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 hepatic expression of the alpha-2u-globulin gene family is controlled by a variety of hormones including steroids, growth hormone and insulin. The mechanisms by which these hormones affect alpha 2u-globulin expression are only partially understood. Recently we isolated and characterized clone RAP 01, an alpha 2u-globulin gene expressed in the liver. In preliminary experiments we noted that partial hepatectomy, a procedure which results in a sharp rise in the level of the oncoproteins c-Fos and c-Jun, also causes a transient induction of the messenger RNA corresponding to clone RAP 01. Using the DNAseI footprinting technique we were able to show that this clone contains a TPA (phorbol 12-myristate 13-acetate)-responsive element (TRE) in its first intron. This element (denoted as element X) is identical to the consensus AP-1 binding site (TGACTCAG) and is protected by rat liver nuclear extracts as well as by purified c-Jun. Gel retardation experiments show that an oligonucleotide containing the TRE consensus sequence competes for binding of liver nuclear proteins to element X and that antibodies directed against the M2 peptide of the mouse Fos protein or the PEP-2 peptide of Jun prevent the formation of specific complexes with the same element. Moreover, element X functions as a TRE in transfected BWTG3 hepatoma cells treated with TPA. Co-transfection with fos and jun expression vectors mimics the effects of TPA suggesting that AP-1 is in fact the mediator of the observed response. It is concluded that the first intron of RAP 01 contains a functional Fos-Jun element.
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PMID:A Fos-Jun element in the first intron of an alpha 2u-globulin gene. 750 7

The effects of a phorbol ester (TPA) and of members of the Jun and Fos oncoprotein family on the activity of the rat alpha-fetoprotein (AFP) promoter were checked by using transient expression experiments in HepG2 hepatoma cells. TPA blocked the activity of the rat AFP promoter in a dose-dependent manner. Overexpression of c-Jun specifically repressed the rat AFP promoter but not the albumin promoter. JunB and JunD were poorer inhibitors. c-Fos expression did not potentiate the negative effect of Jun. The Jun-induced repression does not require binding of c-Jun to the AFP promoter. DNase 1 footprinting experiments did not display any high affinity binding site for Jun on the AFP promoter. Integrity of the c-Jun DNA binding domain is not required for the c-Jun protein to block the AFP promoter. The N-terminal part of Jun, which contains the activating domain, is responsible for the repression as shown by using Jun-Gal4 chimera. Jun likely exerts its negative control on the AFP promoter via protein-protein interactions with a not yet identified trans-activating factor within the -134 to +6 region or with a component of the general machinery of transcription. Jun proteins can thus be key intermediates in regulatory cascades which result in the differential modulation of the AFP and albumin gene expression in the course of liver development and carcinogenesis.
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PMID:The c-jun proto-oncogene down-regulates the rat alpha-fetoprotein promoter in HepG2 hepatoma cells without binding to DNA. 753 66

Basic fibroblast growth factor (bFGF) has been shown to be a potent mitogen and a promoter of angiogenesis. It has been hypothesized that the expression of the bFGF gene may be induced by stress of various types. To test that hypothesis, we investigated the expression of the bFGF gene during heat treatment in adriamycin-resistant (MCF-7/ADR) and -sensitive (MCF-7) human breast carcinoma cells. Under normal growth conditions, the bFGF mRNA was detected in MCF-7/ADR cells, while it was not detectable in MCF-7 cells by Northern blot analysis. During heating at 41 degrees C, the level of bFGF mRNA increased in MCF-7/ADR cells and the message became detectable in the MCF-7 cell line. However, after continuous heating at 41 degrees C for 24 h, the bFGF mRNA level decreased to control level in MCF-7/ADR cells. Interestingly, simultaneous treatment with heat and 60 micrograms/ml H-7 (1-(isoquinolinylsulfonyl)-2-methylpiperazine, a potent PKC inhibitor) decreased the level of bFGF mRNA in MCF-7/ADR cells. These results suggest that a protein kinase, likely PKC, is involved in the transcriptional regulation of the heat-enhanced bFGF gene expression in human breast carcinoma cells. Although no heat shock element can be identified in the promoter of the bFGF gene, we observed that the AP-1 binding activity to a TPA responsive element (TRE)-like sequence in the promoter of bFGF gene was enhanced by heat, as tested by mobility shift assay. Antibody developed against the c-Jun and c-Fos proteins inhibited the AP-1 binding activity to TRE. Therefore, the AP-1 complex appears to be responsible for the heat-enhanced binding to the TRE-like motif of the bFGF gene. Furthermore, the increased AP-1 binding activity does not require new protein synthesis but activation of the preexisting c-Jun proteins.
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PMID:Heat-induced bFGF gene expression in the absence of heat shock element correlates with enhanced AP-1 binding activity. 762 86

The major regulators of the c-jun promoter are ATF-2 and c-Jun. They act as pre-bound heterodimers on two 'AP-1-like' sites, and are preferentially addressed by different types of extracellular signals. The transactivating potential of ATF-2 is stimulated to a higher extent than that of c-Jun by a broad group of agents causing DNA damage and other types of cellular stress, such as short-wavelength UV, or the alkylating compounds N-methyl-N'-nitro-N-nitroso-guanidine (MNNG) or methylmethanesulphonate (MMS). In contrast, treatment with the phorbol ester TPA preferentially enhances c-Jun-dependent transactivation but does not affect ATF-2. Accordingly, UV and MMS but not TPA induce c-jun transcription in F9 cells, which express ATF-2, but not c-Jun. Stimulation of ATF-2-dependent transactivation by genotoxic agents requires the presence of threonines 69 and 71 located in the N-terminal transactivation domain. These sites are the target of p54 and p46 stress-activated protein kinases (SAPKs) which bind to, and phosphorylate ATF-2 in vitro. However, p46 and p54 kinase activity is not increased by phorbol ester, which strongly suggests that the protein kinase phosphorylating c-Jun in response to TPA is distinct from SAPKs and does not act on ATF-2. Our data demonstrate that distinct signal transduction pathways converge at c-Jun/ATF-2, whereby each subunit is individually addressed by a specific class of protein kinases. This allows fine tuned modulation of c-jun expression by a large spectrum of extracellular signals.
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PMID:ATF-2 is preferentially activated by stress-activated protein kinases to mediate c-jun induction in response to genotoxic agents. 773 30

The murine macrophage inflammatory protein 1 beta mRNA (MIP-1 beta) is rapidly and transiently induced in macrophages by lipopolysaccharide (LPS), serum or cycloheximide. Functional studies of the MIP-1 beta proximal promoter indicate that it is cell-specific, and serum- and LPS-responsive in macrophages. A 76-bp proximal promoter sequence (-51 to -127 bp) confers cell-specific and LPS-inducible activity when placed upstream from a heterologous promoter in both orientations. One essential cis-regulatory element within the enhancer-like sequence is an activating transcription factor/cAMP response element (CRE)-binding protein (ATF/CREB)-binding site, although the promoter is not cAMP responsive. Electrophoretic mobility shift assays and mutational analyses suggest that the promoter site is bound by nuclear protein complexes containing cAMP-independent members of the ATF/CREB family of proteins and c-Jun, and are functionally distinct from the AP1-related TPA-response element (TRE) binding activity.
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PMID:An ATF/CREB-binding site is essential for cell-specific and inducible transcription of the murine MIP-1 beta cytokine gene. 783 96

The functional induction of c-fos in the sodium butyrate-induced differentiation of F-98 glioma cells was studied. Fos protein level was increased by butyrate. In contrast, c-Jun protein was constitutively expressed and was not affected by butyrate. Gel-retardation assay indicates Fos as a component of the complex formed between the consensus oligonucleotide of the TPA (PMA, phorbol 12-myristate 13-acetate) response element (TRE) and nuclear extract prepared from butyrate-treated cells. Transfection studies showed that butyrate increased transcription from a multimeric TRE-driven reporter construct, and the effect was mimicked by transfecting cells with fos-expression plasmid. Furthermore, under conditions of c-fos over-expression, transactivation by butyrate was essentially abolished. These data suggest that Fos induction had a functional role in gene activation. Characterization of stable c-fos transfectants demonstrated that these cells displayed alterations in morphology, showed serum-dependent growth, had slower growth rates and grew to lower saturation densities than did untransfected F-98 cells or transfected cells that did not express c-fos. Immunofluorescent staining indicated that fos transfectants also had elevated glial fibrillary acidic protein ('GFAP') expression. Transfection of the c-fos promoter-chloramphenicol acetyltransferase fusion gene into F-98 cells revealed that activation of c-fos by butyrate was exerted at the promoter level, and sequences located within nucleotides -757 to -402 of the c-fos promoter were responsible for butyrate induction. Our data indicate that transcriptional activation of c-fos through its promoter by butyrate resulted in increased Fos protein expression. Transfection studies show that both c-fos and butyrate activate TRE-containing genes, and fos may be a downstream mediator of butyrate. Furthermore, expression of c-fos plays a major role in modulating the growth properties of F-98 cells.
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PMID:Analysis of c-fos expression in the butyrate-induced F-98 glioma cell differentiation. 786 28

1. The human endothelin-1 (ET-1) gene, which is located on chromosome 6, contains cis-regulatory elements in the 5'-flanking region including the TPA-responsive element, nuclear factor 1 binding element and GATA motif. 2. The expression of preproendothelin-1 (PPET-1) mRNA is regulated by a mechanism involving receptor mediated mobilization of intracellular Ca2+ and activation of protein kinase C in endothelial cells. 3. Activation of protein kinase C results in the synthesis of c-Jun protein and the rapid dephosphorylation of c-Jun protein. Consequently, the binding activity of c-Jun protein to the TPA-responsive element increases, and this causes the induction of PPET-1 mRNA. 4. The microtubular system seems to play some important roles in ET-1 secretion, especially in the process of transferring the synthesized ET-1 to the cell surface of the endothelial cells. 5. The secretion of ET-1 from endothelial cells is also regulated by intracellular Ca2+ released from the Ca2+ store and by Ca2+-calmodulin complex. The phosphorylation of the myosin light chain, elicited by myosin light chain kinase and activated by Ca2+-calmodulin complex, facilitates the formation of filamentous myosin and actin which probably participate in ET-1 secretion especially in transporting the ET-1-containing vesicles towards the cell membrane in the stimulated endothelial cells. 6. Many cultured cells, other than endothelial cells, also secret ET-1 into the culture medium and this secretion can be stimulated by a variety of agents.
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PMID:The control of endothelin-1 secretion. 787 27

The rat glutathione transferase P gene has a strong enhancer element, termed GPE I, which is composed of a dyad of palindromicly oriented TPA (phorbol 12-O-tetradecanoate 13-acetate) responsive element (TRE)-like sequences. TRE is a binding sequence of the transcription factor AP-1, which consists of several closely related proteins belonging to the Jun and Fos family. The gel retardation experiments show that all the heterodimers formed between the Jun and Fos related gene products bind to the GPE I as well as to the TRE. In spite of the fact that the GPE I has a stronger activity than the TRE, the binding affinities of these heterodimers to the GPE I are much lower than to the TRE. Co-transfection studies of the reporter construct containing the GPE I and expression constructs of each of the Jun and Fos family cDNAs indicate that FosB and delta FosB repress transcription through the GPE I enhancer. These results suggests that some of Jun/Fos family may regulate the rat GST-P gene expression through the GPE I in vivo.
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PMID:Jun and Fos related gene products bind to and modulate the GPE I, a strong enhancer element of the rat glutathione transferase P gene. 791 48

The indol alkaloid staurosporine is a potent inhibitor of protein kinase C, but has also been shown to have certain effects paradoxically similar to those of protein kinase C-activating phorbol esters. We show here that collagenase mRNA expression is stimulated by 10 nM staurosporine in normal and ras-oncogene-transformed rat fibroblasts. The kinetics of collagenase mRNA induction by staurosporine were slow compared to induction by phorbol ester. Staurosporine induction of the collagenase promoter appeared to be mediated via the TPA response element (TRE). Induction did not involve any increase in jun mRNA expression and did not require expression of c-Jun. Prolonged treatment with phorbol ester to deplete protein kinase C did not inhibit stimulation of the collagenase promoter by staurosporine. Instead, involvement of cAMP-dependent protein kinase (PKA) was indicated by inhibition of staurosporine induction by the PKA inhibitor H-89. In addition, raised levels of cAMP were observed during the first hour of staurosporine treatment. Altogether, our data indicate that staurosporine induces a PKA-dependent pathway leading to c-Jun-independent activation of the collagenase TRE element.
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PMID:Induction of the collagenase phorbol ester response element by staurosporine. 796 79

Growth factors, phorbol esters, and oncogenes such as ras, src, and sis are believed to stimulate c-Jun transcriptional activation by inducing increased phosphorylation at two serine residues (S63 and S73) within the N-terminal transactivation domain. Although S63 and S73 are conserved in the mutant v-Jun oncoprotein, they are not phosphorylated by two enzymes which target the corresponding residues in c-Jun in vitro; namely a partially purified c-Jun kinase from TPA-stimulated U937 cells and purified p54 mitogen activated protein (MAP) kinase. In addition, v-Jun activates transcription more strongly than c-Jun when fused to the Gal4 DNA-binding domain, and transcriptional activation by Gal4-v-Jun is unaffected when S63, S73, or both, are replaced with non-phosphorylatable alanine residues, amino acid substitutions which severely impair transcriptional activation by Gal4-c-Jun. The novel biochemical and transcriptional properties of v-Jun result from deletion of a 27 amino acid segment, termed delta, which is important for transforming activity. On the basis of these results we propose that unlike c-Jun, v-Jun transcriptional activation is independent of positive regulatory phosphorylation and that this may contribute to oncogenesis by v-Jun.
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PMID:Transcriptional activation by the v-Jun oncoprotein is independent of positive regulatory phosphorylation. 803 19


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