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Query: UNIPROT:P05412 (c-Jun)
 11,453 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent advances indicate a link between tumour promoters, transformation, and AP-1 activity. Protein kinase C activation increases AP-1 DNA-binding activity independently of new protein synthesis. AP-1 is also stimulated by transforming oncoproteins and growth factors. These proteins are thought to participate in a signalling cascade affecting the nuclear AP-1 complex composed of the Jun and Fos proteins. Because c-Jun is the most potent transactivator in the AP-1 complex and is elevated in Ha-ras-transformed cells, in which c-Fos is downregulated, we focused on it as a potential target. c-Jun could convert input from an oncogenic signalling cascade into changes in gene expression. Indeed, transformation of rat embryo fibroblasts by c-Jun requires an intact transcriptional activation domain and cooperation with oncogenic Ha-ras. Expression of oncogenic Ha-ras augments transactivation by c-Jun and stimulates its phosphorylation. Here we describe the mapping of the Ha-ras-responsive phosphorylation sites to serines 63 and 73 of c-Jun. Site-directed mutagenesis indicates that phosphorylation of these serines is essential for stimulation of c-Jun activity and for cooperation with Ha-ras in ocogenic transformation.
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PMID:Oncogenic and transcriptional cooperation with Ha-Ras requires phosphorylation of c-Jun on serines 63 and 73. 174 29

Cell proliferation and phenotype of cells from female reproductive tissues are regulated by estrogens. It is therefore important to understand how estrogen action can be modulated. It recently has been reported that certain nuclear receptors can antagonize the tumor promoter 12-O-tetradeconylphorbol-13-acetate (TPA) by direct interaction with the transcription factor AP-1, and that the AP-1 constituents cJun and cFos can inhibit receptor activity. This mutual antagonism appears to be based on direct protein-protein interaction. In the human breast cancer cell line MCF-7, TPA leads to growth arrest and altered cell morphology. We have investigated here whether in MCF-7 cells and other cell lines AP-1 and estrogen receptors (ERs) can inhibit each other's activity. We find that TPA or the AP-1 components cJun and cFos can inhibit estradiol-dependent estrogen receptor activity in most cell lines investigated. In addition, ER mRNA is rapidly down-regulated in MCF-7 cells. Gel retardation experiments show that ER DNA binding is inhibited in vitro by cJun protein, while ER also can inhibit cJun DNA binding. However, in vivo we do not observe inhibition of AP-1 activity by ER in the cell lines investigated here. On the contrary, we observed an enhancing effect at low ER concentrations on AP-1. Together our data suggest a new regulatory pathway by which ER activity can be modulated by AP-1. Several mechanisms including ER-AP-1 protein interaction appear to be involved.
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PMID:Inhibition of estrogen receptor activity by the tumor promoter 12-O-tetradeconylphorbol-13-acetate: a molecular analysis. 179 43

Recent evidence suggests that vasoconstrictive substances, including angiotensin II (Ang II), may function as a vascular smooth muscle growth promoting substance and may contribute to vascular hypertrophy in hypertension. Atrial natriuretic polypeptide (ANP) is known to be a physiological antagonist to Ang II in blood pressure and fluid homeostasis. Moreover, we have demonstrated that ANP can attenuate Ang II's action on vascular hypertrophy. In this study, we investigated the potential molecular mechanisms for the interaction of ANP and Ang II on vascular cell growth. Ang II dose-dependently induced RNA synthesis in post confluent cultured rat aortic smooth muscle (RASM) cells. ANP (10(-7) M) inhibited the hypertrophic effect of Ang II at the concentration of 10(-10) - 10(-8) M) but exerted no effect on the action of higher doses (10(-7) - 10(-6) M) of Ang II. Ang II (10(9) - 10(-8) M) and a protein kinase C activator, phorbol 12-myristate 13-acetate (PMA, 10(-8) M) rapidly induced c-fos as well as c-Jun and Jun-B mRNA expression in RASM cells. ANP (10(-7) M) itself had no apparent effect on the expression of these protooncogenes. Furthermore, ANP did not inhibit the induction of these protooncogenes by Ang II or PMA. Paradoxically, ANP (10(-7) M) significantly enhanced c-fos mRNA expression induced by Ang II and PMA. However, the chloramphenicol acetyl transferase (CAT) assay using a CAT expression vector containing the AP-1 binding element showed that ANP had no effect on the basal and PMA-stimulated AP-1 activity in transfected RASM cells. We conclude, therefore, that the inhibitory effect of ANP on the growth of vascular smooth muscle cells in vitro does not occur through the regulation of these protooncogene expressions.
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PMID:Interaction of atrial natriuretic polypeptide and angiotensin II on protooncogene expression and vascular cell growth. 182 53

We have studied interactions between bacterially produced E1A linked to Sepharose and the various DNA-binding proteins present in HeLa cell nuclear extracts (NE). DNA-binding activities and cross-reactive polypeptides recognizing the cAMP-responsive element (CRE) and the activator protein 1 (AP1) sites were bound to the E1A column, whereas nuclear factor 1 (NF1) and the activator protein 2 (AP2) DNA-binding activities were not retained by E1A. The binding activities that were retained belonged to the CRE and JUN protein family, as judged by Western blot analysis. Authentic CRE-BP1, c-Jun and c-Fos proteins produced by in-vitro translation also bound to the E1A column. However, efficient binding of in-vitro-translated CRE-BP1 and c-Fos proteins to E1A required preincubation with NE. We show here that immobilized E1A sequesters several cellular upstream transcription activators, and suggest a role for members of the AP1 family of transcription factors in E1A-mediated gene regulation.
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PMID:Interactions between adenovirus E1A and members of the AP-1 family of cellular transcription factors. 183 15

In resting human epithelial and fibroblastic cells, c-Jun is phosphorylated on serine and threonine at five sites, three of which are phosphorylated in vitro by glycogen synthase kinase 3 (GSK-3). These three sites are nested within a single tryptic peptide located just upstream of the basic region of the c-Jun DNA-binding domain (residues 227-252). Activation of protein kinase C results in rapid, site-specific dephosphorylation of c-Jun at one or more of these three sites and is coincident with increased AP-1-binding activity. Phosphorylation of recombinant human c-Jun proteins in vitro by GSK-3 decreases their DNA-binding activity. Mutation of serine 243 to phenylalanine blocks phosphorylation of all three sites in vivo and increases the inherent trans-activation ability of c-Jun at least 10-fold. We propose that c-Jun is present in resting cells in a latent, phosphorylated form that can be activated by site-specific dephosphorylation in response to protein kinase C activation.
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PMID:Activation of protein kinase C decreases phosphorylation of c-Jun at sites that negatively regulate its DNA-binding activity. 184 81

Products of the adenovirus E1A gene can act synergistically with cAMP to activate transcription of several viral early genes and the cellular genes c-fos and jun-B. Transcription factor AP-1-binding activity is also induced by the combined action of E1A and cAMP. Mouse S49 cells were infected with adenovirus variants expressing either the 243- or 289-amino acid E1A protein and treated with the cAMP analog dibutyryl-cAMP. Significant E1A-dependent induction of c-fos mRNA and AP-1-binding activity was observed in cells expressing either E1A protein. These effects absolutely required the presence of cAMP. In contrast, the 243-amino acid protein was a poor activator of the viral early genes E2 and E4 compared with the 289-amino acid protein. These data suggest that the 243- and 289-amino acid E1A proteins both interact functionally with the cAMP signaling system to activate transcription of a cellular gene and AP-1-binding activity. The mechanism involved in this process is probably different from the mechanism of transcriptional activation of viral genes.
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PMID:Induction of c-fos mRNA and AP-1 DNA-binding activity by cAMP in cooperation with either the adenovirus 243- or the adenovirus 289-amino acid E1A protein. 185 Aug 43

When the level of c-jun mRNA was analyzed in WI-38 human fibroblasts exciting short- and long-term quiescence, two peaks of c-jun mRNA accumulation were found. The first occurred one hour after stimulation and lasted three to five hours, whereas the second occurred at the G1/S border and was coupled to the time of entry to S phase rather than to the time of stimulation. The early peak is well documented and in agreement with the proposed role of c-Jun/AP-1 in mediating cellular responses to receptor-generated signals. The later peak, however, has not been previously reported. Additional follow-up studies showed that late G1/S expression was not solely a phenomenon of cells existing a quiescent state, nor was it restricted only to human cells. Gel retardation studies confirmed that there is AP-1 specific DNA binding activity in nuclear extracts isolated in late G1 and S phase, and that this AP-1 binding activity is due to the presence of Jun protein. An anti-Fos antibody was able to significantly decrease AB-1 binding activity in early G1 extracts, but had no effect on extracts isolated in late G1 and S phase, indicating that the complexes observed in late G1 and S phase are clearly different from those seen in early G1. These studies are among the first to suggest a functional dissociation of c-Jun from c-Fos. Our results identify a new, previously unreported role for c-Jun/AP-1 in regulation of cell cycle progression and mammalian cell growth.
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PMID:A potential role for c-jun in cell cycle progression through late G1 and S. 190 Mar 57

Transcription factor AP-1 is inducible by phorbol esters and thus could be considered to be one final target of the protein kinase C signal transduction pathway. AP-1 consists of the products of the fos and jun oncogenes, which associate as dimers to bind TPA-responsive promoter elements (TRE) efficiently. We show that AP-1 activity is modulated by an inhibitory protein (IP-1), present both in the nucleus and cytoplasm of several cell types. IP-1 specifically blocks DNA binding of AP-1 from nuclear extracts and of in vitro synthesized Fos/Jun proteins. It is a labile protein of 30-40 kd, which exerts its activity only in the nonphosphorylated form. Block of IP-1 function is obtained by PKA-mediated phosphorylation, possibly suggesting a cross talk mechanism at transcriptional level. Competition experiments with synthetic peptides suggest that IP-1 could interact with Fos and/or Jun leucine zippers. We speculate that IP-1 might act as a transcriptional antioncogene.
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PMID:IP-1: a dominant inhibitor of Fos/Jun whose activity is modulated by phosphorylation. 190 Apr 58

Two forms of FosB transcript and their products can be identified in mouse NIH 3T3 cells following serum induction. The larger RNA codes for a 338-amino acid protein, whereas the smaller RNA results from the removal of an additional 140 nucleotides from FosB mRNA by alternative splicing. This alternative splicing event places a stop codon following the "leucine zipper" region and results in a shorter protein (FosB2) of 237 amino acids that lacks 101 amino acids at the carboxyl terminus. FosB2 is able to form heterodimers with c-Jun and bind to an AP-1 site but is not able to activate the transcription of promoters containing AP-1 sites. Furthermore, FosB2 can not only suppress the transcriptional activation by c-Fos and c-Jun of promoters containing an AP-1 site but also interferes with the transforming potential of viral and cellular Fos proteins. We propose that FosB2 protein functions as a trans-negative regulator.
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PMID:An alternative spliced form of FosB is a negative regulator of transcriptional activation and transformation by Fos proteins. 190 17

Curcumin, a dietary pigment responsible for the yellow color of curry, is a potent inhibitor of tumor promotion by phorbol esters. Functional activation of transcriptional factor c-Jun/AP-1 is believed to play an important role in signal transduction of phorbol 12-myristate 13-acetate-induced tumor promotion. Suppression of the c-Jun/AP-1 activation by curcumin is observed in mouse fibroblast cells. In vitro experiments indicate that inhibition of c-Jun/AP-1 binding to its cognate motif by curcumin may be responsible for the inhibition of c-Jun/AP-1-mediated gene expression. These findings show that the effect of curcumin on phorbol 12-myristate 13-acetate-induced inflammation/tumor promotion could be studied at the molecular level.
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PMID:Suppression of c-Jun/AP-1 activation by an inhibitor of tumor promotion in mouse fibroblast cells. 190 19


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