Surprisingly, an active not dominant negative form of MEKK1 (CA-MEKK1) remarkably inhibited the colony formation of HCC cells. Gel retardation assays indicated that CA-MEKK1 induces c-Jun DNA binding, and luciferase assays exhibited that CA-MEKK1 enhances the transactivating activity of c-Jun in HCC cells. These results suggested that the inhibitory effect of CA-MEKK1 on colony formation is likely to be mediated by c-Jun. As expected, when wild-type c-Jun was transfected, the colony formation was significantly reduced. Especially in HuH7 cells, c-Jun transfected cells failed to make any colonies. Our data suggested that c-Jun activation can induce negative effect on survival and proliferation of HCC cells.
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PMID:MEKK1 induces c-Jun complexes that act as negative regulators for cell survival and proliferation of HCC cells. 1216 99

We previously found that human chymase cleaves big endothelins (ETs) at the Tyr(31)-Gly(32) bond and produces 31-amino acid ETs (1-31), without any further degradation products. In the present study, we investigated the effects of various antioxidants on the ET-1 (1-31)-induced change in intracellular signaling and proliferation of cultured rat aortic smooth muscle cells (RASMC). ET-1 (1-31) stimulated rapid and significant activation of the mitogen-activated protein (MAP) kinase family, i.e. extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun NH(2)-terminal kinase (JNK), and p38 MAPK, in RASMC to an extent similar to that of ET-1. All of the antioxidants examined, i.e. N-acetyl-L-cysteine (NAC), diphenyleneiodonium chloride (DPI), and L-(+)-ascorbic acid (ascorbic acid), inhibited both ET-1 (1-31)- and ET-1-induced JNK and p38 MAPK activation but not ERK1/2 activation. Electron paramagnetic resonance (EPR) spectroscopy measurements revealed that NAC, DPI, and ascorbic acid inhibited xanthine oxidase-induced superoxide (O(2)(.-)) generation in a cell-free system. ET-1 (1-31) in addition to ET-1 increased the generation of cellular reactive oxygen species (ROS) in RASMC. ET-1 (1-31)- and ET-1-induced cellular ROS generation was inhibited similarly by NAC, DPI, and ascorbic acid in RASMC. Gel-mobility shift analysis showed that ET-1 (1-31) and ET-1 caused an increase in activator protein-1 (AP-1)-DNA binding activity in RASMC that was inhibited by the above three antioxidants. ET-1 (1-31) increased [3H]thymidine incorporation into cells to an extent similar to that of ET-1. This ET-1 (1-31)-induced increase in [3H]thymidine incorporation was also inhibited by NAC and DPI, but not by ascorbic acid. These results suggest that antioxidants inhibit ET-1 (1-31)-induced RASMC proliferation by inhibiting ROS generation within the cells. The underlying mechanisms of the inhibition of cellular proliferation by antioxidants may be explained, in part, by the inhibition of JNK activation and the resultant inhibition of AP-1-DNA binding.
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PMID:Antioxidants inhibit endothelin-1 (1-31)-induced proliferation of vascular smooth muscle cells via the inhibition of mitogen-activated protein (MAP) kinase and activator protein-1 (AP-1). 1241 65

In skin, the profibrotic protein connective tissue growth factor (CTGF) is not normally expressed. However, when skin cells are exposed to transforming growth factor-beta (TGF-beta), CTGF is induced in fibroblasts but not in epithelial cells. We have begun to investigate the requirements for the fibroblast-selective induction of CTGF by TGF-beta. Previously we found that this response was Smad-dependent. Now we show that protein kinase C and Ras/MEK/ERK are necessary for the TGF-beta induction of the CTGF promoter but not of a generic Smad-responsive promoter (SBE-lux). Induction of the CTGF promoter is antagonized by c-Jun or by MEKK1, suggesting that a proper balance between the Ras/MEK/ERK and JNK MAPK cascades is necessary for TGF-beta induction of CTGF. We identify the minimal CTGF promoter element necessary and sufficient to confer TGF-beta responsiveness to a heterologous promoter and show that a tandem repeat of a consensus transcription enhancer factor binding element, 5'-GAGGAATGG-3', is necessary for this induction. This element has not been previously shown to play a role in TGF-beta induction of gene expression in fibroblasts. Gel shift analysis shows that this sequence binds nuclear factors that are greatly enriched in fibroblasts relative to epithelial cells. Thus Smads, Ras/MEK/ERK, protein kinase C, and fibroblast-enriched factors that bind GAGGAATGG act together to drive the TGF-beta-mediated induction of CTGF in fibroblasts.
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PMID:Connective tissue growth factor gene regulation. Requirements for its induction by transforming growth factor-beta 2 in fibroblasts. 1257 Dec 53

Transformation suppressor Pdcd4 is downregulated in transformed (Tx) mouse epidermal JB6 RT101 cells relative to transformation-resistant (P-) and susceptible (P+) variants. Whether Pdcd4 downregulation is necessary not only to induce transformation but also to maintain tumor phenotypes has not been determined previously. In the present study, overexpression of Pdcd4 cDNA in stably transfected RT101 cells resulted in 40% fewer anchorage-independent colonies that were smaller in size than the vector control colonies, indicating that elevated Pdcd4 expression is sufficient to suppress tumor phenotype. Transient transfection of Pdcd4 expression plasmid and 4 x AP-1 reporter gene showed that activation of AP-1-dependent transcription was inhibited by Pdcd4 expression in a concentration-dependent manner. In contrast, Pdcd4 did not inhibit serum response element-dependent transcription, indicating specificity. In a Gal4 fusion assay, Pdcd4 specifically inhibited activation of c-Jun and c-Fos activation domains, but did not inhibit activation of JunB, JunD, Fra-1, or Fra-2. Gel mobility shift assay demonstrated that c-Jun is the major component detected in the AP-1 complex in RT101 cells. Previous studies suggested that AP-1 activity is required for maintaining the transformed phenotype in RT101 cells. Thus, Pdcd4 suppresses tumor phenotype by inhibiting AP-1-dependent transcription, possibly through inhibiting c-Jun and c-Fos activation.
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PMID:Pdcd4 suppresses tumor phenotype in JB6 cells by inhibiting AP-1 transactivation. 1280 78

Astrocytes have become a focal point for research in neurobiology, especially regarding their purported ability to regulate neuronal communication and survival. The present study addressed a poorly understood but important focus in this area, the mechanism(s) underlying astrocyte-induced survival of neurons. The results of the study show that soluble factors in astrocyte-conditioned media (ACM) protect murine GT1-7 neurons from serum deprivation-induced cell death and that this neuroprotection is correlated with enhanced activation/phosphorylation of the AP-1 transcription factor, c-JunSer-63. A parallel and correlated activation of the upstream kinases, c-Jun N-terminal kinase (JNK) and mitogen-activated protein kinase kinase-4 (MKK4) was also demonstrated. Furthermore, co-administration of JNK inhibitors, but not a MEK inhibitor, significantly attenuated ACM-induced phosphorylation of c-JunSer-63 and blocked its neuroprotective action. Gel shift analysis demonstrated that ACM enhanced AP-1 binding, an effect that appears functionally important, since an AP-1 binding inhibitor significantly attenuated the neuroprotective action of ACM. Further studies implicated transforming growth factor (TGF)-beta1 and TGF-beta2 as critical active soluble factors released by astrocytes, since both were demonstrated in ACM, and immunoneutralization of the conditioned media with a panspecific TGF-beta antibody significantly attenuated the enhanced AP-1 binding and neuroprotective action of the ACM. Furthermore, exogenous application of TGF-beta1 and TGF-beta2 was found to enhance c-JunSer-63 phosphorylation and to be neuroprotective, and co-administration of JNK inhibitors or an AP-1 binding inhibitor blocked TGF-beta-induced neuroprotection. Taken together, these studies suggest that astrocytes can protect neurons from serum deprivation-induced cell death, at least in part, by release of TGF-beta and activation of a c-Jun/AP-1 protective pathway.
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PMID:Astrocyte protection of neurons: role of transforming growth factor-beta signaling via a c-Jun-AP-1 protective pathway. 1288 49

In the present study the molecular mechanisms underlying tetradecanoylphorbol-13-acetate (TPA) mediated regulation of the human gamma-glutamyltransferase (GGT) gene were examined. TPA challenge of HeLa cells resulted in an increase of GGT mRNA and enzyme activity. Deletion analysis of the promoter revealed that the -348 to +60 fragment was able to mediate TPA induced expression. Gel shift and supershift analyses showed that TPA treatment increased nuclear protein binding to a putative AP-1 site (-225 to -214) and that c-Jun was part of the complex. This AP-1 element, when cloned either in its native arrangement or as tandem repeat 5' of the minimal thymidine kinase promoter, mediated a significant increase of luciferase activity after TPA treatment of transfected HeLa cells, while its mutated counterpart abolished the induction. The same AP-1 element was able to mediate TPA induced expression in HepG2 cells. Collectively these results indicate that like other GSH metabolising enzymes, GGT too is a target for AP-1 mediated regulation.
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PMID:Phorbol ester regulation of the human gamma-glutamyltransferase gene promoter. 1468 60


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