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)

Constitutive expression of c-Fos, FosB, Fra-1, or c-Jun in rat fibroblasts leads to up-regulation of the immediate-early gene fra-1. Using the posttranslational FosER induction system, we demonstrate that this AP-1-dependent stimulation of fra-1 expression is rapid, depends on a functional DNA-binding domain of FosER, and is a general phenomenon observed in different cell types. In vitro mutagenesis and functional analysis of the rat fra-1 gene in stably transfected Rat-1A-FosER fibroblasts indicated that basal and AP-1-regulated expression of the fra-1 gene depends on regulatory sequences in the first intron which comprise a consensus AP-1 site and two AP-1-like elements. We have also investigated the transactivating and transforming properties of the Fra-1 protein to address the significance of fra-1 up-regulation. The entire Fra-1 protein fused to the DNA-binding domain of Ga14 is shown to lack any transactivation function, and yet it possesses oncogenic potential, as overexpression of Fra-1 in established rat fibroblasts results in anchorage-independent growth in vitro and tumor development in athymic mice, fra-1 is therefore not only induced by members of the Fos family, but its gene product may also contribute to cellular transformation by these proteins. Together, these data identify fra-1 as a unique member of the fos gene family which is under positive control by AP-1 activity.
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PMID:Transcriptional activation of the fra-1 gene by AP-1 is mediated by regulatory sequences in the first intron. 779 82

The closely-related proteins c-Jun, JunB and JunD form a family of transcription factors which require dimerization for DNA-binding and transcriptional activity. Dimerization is mediated by a conserved amphipathic alpha-helix located adjacent to a highly charged DNA-binding domain. The Jun proteins can form both homo- and heterodimers within the Jun family and can also cross-dimerize with the Fos proteins. When expressed at high levels in primary chicken cells, each mouse Jun displays distinct transforming capacities: c-Jun transforms efficiently, JunB transforms poorly, and JunD does not transform at all. The composition of the transforming dimers, however, is unknown. To study the activity of Jun-Jun homodimers we constructed artificial derivatives, denoted Juneb1, in which the naturally occurring dimerization domain has been replaced by an heterologous homodimerization domain from the Epstein-Barr virus transcription factor EB1. These derivatives were introduced into chicken cells and assayed for their ability to affect growth. Unexpectedly, all three Juneb1 proteins conferred a transformed phenotype to primary cultures, promoting sustained growth in low-serum medium and colony formation from single cells in agar. These data demonstrate that when forced to accumulate as homodimers, both JunB and JunD can transform cells. They also suggest that the poor transforming activity of JunB and the absence of transforming activity of JunD may be due to their inability to accumulate to high levels as homodimers.
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PMID:Increased transforming activity of JunB and JunD by introduction of an heterologous homodimerization domain. 784 74

Human proenkephalin gene transcription is transactivated by human T-cell leukemia virus type I (HTLV-I) Tax in human Jurkat T lymphocytes. This transactivation was further enhanced in Jurkat cells treated with concanavalin A, cyclic AMP, or 12-O-tetradecanoylphorbol-13-acetate. Deletion and cis-element transfer analyses of the human proenkephalin promoter identified a cyclic AMP-responsive AP-1 element (-92 to -86) as both necessary and sufficient to confer Tax-dependent transactivation. Different AP-1 or cyclic AMP-responsive element-binding protein (CREB)/activating transcription factor (ATF) proteins which bind this element were expressed in murine teratocarcinoma F9 cells to identify those capable of mediating Tax-dependent transactivation of human proenkephalin gene transcription. Although CREB, c-Fos, c-Jun, and JunD did not have significant effects, JunB inhibited the Tax-dependent transactivation. In contrast, ATF3 dramatically induced Tax-dependent transactivation, which was further enhanced by protein kinase A. Electrophoretic mobility shift assays with recombinant fusion proteins expressed and purified from bacteria indicate that the DNA-binding activity of ATF3 is also dramatically enhanced by Tax. Chimeric fusion proteins consisting of the DNA-binding domain of the yeast transcription factor Gal4 and the amino-terminal domain (residues 1 to 66) of ATF3 were able to mediate Tax-dependent transactivation of a Gal4-responsive promoter, which suggests a direct involvement of this region of ATF3. Recombinant fusion proteins of glutathione S-transferase with either the amino- or carboxy-terminal (residues 139 to 181) domain of ATF3 were able to specifically interact with Tax. Furthermore, specific antisera directed against Tax coimmunoprecipitated ATF3 only in the presence of Tax.
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PMID:Novel interactions between human T-cell leukemia virus type I Tax and activating transcription factor 3 at a cyclic AMP-responsive element. 800 91

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

The cellular c-myb gene encodes a transcription factor composed of a DNA-binding domain, a transactivating domain and a regulatory domain located at its carboxy (C-) terminus. The latter one is deleted in the transforming viral protein v-Myb. Here we show that deletion of the C-terminus of c-Myb increases the transcriptional transactivation activity of c-Myb defining it as cis-acting negative regulatory domain. Cotransfection of the C-terminus in an in vivo competition assay causes stimulation of the transcriptional activity of various v- and c-Myb expression constructs in trans. The effect is dose-dependent and independent of the kind of DNA-binding domain, since c-Myb as well as GAL4-c-Myb chimaeras can be stimulated in trans. Other transcription factors, such as GAL4-VP16, GAL4, c-Jun or C/EBP beta are also stimulated by the cotransfected C-terminus. In contrast, human B-Myb is not stimulated by the c-Myb C-terminus in trans. The data suggest that the C-terminus of c-Myb may interact with a cellular inhibitor which is part of the protein complex mediating activated transcription and may stimulate in trans by sequestering away such an inhibitor. Binding of c-Myb to a putative inhibitor would explain differences between c-Myb in comparison to B- and v-Myb in transcriptional regulation.
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PMID:The carboxyterminus of human c-myb protein stimulates activated transcription in trans. 804 7

In mammals, testis determination is under the control of the chromosome Y-linked SRY gene. Sry is expressed in the fetal mouse just before development of the testis and shows germ-cell-dependent expression in the adult mouse. SRY protein contains a high-mobility-group (HMG)-box DNA-binding domain, and potential target sequences have been identified. The fos-related antigen 1 (fra-1) gene is closely related to the protooncogene c-fos and encodes a component of transcription factor AP-1. Fra-1 is expressed during spermatogenesis, and the promoter of the rat fra-1 gene contains several potential binding sites for members of the HMG-box family of DNA-binding proteins. We demonstrate that purified SRY protein binds strongly to one of the putative fra-1 HMG-box response elements and that SRY enhances the transcription of rat fra-1 promoter constructs in cotransfection experiments. These results suggest that the function of HMG-box transcription factors may be mediated, in part, by activation of members of the AP-1 transcription factor family.
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PMID:SRY protein enhances transcription of Fos-related antigen 1 promoter constructs. 818 16

The transactivator protein of human T-lymphotropic virus type I (HTLV-I), Tax, forms multiprotein complexes with the ubiquitous transcription factor CREB and the CREB/ATF-1 heterodimer. The interaction between Tax and CREB is highly specific and results in increased binding of the Tax/CREB complexes to the HTLV-I 21-bp repeats. Despite the extensive sequence similarities between CREB and ATF-1, Tax interacts with ATF-1 only marginally. Compared with CREB, Tax/CREB exhibits greatly increased DNA recognition specificity and preferentially assembles on a consensus binding site, GGGGG(T/A)TGACG(T/C)(A/C)TA(T/C)C-CCCC, homologous to the HTLV-I 21-bp repeats. Here we report that Tax affects CREB binding to the Tax-inducible DNA elements by interacting with the basic-leucine zipper (bZip) domain of CREB. We show by domain switching that the basic region in CREB bZip can confer on c-Jun and ATF-1 leucine zippers the ability to interact with Tax in vitro. Mutational analyses further demonstrate that the amino acid residues of CREB critical for Tax/CREB interaction are Ala-Ala-Arg at positions 282-284 (AAR284), immediately upstream of the highly conserved DNA-binding domain (R/K)XX(R/K) N(R/K)XAAXX(S/C)RX(R/K)(K/R) characteristic of all bZip proteins. Specific amino acid substitutions in AAR284 of CREB weakened or abolished Tax/CREB interaction, whereas reciprocal changes in ATF-1 allowed it to interact with Tax. These results support a model in which the specific interaction between Tax and the AAR284 residues near the DNA-binding domain of CREB results in a multiprotein complex with altered DNA recognition property. This protein complex assembles selectively on the viral Tax-responsive 21-bp repeats to augment transcription.
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PMID:Expansion of CREB's DNA recognition specificity by Tax results from interaction with Ala-Ala-Arg at positions 282-284 near the conserved DNA-binding domain of CREB. 820 41

Nuclear levels of c-Jun, JunB, c-Fos, and LRF-1 (liver regeneration factor) are high for a large fraction of the G1 phase in regenerating liver and mitogen-stimulated hepatic cells. Previously, JunB was regarded as a less potent transcriptional activator than c-Jun that could also function as a repressor. However, we found that, like c-Jun, JunB alone or LRF-1/JunB strongly transactivates a cAMP-responsive promoter. Unlike c-Jun, JunB represses several AP-1 or activator of transcription factor site-containing promoters, and this inhibition is greatly enhanced in the presence of LRF-1. Here, we identify separate regions of JunB required for trans-activation and repression of these promoters. Deletion analysis shows that the region involved in trans-activation function is highly conserved among all Jun family members and corresponds to activator domain (A1) of c-Jun. In contrast, repression is maximal in the presence of both the DNA-binding domain and a region proximal to the basic region that is highly divergent among Jun proteins. Functional distinctions between Jun proteins during induction of the growth response and tumorigenesis may be accounted for by promoter-specific activation and repression mediated by regional differences in Jun family proteins.
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PMID:Promoter-specific trans-activation and inhibition mediated by JunB. 833 92

CRE-BPa, here designated as CRE-BPa alpha, is a novel member of the CRE (cAMP response element)-binding protein CRE-BP1 family. CRE-BPa alpha has four regions highly homologous to CRE-BP1, including a putative metal finger structure and a DNA-binding domain consisting of a basic amino acid cluster and a leucine zipper. CRE-BPa specifically binds to CRE as a homodimer or heterodimer with c-Jun or CRE-BP1. Here we report three alternative splicing forms of CRE-BPa alpha: two of them, CRE-BPa beta and CRE-BPa gamma, lack the N-terminal 7 and 33 amino acids of CRE-BPa alpha, and the third one CRE-BPa delta, has 16 additional amino acids in the N-terminus and amino acids 156-508 of CRE-BPa alpha. In CAT cotransfection experiments using CV-1 cells, transient expression of each of four CRE-BPa proteins caused a 1.6- to 3.4-fold increase of CRE-dependent transcription, respectively. Interestingly, these weak trans-activating capacities of CRE-BPa proteins were enhanced 2.7- to 3.6-fold by treatment of cells with 12-O-tetradecanoyl-phorbol 13-acetate (TPA). However, CRE-BPa did not affect the TPA-induced and TRE (TPA response element)-dependent transcription. These results indicate that CRE-BPa is a CRE-dependent trans-activator, and that CRE-BPa can confer TPA inducibility on CRE. Thus, CRE-BPa has an unique characteristic of cross-talk between cAMP pathway and TPA pathway.
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PMID:Regulation of trans-activating capacity of CRE-BPa by phorbol ester tumor promoter TPA. 837 84

Expression of immediate-early genes involving the 12-O-tetradecanoyl phorbol 13-acetate (TPA)-responsive element (TRE) is modulated by post-translational modification of pre-existing activator protein 1 (AP-1) constituents. One of the components of AP-1, c-Jun, has been shown to be phosphorylated by glycogen synthase kinase 3 (GSK-3) in vitro in a region proximal to the DNA-binding domain, resulting in decreased DNA binding. Here, we have used transient transfection to show that AP-1 activity is inhibitable by coexpression of GSK-3 in intact cells. Furthermore, we show that the c-Jun-related proteins JunD and JunB are subject to similar regulation by GSK-3 in intact cells. Comparison of tryptic phosphopeptide maps of the three Jun proteins incubated with GSK-3 in vitro with maps of the same proteins immunoprecipitated from 32P-labelled cells indicates similar sites of phosphorylation. Together, these data support the hypothesis that GSK-3 is an important regulator of AP-1 activity in vivo.
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PMID:Glycogen synthase kinase 3 phosphorylates Jun family members in vitro and negatively regulates their transactivating potential in intact cells. 838 54


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