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

The origins of DNA replication (ori) in simian virus 40 (SV40) and polyomavirus (Py) contain an auxiliary component (aux-2) composed of multiple transcription factor binding sites. To determine whether this component stimulated replication by binding specific transcription factors, aux-2 was replaced by synthetic oligonucleotides that bound a single transcription factor. Sp1 and T-antigen (T-ag) sites, which exist in the natural SV40 aux-2 sequence, provided approximately 75 and approximately 20%, respectively, of aux-2 activity when transfected into monkey cells. In cell extracts, only T-ag sites were active. AP1 binding sites could replace completely either SV40 or Py aux-2. Mutations that eliminated AP1 binding also eliminated AP1 stimulation of replication. Yeast GAL4 binding sites that strongly stimulated transcription in the presence of GAL4 proteins failed to stimulate SV40 DNA replication, although they did partially replace Py aux-2. Stimulation required the presence of proteins consisting of the GAL4 DNA binding domain fused to specific activation domains such as VP16 or c-Jun. These data demonstrate a clear role for transcription factors with specific activation domains in activating both SV40 and Py ori. However, no correlation was observed between the ability of specific proteins to stimulate promoter activity and their ability to stimulate origin activity. We propose that only transcription factors whose specific activation domains can interact with the T-ag initiation complex can stimulate SV40 and Py ori-core activity.
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PMID:Specific transcription factors stimulate simian virus 40 and polyomavirus origins of DNA replication. 131 5

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 ability of the c-Jun protein, the main component of the transcription factor AP1, to interact directly or indirectly with the RNA polymerase II-initiation complex to activate transcription was investigated by in vivo transcription interference ("squelching") experiments. Coexpression of a Jun mutant lacking its DNA binding domain strongly represses the activity of wild-type c-Jun. Repression depends on the presence of the transactivation domains (TADs), suggesting that a limiting factor interacting with the TADs is essential to link Jun and the components of the transcriptional machinery. The activity of this intermediary factor(s) is restricted to TADs characterized by an abundance of negatively charged amino acids, as demonstrated by the abilities of the TADs of JunB, GAL4, and VP16 to repress c-Jun activity. Depending on the presence of the TADs of Jun, we found physical interaction between Jun and a cluster of three proteins with molecular masses of 52, 53, and 54 kDa (p52/54). Association between Jun and p52/54 is strongly reduced in the presence of VP16, suggesting that the two proteins compete for binding to p52/54. Transcription factors containing a different type of TAD (e.g., GHF1, estrogen receptor, or serum response factor) fail to inhibit Jun activity, suggesting that these proteins act through a different mechanism. We consider the requirement of Jun to interact with p52/54 utilized by other transcription factors a new mechanism in the regulation of transcription of Jun-dependent target genes.
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PMID:A common intermediary factor (p52/54) recognizing "acidic blob"-type domains is required for transcriptional activation by the Jun proteins. 144 82

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

The AP-1 family of transcription factors, which includes the proto-oncogene products c-Jun and c-Fos, controls the stimulation of cellular genes by growth factors and the expression of oncogenes, including src and ras. Transcriptional activation by c-Jun is regulated by a cell-type-specific inhibitor that represses the activity of a transcriptional activation domain (A1) of c-Jun by operating through the adjacent negative regulatory region (delta). Here we show that cotransfection of the src or ras oncogene enhances the transcriptional activity of a GAL4:c-Jun hybrid that includes the delta-A1 region of c-Jun, suggesting that the DNA binding and dimerization domain of c-Jun is not required for stimulation by Src or Ras. Moreover, induction of c-Jun activity by Src and Ras occurs in cell lines containing the c-Jun inhibitor but not in a cell line lacking it. The region in c-Jun essential for the stimulatory action of these oncogenes maps to domain A1. These findings suggest the existence of signal-transduction pathways that result in an increase in transcriptional activity of c-Jun and AP-1 by disrupting the c-Jun:inhibitor interaction.
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PMID:v-Src and EJ Ras alleviate repression of c-Jun by a cell-specific inhibitor. 190 40

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

Using rigorous statistical methods, we have identified and evaluated unusual properties of the distribution of charged residues within the sequences of eukaryotic cellular transcription factors. Virtually all transcription factors, including GAL4, c-Jun, C/EBP, CREB, Oct-1, Oct-2, Sp1, Egr-1, CTF-1, steroid and thyroid hormone receptors, and others, carry one or more highly significant charge clusters. For the most part these clusters (conserved within families of homologous proteins) are of positive net charge but contain also substantial numbers of acidic residues. Predominantly basic charge clusters are often, but not exclusively, associated with DNA-binding domains, and vice versa. Negative charge clusters of note occur only in the yeast protein PHO4 and in the proteins encoded at the Drosophila loci zeste (zeta) and knrl. This dearth of statistically significant negative charge clusters raises questions with respect to the generality of acidic activation domains. A number of sequences (Oct-1, Oct-2, zeste, Dhr23, E75, and knrl) contain multiple charge clusters together with one or more significantly long uncharged regions. The occurrence of multiple charge clusters is a rare phenomenon (found in less than 3% of all proteins, mainly in Drosophila developmental control proteins and in transactivators of eukaryotic DNA viruses). Most of the proteins with zinc-binding "fingers" carry a mixed charge cluster centered at the zinc-finger motif preceded by a long uncharged stretch, suggestive of a modular structure for these proteins.
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PMID:Association of charge clusters with functional domains of cellular transcription factors. 256 37

The adenovirus early region 3 (E3) promoter is an early viral promoter which is strongly induced by the adenovirus transactivator protein E1A. DNase I footprinting with HeLa cell extracts has identified four factor-binding domains which appear to be involved in basal and E1A-induced transcriptional regulation. These binding domains may bind TATA region-binding factors (site I), the CREB/ATF protein (site II), the AP-1 protein (site III), and nuclear factor I/CTF (site IV). Recently, it has been shown that the DNA-binding domain of transcription factor AP-1 has homology with the yeast transcription factor GCN4 and that the yeast transactivator protein GAL4 is able to stimulate transcription in HeLa cells from promoters containing GAL4-binding sites. These results suggest an evolutionary conservation of both transcription factors and the mechanisms responsible for transcriptional activation in Saccharomyces cerevisiae and higher eucaryotic organisms. To determine whether similar patterns of transcriptional regulation were seen with the E3 promoter in HeLa and yeast cells, the E3 promoter fused to the chloramphenicol acetyltransferase (cat) gene was cloned into a high-copy-number plasmid and stably introduced into yeast cells. S1 analysis revealed that similar E3 promoter mRNA start sites were found in yeast and HeLa cells. DNase I footprinting with partially purified yeast extracts revealed that four regions of the E3 promoter were protected. Several of these regions were similar to binding sites determined by using HeLa cell extracts. Oligonucleotide mutagenesis of these binding domains indicated their importance in the transcriptional regulation of the E3 promoter in yeast cells. These results suggest that similar cellular transcription factor-binding sites may be involved in the regulation of promoters in both yeast and mammalian cells.
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PMID:Adenovirus transcriptional regulatory regions are conserved in mammalian cells and Saccharomyces cerevisiae. 297 53

The P-450 side chain cleavage (CYP11A1) gene encodes the enzyme that catalyzes the initial step in steroid biosynthesis, resulting in the conversion of cholesterol to pregnenolone. Expression of the CYP11A1 gene is increased by hormones, such as adrenocorticotropin and luteinizing hormone, as well as by a number of growth factors, suggesting that its promoter may contain regulatory elements that respond to multiple signal transduction pathways. Using transient expression assays of the ovine CYP11A1 promoter in JEG-3 placental cells, distinct regulatory elements were found to mediate transcriptional stimulation by cAMP and epidermal growth factor (EGF). The cAMP response was mediated through a GC-rich sequence localized between -117 and -92. In contrast, EGF induced CYP11A1 transcription through an adjacent but distinct sequence (-92 to -77 base pairs) that was shown previously to bind nuclear proteins in DNase I footprinting reactions. This EGF-responsive element (EGF-RE) resembles an activator protein-1 (AP-1) site and was also required for transactivation by co-transfected c-Jun. A point mutation within the EGF-RE impaired stimulation by both EGF and c-Jun, suggesting that these pathways converge on a common regulatory element. Transfer of single or multiple copies of the EGF-RE upstream of an heterologous promotor conferrd EGF and c-Jun responses, providing further evidence that this element is sufficient for both responses. Transfection studies employing mutant c-Jun proteins confirmed a requirement for its DNA binding, leucine zipper and amino-terminal domains, each of which are required for activation of a classical AP-1 reporter. Gel shift studies demonstrated that protein binding to the CYP11A1 EGF-RE was competed specifically by a canonical AP-1 site, and the addition of an anti-JUN antibody confirmed the presence of AP-1 proteins. Consistent with the possibility that EGF may act in part via c-Jun, EGF stimulated the activity of a chimeric GAL4 c-Jun protein, indicating that JUN can serve as a potential target of EGF in JEG-3 cells. EGF also induced mitogen-activated protein kinase activity, and a dominant negative mutant of mitogen-activated protein kinase partially blocked EGF stimulation of GAL4 c-Jun activity. We conclude that EGF stimulates the CYP11A1 promoter through an AP-1 like element and that c-Jun is one of the targets of EGF action.
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PMID:Epidermal growth factor and c-Jun act via a common DNA regulatory element to stimulate transcription of the ovine P-450 cholesterol side chain cleavage (CYP11A1) promoter. 762 50


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