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)

Members of the helix-loop-helix (HLH) family of proteins bind DNA and activate transcription as homo- and heterodimers. Myogenin is a muscle-specific HLH protein that binds DNA in vitro as a heterodimer with several widely expressed HLH proteins, such as the E2A gene products E12 and E47. We describe a method for detection of protein-protein interactions among HLH proteins in vivo in which dimerization through the HLH motif reconstructs a hybrid transcription factor containing the DNA-binding domain of yeast GAL4 linked to one HLH motif and the activation domain of VP-16 linked to another. We have used this assay to investiagate whether myogenin forms homomeric or heteromeric complexes in vivo and to determine whether growth factors and oncogenes that inhibit myogenesis influence myogenin's ability to dimerize. The results show that myogenin heterodimerizes with E12 and E47 in vivo, but it does not homodimerize to a measurable extent. Peptide growth factors, as well as the immediate early gene products c-Jun, v-Fos, and c-Myc, inhibit the activity of myogenin through a mechanism independent of its association with E2A products.
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PMID:Analysis of the oligomerization of myogenin and E2A products in vivo using a two-hybrid assay system. 132 37

Two functionally distinct proteins derived from the FosB gene by alternative splicing have recently been described. FosB protein transforms fibroblasts efficiently, whereas FosB2 protein, a carboxy-terminally truncated form of FosB, does not, despite the fact that both proteins can participate in high-affinity, sequence-specific DNA binding as part of a heterodimeric complex with c-Jun protein. We show here that the functional difference between these proteins is the result of the presence of a potent proline-rich transcriptional activation domain in the carboxy-terminal amino acids unique to FosB. This conclusion is supported by three lines of evidence: (1) Mutations in the carboxy-terminal region of FosB that impair transcriptional activation also reduce transforming potential, despite the fact that DNA binding as part of a complex with c-Jun is not affected; (2) the carboxy-terminal region unique to FosB functions as an activation domain when fused to the DNA-binding domain of GAL4; and (3) transforming potential can be conferred on FosB2 by fusing any of several different well-characterized trans-activation domains. These results identify an additional functional requirement for transformation by Fos proteins and have implications for the mechanism(s) of mitogenic signaling by the AP-1 transcription complex.
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PMID:Transformation by FosB requires a trans-activation domain missing in FosB2 that can be substituted by heterologous activation domains. 137 18

The DNA-binding activity of c-Jun expressed in eukaryotic cells was found to be markedly enhanced if the intracellular concentration of binding sites for this transcription factor was increased by cotransfection of specific plasmid DNA. Dephosphorylation experiments, phosphate mapping studies, and mutational analysis indicate that phosphorylation of a cluster of serine and threonine residues situated in close proximity to the DNA-binding domain is responsible for the observed adaptation of c-Jun activity to the intracellular concentration of accessible target sites.
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PMID:Phosphorylation state and DNA-binding activity of c-Jun depend on the intracellular concentration of binding sites. 145 48

Phorbol ester tumor promoters activate gene transcription by regulating both the synthesis and posttranslational modification of the activator protein 1 (AP-1) transcription factor, c-Jun and JunB are components of the mammalian AP-1 complex. Here we demonstrate that in U-937 human leukemic cells, phorbol esters stimulate the phosphorylation of the amino terminus of human c-Jun (JUN) but not human JunB (JUNB). Mutational analysis indicates that serine-63 and -73, which reside within the putative regulatory domain of JUN, are required for both constitutive and phorbol 12-myristate 13-acetate-inducible N-terminal JUN phosphorylation. To determine the functional role of this N-terminal phosphorylation, we prepared several chimeric proteins containing the N-terminal 84 amino acids (positions 5-89) of human JUN or murine JUNB fused to the yeast GAL4 DNA-binding domain. This region was found to be sufficient for the phorbol ester-inducible transcriptional activity of JUN, but not JUNB. This induction was abolished by the mutation of serine-63 and -73 to leucine residues. Thus, we propose that phorbol esters enhance the trans-activation potential of JUN, but not JUNB, by the phosphorylation of the N-terminal regulatory domain of JUN.
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PMID:Phorbol ester-induced amino-terminal phosphorylation of human JUN but not JUNB regulates transcriptional activation. 149 19

c-Jun, a major component of the inducible transcription factor AP-1, is a phosphoprotein. In nonstimulated fibroblasts and epithelial cells, c-Jun is phosphorylated on a cluster of two to three sites abutting its DNA-binding domain. Phosphorylation of these sites inhibits DNA binding, and their dephosphorylation correlates with increased AP-1 activity. We show that two of these sites, Thr-231 and Ser-249, are phosphorylated by casein kinase II (CKII). Substitution of the third site, Ser-243, by Phe interferes with phosphorylation of the inhibitory sites in vivo and by purified CKII in vitro. Microinjection into living cells of synthetic peptides that are specific competitive substrates or inhibitors of CKII results in induction of AP-1 activity and c-Jun expression. Microinjection of CKII suppresses induction of AP-1 by either phorbol ester or an inhibitory peptide. These results suggest that one of the roles of CKII, a major nuclear protein kinase with no known functions, is to attenuate AP-1 activity through phosphorylation of c-Jun.
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PMID:Casein kinase II is a negative regulator of c-Jun DNA binding and AP-1 activity. 142 36

Transcription factor c-Jun appears to be a nuclear target of the Ras-induced signal transduction pathway. In fact, some experiments show that transforming forms of the Ras protein cooperate with Jun in transcriptional activation mediated by an AP-1 site and others indicate that the two oncoproteins cooperate in cellular transformation. Although it is likely that intracellular signaling systems activated by Ras might act directly on c-Jun by inducing specific phosphorylation, it is unclear how c-Jun participates in the transformation process. Here, we present results obtained with a LexA-Jun zipper fusion that lacks both the transcriptional activation domains and the basic region of the DNA-binding domain of c-Jun and contains only the intact leucine-zipper domain. This fusion product has a dominant negative effect on the transcriptional activation elicited by phorbol esters, c-Jun, c-Fos, Ras and E1A on an AP-1-responsive site. An analogous LexA-Fos zipper fusion has similar effects on transcriptional induction. The LexA-Jun zipper fusion acts further as a transformation suppressor, since it causes the generation of nontransformed revertants of ras-transformed cells. This effect is likely to be elicited by the dimerization potential of the Jun leucine zipper trapping cellular Jun and/or Fos in a protein complex unable to bind to DNA. These data implicate further that Ras-mediated transformation involves functional transcription factor AP-1 and that it is possible to interfere with cell transformation by interfering simply with the dimerization of transcription factors involved in the transformation process.
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PMID:Transformation and transactivation suppressor activity of the c-Jun leucine zipper fused to a bacterial repressor. 158 58

We present evidence that retinoic acid can down-regulate transcriptional activation by the nuclear protooncogene c-jun. All three members of the retinoic acid receptor (RAR) subfamily (RAR alpha, RAR beta, and RAR gamma) can repress transcriptional induction of the human collagenase gene or a heterologous promoter that contains the collagenase promoter AP-1-binding site. In contrast, the retinoid X receptor fails to repress Jun/AP-1 activity, demonstrating a significant difference between the two regulatory systems through which retinoids exert their transcriptional control. Analysis of RAR alpha mutants in transfection studies reveals that the DNA-binding domain is important for the inhibition of Jun/AP-1 activity, even though the RAR does not bind the collagenase AP-1 site. Rather, gel-retardation assays reveal that bacterially expressed full-length RAR alpha inhibits binding of Jun protein to target DNA. These data suggest that the RAR alpha may form a nonproductive complex with c-Jun and provides a simple mechanisms by which retinoic acid may limit cell growth and possibly malignant progression.
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PMID:Retinoic acid is a negative regulator of AP-1-responsive genes. 164 28

We present evidence that CRE-BP1 binding to the cyclic AMP (cAMP) response element (CRE) is a transcriptional activator. Transcriptional activation was assayed by cotransfection into CV-1 cells of a CRE-BP1 expression plasmid together with a reporter plasmid in which the thymidine kinase promoter and four tandem repeats of CRE were linked to the chloramphenicol acetyltransferase (CAT) gene. Cotransfection with the CRE-BP1 expression plasmid caused an 8-fold stimulation of CAT activity, while cotransfection with the plasmids to express CRE-BP1 and c-Jun induced a 32-fold stimulation of CAT activity, suggesting that a heterodimer of CRE-BP1 with c-Jun is a stronger trans-activator than a homodimer of CRE-BP1. By using a series of deletion and point mutants of CRE-BP1 in this cotransfection assay, two functional domains of CRE-BP1 were identified: the putative metal finger structure in the amino-terminal region and the leucine zipper motif linked to a cluster of basic amino acids in the carboxyl-terminal region. The former was a transcriptional activation domain in the absence of c-Jun. The latter was a DNA-binding domain, and was essential in both the presence and absence of c-Jun.
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PMID:Identification of the functional domains of the transcriptional regulator CRE-BP1. 183 93

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

The physiological significance of in vitro leucine zipper interactions was studied by the use of two strategies which detect specific protein-protein interactions in mammalian cells. Fusion genes were constructed which produce chimeric proteins containing leucine zipper domains from several proteins fused either to the DNA-binding domain of the Saccharomyces cerevisiae GAL4 protein or to the transcriptional activation domain of the herpes simplex virus VP16 protein. Previous studies in mammalian cells have demonstrated that a single chimeric polypeptide containing these two domains will activate transcription of a reporter gene present downstream of the GAL4 DNA-binding site. Similarly, if the GAL4 DNA-binding domain of a chimeric protein could be complexed through leucine zipper interactions with the VP16 activation domain of another chimeric protein, then transcriptional activation of the reporter gene would be detected. Using this strategy for detecting leucine zipper interactions, we observed homo-oligomerization between leucine zipper domains of the yeast protein GCN4 and hetero-oligomerization between leucine zipper regions from the mammalian transcriptional regulating proteins c-Jun and c-Fos. In contrast, homo-oligomerization of the leucine zipper domain from c-Myc was not detectable in cells. The inability of the c-Myc leucine zipper to homo-oligomerize strongly in cells was confirmed independently. The second strategy to detect leucine zipper interactions takes advantage of the observation that the addition of nuclear localization sequences to a cytoplasmic protein will allow the cytoplasmic protein to be transported to and retained in the nucleus. Chimeric genes encoding proteins with sequences from a cytoplasmic protein fused either to the GCN4 or c-Myc leucine zipper domains were constructed. Experiments with the c-Myc chimeric protein failed to demonstrate transport of the cytoplasmic marker protein to the nucleus in cells expressing the wild-type c-Myc protein. In contrast, the cytoplasmic marker was translocated into the nucleus when the GCN4 leucine zippers were present on both the cytoplasmic marker and a nuclear protein, presumably as a result of leucine zipper interaction. These results suggest that c-Myc function requires hetero-oligomerization to an as yet undefined factor.
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PMID:Intracellular leucine zipper interactions suggest c-Myc hetero-oligomerization. 199 Feb 93


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