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 present studies have characterized the regulation of interleukin-6 (IL-6) gene expression during pokeweed mitogen (PWM)-driven human B-cell differentiation. PWM induced an early and transient increase in the expression of immediate-early response genes of the jun/fos leucine zipper family (c-jun, jun B, c-fos, and fos-B). The induction of c-jun mRNA by PWM was concentration dependent. Nuclear run-on assays showed that PWM treatment is associated with an increased rate of c-jun gene transcription. The induction of c-jun mRNA precedes the induction of IL-6 gene expression and IL-6 secretion by the B cells. c-Jun antisense, but not sense, oligodeoxynucleotide (ODN) significantly decreases PWM-related B-cell (1) proliferation; (2) IL-6 mRNA induction; (3) IL-6 secretion; and (4) nuclear extract binding to AP-1 in electrophoretic mobility shift assay. In contrast, c-Fos anti-sense ODN did not effect either IL-6 mRNA induction or IL-6 secretion triggered in B cells by PWM. The results further show activation of c-Raf-1 kinase in PWM-treated B cells. Raf-1 acts upstream to mitogen-activated protein (MAP) kinase; therefore, studies were performed to assay for MAP kinase activation in these cells. The results show an increase in phosphorylation of myelin basic protein (MBP) and c-Jun "Y" peptide in PWM-treated B cells. Taken together, these findings suggest that PWM is able to initiate an intracytoplasmic signaling cascade in normal human splenic B cells, which, at least in part, involves serine/threonine protein kinases. These results show transient induction of immediate-early response genes in B cells and support a potential role for the c-jun gene product in regulation of IL-6 transcription and secretion.
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PMID:Identification of upstream signals regulating interleukin-6 gene expression during in vitro treatment of human B cells with pokeweed mitogen. 791 42

Chorionic gonadotropin (CG) is a heterodimeric placental hormone encoded by separate alpha and beta subunit genes that is essential for the maintenance of pregnancy. The production of CG is stimulated by DNA synthesis inhibitors and by cAMP. The present study demonstrates that the proto-oncogene c-jun represses transcription of the human CG alpha and CG beta promoters. c-Jun repressed the CG alpha promoter through a canonical cAMP response element (CRE) that is known to bind c-Jun and other members of the B-Zip transcription factor family. In the CG beta promoter, two adjacent sites, CRE1 (-299 to -289) and CRE2 (-240 to -219), conveyed cAMP responsiveness via sequences that are distinct from the canonical element, TGACGTCA. Mutations within CG beta CRE1 or CRE2 reduced or abolished, respectively, c-Jun-mediated repression. Although the CG beta CREs do not contain consensus sequences previously described to bind c-Jun, CRE2 bound c-Jun and c-Fos in electrophoretic mobility shift assays. Supershift assays, using anti-JUN antibody, demonstrated that Jun formed part of the native complex that binds the CRE2 in JEG-3 cells. A series of c-Jun mutants were used to analyze the transcription factor domains required for repression of the CG subunit promoters. The DNA binding and leucine zipper domains of c-Jun as well as the amino terminus, were required for repression of both subunit promoters. Thus, both the CG alpha and CG beta genes are repressed by c-Jun through promoter regions that convey cAMP-induced transcription, although these DNA sequences are unrelated.
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PMID:c-Jun represses transcription of the human chorionic gonadotropin alpha and beta genes through distinct types of CREs. 798 49

The AP-1 transcriptional activating complex, made up of Jun and Fos protein, is involved in controlling many cellular processes such as cell proliferation, differentiation and transformation. We have previously characterized a dominant-negative mutant of c-Jun called TAM-67 which forms dimers with c-Jun and c-Fos, and binds DNA as a homodimer or heterodimer with c-Jun or c-Fos. This dominant-negative mutant is a potent inhibitor of AP-1 mediated transactivation, as well as c-jun/ras and TPA/ras-induced transformation. The present report describes experiments designed to elucidate the exact molecular mechanism of this dominant-negative inhibitor. The DNA binding kinetics of both TAM-67:TAM-67 homodimers as well as TAM-67:Fos heterodimers were studied and compared to those of c-Jun and other transactivation-deficient mutants of c-Jun. These studies demonstrated that the TAM-67 proteins have similar DNA binding kinetics to c-Jun and other Jun mutant proteins. Thus, the deletion of the amino-terminal end of the Jun protein does not significantly alter the protein's affinity for DNA. In addition, to determine whether TAM-67 functions through the formation of homodimers, or through interactions with endogenous c-Jun or c-Fos, we constructed a pair of chimeric proteins made by replacing the leucine zipper of TAM-67 with the leucine zippers of GCN4 and c-Fos. These chimeric proteins, termed TAM/GCN4 and TAM/Fos, were then tested for their ability to bind DNA, inhibit c-Jun-induced transactivation, and inhibit TPA/ras-mediated transformation. The results of these studies show that while both chimeric proteins bind equally well to DNA, only the TAM/Fos protein, and not the TAM/GCN4 protein, inhibits AP-1-induced transactivation and TPA/ras-induced transformation. When compared to the TAM-67 protein, the TAM/Fos protein is an equally potent inhibitor of transactivation and transformation. These results suggest that TAM-67 inhibits AP-1-mediated processes through a 'quenching' mechanism by inhibiting the function of endogenous Jun and/or Fos proteins. The implications of these mechanistic findings on the development of potent inhibitors of signal transduction pathways are discussed.
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PMID:Mechanism of action of a dominant-negative mutant of c-Jun. 810 21

Association of the human c-Jun and c-Fos proteins depends upon interactions involving their leucine zipper domains. We are interested in elucidating the tertiary structure of the Jun and Fos leucine zipper domains with a view to understanding the precise intermolecular interactions which govern the affinity and specificity of interaction in these proteins, which have the unusual capacity to form either homodimeric or heterodimeric zipper pairs. With this goal in mind, we have developed a bacterial expression system for the efficient production of both unlabelled and isotopically labelled c-Jun leucine zipper domain. A synthetic junLZ gene was created by annealing, ligation, and polymerase-chain-reaction amplification of overlapping synthetic oligonucleotides which comprised 132 bp of coding sequence encompassing residues Arg276-Asn314 of c-Jun plus a total of five engineered non-native residues at the N- and C-termini. The junLZ gene was cloned into the pGEX-2T vector from which recombinant c-Jun leucine zipper domain (rJunLZ; 46 residues, 5.1 kDa) was overexpressed (approximately 15% total cell protein) in Escherichia coli as a fusion protein of 31.4 kDa, consisting of rJunLZ fused to the carboxy-terminal portion of Schistosoma japonicum glutathione S-transferase. Two markedly different expression strategies have been devised which allow purification of rJunLZ from the soluble or inclusion-body fraction of induced cells. We have used these strategies to produce unlabelled and uniformly 15N-labelled rJunLZ for NMR studies which, in combination with circular dichroic measurements, reveal that rJunLZ most likely forms a symmetric coiled-coil of parallel alpha-helices. We also present 15N-NMR chemical shift assignments for the backbone and sidechain amide nitrogens of rJunLZ, which should assist in determination of a high-resolution structure of the homodimeric Jun leucine zipper using heteronuclear three-dimensional NMR spectroscopy.
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PMID:Cloning, expression, and spectroscopic studies of the Jun leucine zipper domain. 811 39

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

The product of the c-myb proto-oncogene, c-Myb, binds DNA and can enhance transcription of genes bearing copies of the DNA sequence it recognises. Deletion or disruption of a negative regulatory domain (NRD) in the carboxyl portion of c-Myb results in enhanced transactivating capacity and in parallel, leads to activation of its ability to transform haemopoietic cells. Since mutational analysis has shown that one critical element within the NRD is a leucine zipper motif, we have sought to identify cellular proteins that can interact with the c-Myb leucine zipper. Using fusion proteins containing this region as an affinity reagent, we have identified two nuclear proteins, p67 and p160, that bind to the wild-type, but not to a mutated c-Myb leucine zipper. These two proteins were shown to be related by comparison of peptides generated by partial digestion. While p160 was found to be ubiquitous amongst different murine haemopoietic cell lines, and was also present in NIH3T3 fibroblasts, p67 was detected in a restricted set of immature myeloid cells. Intriguingly p160, but not p67, could also bind to the c-Jun leucine zipper.
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PMID:Detection of proteins that bind to the leucine zipper motif of c-Myb. 830 94

The high mobility group protein HMG I(Y) and the transcription factor NF-kappa B are required for the activity of positive regulatory domain II (PRDII), a virus-inducible regulatory element of the human interferon-beta gene promoter. In this paper we provide evidence that HMG I(Y) is also required for the activity of PRDIV, a regulatory element that synergizes with PRDII. In this case, HMG I(Y) stimulates binding of activating transcription factor 2 (ATF-2) and the assembly of inducible complexes containing ATF-2 and c-Jun. Remarkably, HMG I(Y) also specifically interacts with the leucine zipper/basic region of ATF-2, and ATF-2 in turn interacts with NF-kappa B. We therefore propose that the HMG I(Y) plays a critical structural role in establishing transcriptional synergy between PRDII and PRDIV by promoting the activities and/or binding of NF-kappa B and ATF-2 and by facilitating their interaction.
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PMID:Mechanisms of transcriptional synergism between distinct virus-inducible enhancer elements. 837 55

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

The Epstein-Barr virus BZLF1 gene product EB1 (also called ZEBRA and Zta), is a transcription factor belonging to the bZIP (basic domain leucine zipper) family of nuclear proteins. Translocation to the nucleus of EB1 (J. Becker, U. Leser, M. Marschall, A. Langford, W. Jilg, H. Gelderblom, P. Reichart, and H. Wolf, Proc. Natl. Acad. Sci. USA 88:8332-8336, 1991) and of two other bZIP proteins, c-Jun and c-Fos (P. Roux, J.-M. Blanchard, A. Fernandez, N. Lamb, P. Jeanteur, and M. Piechaczyk, Cell 63:341-351, 1990), has been shown to be subject to regulation. We show here that for both EB1 and Jun the nuclear targeting signals (NTS) in the proteins' primary sequences are two clusters of positively charged amino acids. These clusters, called BRA and BRB, are necessary and sufficient to direct beta-galactosidase to the nuclear compartment and act as a bipartite NTS. They are conserved among all the bZIP proteins, and although they are not identical, they probably share the same function. Site-directed mutagenesis studies made on these basic clusters suggest that they also act as a bipartite NTS in the EB1 protein. Our results also demonstrate that in EB1 and Jun, these bipartite NTS are superimposed with bipartite DNA-binding domains, since BRA and BRB are required in vitro for direct and specific contact between these proteins and their DNA-binding sites.
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PMID:The DNA-binding domain of two bZIP transcription factors, the Epstein-Barr virus switch gene product EB1 and Jun, is a bipartite nuclear targeting sequence. 838 Apr 64

JunB differs considerably from c-Jun in its ability to activate AP-1-responsive genes and induce oncogenic transformation. We demonstrate that the decreased ability of JunB to activate gene expression is the result of a small number of amino acid changes between its DNA-binding and dimerization motifs and the corresponding regions of c-Jun. These changes lead to a 10-fold decrease in the DNA-binding activity of JunB. JunB can be converted into a c-Jun-like activator by substituting four amino acids in its DNA-binding and dimerization motifs with the corresponding c-Jun sequences. JunB can also attenuate trans-activation by c-Jun, an activity mediated by its leucine zipper. This ability depends on two glycine residues that decrease the stability of the JunB leucine zipper, resulting in decreased homodimerization and increased heterodimerization. These results illustrate how small changes in primary structure, including chemically conservative changes, can result in functional divergence of two highly related transcriptional regulators.
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PMID:JunB differs from c-Jun in its DNA-binding and dimerization domains, and represses c-Jun by formation of inactive heterodimers. 838 24


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