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)

DNA topoisomerase II (topo II) is an essential nuclear enzyme which catalyzes the interconversions of various forms of DNA. As predicted from the human topo II cDNA, the enzyme contains a potential leucine zipper protein dimerization motif. We therefore tested whether topo II could enter protein-protein interactions with other better characterized leucine zipper-containing proteins and determined if these interactions could modify topo II enzymatic activity in vitro. By far Western analyses, a large C-terminal fragment of human topo II was shown to interact with the DNA binding and dimerization regions of either cAMP response element binding protein (CREB) or the activating transcription factor-2. The C-terminal topo II fragment also interacted with full-length c-Jun, but not with full-length c-Fos. Using CREB as a prototype, the effect of this interaction on various topo II catalytic activities was assessed in vitro. CREB, at a 1- to 10-fold molar excess relative to topo II, inhibited site-specific DNA cleavage activity on a 242-base pair fragment of the human alpha-glycoprotein hormone subunit gene promoter. Very high CREB concentrations (400-fold excess) apparently inhibited topo II DNA relaxation activity, but this result was likely a direct effect of CREB on the topology of the DNA substrate. More interestingly, a 10-fold molar excess of CREB stimulated topo II decatenation activity, the essential function of this enzyme in cell division. This stimulatory effect could also be elicited by c-Jun, which interacts with topo II, but not by c-Fos, which does not bind topo II in our in vitro assay. Since similar amounts of CREB reduced the abundance of topo II DNA cleavage products from the human alpha-CG promoter yet also stimulated decatenation activity, it can be concluded that either: 1) CREB stimulated the religation rate of topo II; or 2) CREB directed topo II to a new cleavage site present on the decatenation substrate but not present on the limited alpha-CG promoter. The structural requirements for topo II protein-protein interactions were also investigated. Site-directed mutations which destroyed the putative topo II leucine zipper did not disrupt topo II protein-protein interactions. Since the putative leucine zipper in topo II does not appear to mediate protein-protein interactions, we propose that an alternate as yet uncharacterized structure is involved in the association of topo II with itself and other regulatory proteins.
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PMID:Modification of DNA topoisomerase II activity via direct interactions with the cyclic adenosine-3',5'-monophosphate response element-binding protein and related transcription factors. 838 55

Among multiple CRE (cyclic AMP response element)-binding proteins, CRE-BP1 (also designated ATF-2) has two unique characteristics: it mediates the adenovirus E1A-induced trans-activation and forms a heterodimer with c-Jun. Two structures, a putative metal finger and a leucine zipper, in CRE-BP1 are responsible for these capacities. As a new member of a CRE-BP1 family that has similar metal finger and leucine zipper structures, we have isolated cDNA clones of CRE-BPa by cross-hybridization with CRE-BP1 cDNA. CRE-BPa protein consists of 508 amino acids and has a molecular weight of 56,840. CRE-BPa protein is highly homologous with CRE-BP1 in four regions: two of them are the regions containing the putative metal finger or the DNA-binding domain consisting of the basic amino acid cluster and the leucine zipper. Like CRE-BP1, CRE-BPa binds to CRE with higher affinity than to the 12-O-tetradecanoylphorbol-13-acetate response element as a homodimer or a CRE-BPa/c-Jun or CRE-BPa/CRE-BP1 heterodimer. However, using the c-Myb-CRE-BPa fusion protein, it was show that CRE-BPa could not mediate the E1A-induced trans-activation. Expression of CRE-BPa mRNA was found in a limited number of cell lines, and multiple sizes of CRE-BPa mRNA species were detected in some cell lines and tissues. CRE-BPa will be useful to clarify the mechanism of CRE-mediated transcriptional activation by E1A or c-Jun.
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PMID:Isolation and characterization of a novel member of the gene family encoding the cAMP response element-binding protein CRE-BP1. 844 Jul 10

Jun and Fos proteins are DNA-binding proteins that are involved in the control of gene expression through transcriptional regulation. We have made a deletion mutant of the c-jun gene that lacks amino acids 3-122 of c-jun, and thus is missing the major transactivation domain of c-jun, but retains the DNA-binding and leucine zipper domains. Unlike c-Jun, the mutant protein is unable to stimulate the transcription of an AP-1 responsive gene, and unlike c-jun this mutant gene is unable to transform rat embryo cells in cooperation with an activated ras gene. However, this mutant protein blocks in vitro DNA binding of Jun-Jun homodimers and Jun-Fos heterodimers, transcriptional activation induced by c-jun or c-fos and transformation of rat embryo cells induced by an activated ras gene and a deregulated c-jun or c-fos gene. In addition, transformation of rat embryo cells induced by an activated ras gene in the presence of the tumor promoter 12-O-tetradecanoyl phorbol 13-acetate (TPA) or by ras plus SV40 large T antigen is also inhibited by this dominant-negative mutant, suggesting that a member of the jun or fos family is involved in the pathways leading to transformation in these systems as well. The possible molecular mechanisms by which this dominant-negative mutant of c-jun blocks the functions of wild-type jun and fos family members are discussed.
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PMID:Suppression of oncogene-induced transformation by a deletion mutant of c-jun. 845 42

A new member of the ATF/CREB family of transcription factors, called B-ATF, has been isolated from a cDNA library prepared from Epstein-Barr virus stimulated human B cells. B-ATF is a 125 amino acid nuclear protein possessing a basic leucine zipper domain that is most similar to the basic leucine zipper of ATF-3. Northern blot analysis of polyadenylated mRNA isolated from a variety of human tissues and established cell lines indicates that the 1.0 kilobase B-ATF mRNA is expressed differentially, with the strongest hybridization detected in lung and in Raji Burkitt's lymphoma. Efficient homodimerization of the B-ATF protein cannot be detected using the yeast two hybrid system or using in vitro binding assays with glutathione-s-transferase-B-ATF and maltose binding protein-B-ATF fusion proteins produced in E. coli. However, a yeast two hybrid library screen has identified the human oncoprotein JunB as a specific binding partner for B-ATF. Glutathione-s-transferase-B-ATF heterodimerizes efficiently with in vitro translated JunB, c-Jun, and JunD, but only weakly associates with c-Fos. In addition, electrophoretic mobility shift assays demonstrate that a B-ATF/c-Jun protein complex can interact with DNA containing a consensus binding site for AP-1, suggesting that B-ATF functions as a tissue-specific modulator of the AP-1 transcription complex in human cells.
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PMID:B-ATF: a novel human bZIP protein that associates with members of the AP-1 transcription factor family. 857 Jan 75

High-level globin expression in erythroid precursor cells depends on the integrity of NF-E2 recognition sites, transcription factor AP-1-like protein-binding motifs, located in the upstream regulatory regions of the alpha- and beta-globin loci. The NF-E2 transcription factor, which recognizes these sites, is a heterodimer consisting of (i) p45 NF-E2 (the larger subunit), a hematopoietic-restricted basic leucine zipper protein, and (ii) a widely expressed basic leucine zipper factor, p18 NF-E2, the smaller subunit. p18 NF-E2 protein shares extensive homology with the maf protooncogene family. To determine an in vivo role for p18 NF-E2 protein we disrupted the p18 NF-E2-encoding gene by homologous recombination in murine embryonic stem cells and generated p18 NF-E2-/- mice. These mice are indistinguishable from littermates throughout all phases of development and remain healthy in adulthood. Despite the absence of expressed p18 NF-E2, DNA-binding activity with the properties of the NF-E2 heterodimer is present in fetal liver erythroid cells of p18 NF-E2-/- mice. We speculate that another member of the maf basic leucine zipper family substitutes for the p18 subunit in a complex with p45 NF-E2. Thus, p18 NF-E2 per se appears to be dispensable in vivo.
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PMID:Complexity of the erythroid transcription factor NF-E2 as revealed by gene targeting of the mouse p18 NF-E2 locus. 862 68

A novel cellular gene, SFA-2, was isolated by differential hybridization of a cDNA library, using probes obtained from an adult T-cell leukemia cell line in comparison with normal CD4+ T cells and MOLT-4 cell line. The mRNA of the SFA-2 gene is approximately 0.9-kb in size and encodes a protein of 125 amino acids, containing a basic region-leucine zipper DNA-binding domain. The N-terminal region of SFA-2 is rich in serine and contains a consensus sequence for casein kinase II phosphorylation. The SFA-2 gene was strongly expressed in mature T and B lymphocytes, and was up-regulated after transformation by human T-cell leukemia virus type I. The SFA-2 did not homodimerize efficiently but formed heterodimer preferentially with c-Jun. The SFA-2/c-Jun heterodimer bound preferentially to the AP-1 and CRE sites.
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PMID:SFA-2, a novel bZIP transcription factor induced by human T-cell leukemia virus type I, is highly expressed in mature lymphocytes. 863 63

The solution structure of the c-Jun leucine zipper domain has been determined to high resolution using a new calculation protocol designed to handle highly ambiguous sets of interproton distance restraints. The domain comprises a coiled coil of parallel alpha-helices in which most of the hydrophobic residues are buried at the highly symmetrical dimer interface; this interface extends over 10 helical turns and is the most elongated protein domain solved to date using NMR methods. The backbone fold is very similar to that seen in crystal structures of the GCN4 and Jun-Fos leucine zippers; however, in contrast with these crystal structures, the Jun leucine zipper dimer appears to be devoid of favorable intermolecular electrostatic interactions. A polar asparagine residue, located at the dimer interface, forms the sole point of asymmetry in the structure; furthermore, the side chain of this residue is disordered due to motional averaging. This residue, which is highly conserved in the leucine zipper family of transcription factors, provides a destabilizing influence that is likely to facilitate the rapid exchange of zipper strands in vivo.
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PMID:High resolution NMR solution structure of the leucine zipper domain of the c-Jun homodimer. 866 24

The backbone dynamics of the coiled-coil leucine zipper domain of c-Jun have been studied using proton-detected two-dimensional 1H-15N NMR spectroscopy. Longitudinal (T1) and transverse (T2) 15N relaxation times, together with {1H}15N NOEs, were measured and analyzed by considering the protein to approximate a prolate ellipsoid. An analysis of the T1/T2 ratios for residues in the well-structured section of the protein showed that a model for the spectral density function in which the protein is considered to reorient anisotropically fitted the data significantly better than an isotropic model. Order parameters (S2) in the range 0.7-0.9 were observed for most residues, with lower values near the C-terminus, consistent with fraying of the two helices comprising the coiled-coil. Because nearly all of the N-H vectors have small angles to the long axis of the molecule, there was some uncertainty in the value of the rotational diffusion coefficient Dpar, which describes rotation about the long axis. Thus, an alternative method was examined for its ability to provide independent estimates of Dpar and Dperp (the diffusion coefficient describing rotation about axes perpendicular to the long axis); the transitional diffusion coefficient (Dt) of the protein was measured, and hydrodynamic calculations were used to predict Dpar and Dperp. However, the derived rotational diffusion coefficients proved to be very dependent on the hydrodynamic model used to relate Dt to Dpar and Dperp, and consequently the values obtained from the T1/T2 analysis were used in the order-paramenter analysis. Although it has previously been reported that the side chain of a polar residue at the dimer interface, Asn22, undergoes a conformational exchange process and destabilizes the dimer, no evidence of increased backbone mobility in this region was detected, suggesting that this process is confined to the Asn side chain.
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PMID:Backbone dynamics of the c-Jun leucine zipper: 15N NMR relaxation studies. 866 78

c-Jun and c-Fos belong to the bZIP class of transcriptional activator proteins, many of which have been implicated in the neoplastic transformation of cells. We are interested in engineering dominant-negative leucine zipper (LZ) peptides as a means of sequestering these proteins in vivo in order to suppress their transcriptional regulatory activity. Toward this end, we have developed a novel immunoassay for measuring the dimerization affinities of dimeric Jun and Fos complexes. This peptide-based ELISA relies on the fact that Jun and Fos preferentially form heterodimers via their leucine zipper domains. Recombinant Jun leucine zipper peptides (either native JunLZ or a V36 --> E point mutant) were labeled with biotin and specifically bound through a leucine zipper interaction to a FosLZ-glutathione S-transferase fusion protein adsorbed onto the wells of an ELISA tray. Jun:Fos complexes were subsequently detected using a recently developed streptavidin-based amplification system known as enzyme complex amplification [Wilson, M. R., & Easterbrook-Smith, S.B. (1993) Anal. Biochem. 209, 183-187]. This ELISA system can detect subnanomolar concentrations of Jun and Fos, thus allowing determination of the dissociation constants for complex formation. The dissociation constant for formation of the native JunLZ:FosLZ heterodimer at 37 degrees C was determined to be 0.99 +/- 0.30 nM, while that for JunLZ(V36E):FosLZ heterodimer was 0.90 +/- 0.13 microM. These results demonstrate that the novel peptide-based ELISA described herein is simple and sensitive and can be used to rapidly screen for potential dominant-negative leucine zipper peptides.
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PMID:Development of a sensitive peptide-based immunoassay: application to detection of the Jun and Fos oncoproteins. 870 10

Marek's disease virus is a highly oncogenic herpesvirus that can cause T lymphomas and peripheral nerve demyelination in chickens. meq, a candidate oncogene of Marek's disease virus, encodes a basic leucine zipper (bZIP) transcription factor which contains a large proline-rich domain in its C terminus. On the basis of its bZIP structural homology, meq is perhaps the only member of the jun-fos gene family completely viral in origin. We previously showed that Meq's C-terminal domain has potent transactivation activity and that its bZIP domain can dimerize with itself and with c-Jun also. In an effort to identify viral and cellular targets of Meq, we have determined the optimal binding sites for Meq-Jun heterodimers and Meq-Meq homodimers. By a PCR-based approach using cyclic amplification of selected targets, Meq-Jun heterodimers were found to optimally bind tetradecanoylphorbol acetate response element (TRE) and cyclic AMP response element (CRE) consensus sequences. This result was consistent with the results of our previous functional analysis implicating Meq-Jun heterodimers in the transactivation of the Meq promoter through a TRE- or CRE-like sequence. Interestingly, Meq-Meq homodimers were found to bind two distinct motif elements. The first [GAGTGATG AC(G)TCATC] has a consensus which includes a TRE or CRE core flanked by additional nucleotides critical for tight binding. Methylation interference and mutational analyses confirmed the importance of the flanking residues. The sequences of a subset of TRE and CRE sites selected by Meq-Meq are closely related to the binding motif of Maf, another bZIP oncoprotein. The second putative Meq binding site (RACACACAY) bears a completely different consensus not shared by other bZIP proteins. Binding to this consensus sequence also requires secondary structure characteristics associated with DNA bending. CACA motifs are known to promote DNA curvature and function in a number of special biological processes. Our results lend further weight to the increasing importance of DNA bending in transcriptional regulation and provide a baseline for the identification of Meq-responsive targets.
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PMID:Novel DNA binding specificities of a putative herpesvirus bZIP oncoprotein. 879 63


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