Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P05412 (c-Jun)
 11,453 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

U937 promonocytic cells, either treated or untreated with phorbol-esters, were used for transient expression assays. We analyzed a series of visna LTR plasmids containing either the AP-1 or the AP-4 or both target responsive sequences for visna Tat transactivation. A 5' deletion mutant of the LTR containing a truncated AP-4 target sequence lost the Tat-mediated transactivation, while phorbol ester-mediated transactivation was not affected. Furthermore, the absence of this AP-4 sequence dramatically decreased the additive effect observed when U937 cells were both treated by phorbol ester and expressed the tat gene product, suggesting a high interdependence of the AP-1 and AP-4 sequences for the regulation of the transcription driven by the visna LTR. The c-Jun/AP-1 factor was a prerequisite for the modulation of the activity of the LTR since no Tat-mediated transactivation was found when transfection experiments were carried out in F9 teratocarcinoma cells which are deficient for AP-1 activity. Because the Tat product enhanced the transcription of the visna LTR via the AP-1 site, we asked whether this viral factor could regulate the expression of cellular factors involved in one of the cellular activation pathways. Northern analysis of U937 cells clearly indicated that visna Tat promoted the c-jun mRNA expression, in contrast to the c-fos mRNA expression. Next, we examined nuclear extracts prepared at various times after infection of permissive ovine cells with visna virus, and showed an increased level in the c-Jun DNA binding activity. These data indicated that viral infection can induce a cellular activation pathway in permissive cells.
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PMID:The visna transcriptional activator Tat: effects on the viral LTR and on cellular genes. 821 59

Interactions between the glucocorticoid receptor (GR) and c-Jun/c-Jun homodimer (JUN) on the promoter DNA of mouse mammary tumor virus-long terminal repeat (MMTV-LTR) are reported here using the electrophoretic mobility shift assay (EMSA). Both GR and JUN are capable of independently binding to their respective response elements, including glucocorticoid response element (GRE) and phorbol ester response element (TRE), on MMTV-LTR promoter. The protein-DNA complex, assembled by pre-incubating JUN and DNA before the addition of GR, migrates slower (supershift) on gel electrophoresis than do the complexes formed by the other orders of addition. The formation of the supershifted complex is GR and JUN dose-dependent. The supershift is not detected with the cleaved fragments of MMTV-LTR promoter that separate GRE from TRE, indicating that the integrity of the promoter and possibly the spacing between GRE and TRE are important. The interaction of GR and JUN on the MMTV-LTR promoter appears to be more complex than simple protein-protein interaction.
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PMID:Assembly of glucocorticoid receptor and c-JUN homodimer on the promoter of mouse mammary tumor virus-long terminal repeat is influenced by order of addition. 828 Jan 42

In the human promonocytic U937 cell line, pyrrolidine dithiocarbamate (PDTC) was a potent inhibitor of the nuclear factor-kappaB (NF-kappaB) signalling pathway induced by the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA). However, PDTC did not inhibit tumour necrosis factor-alpha (TNF-alpha)-induced NF-kappaB DNA binding activity but potentiated the effect of TNF-alpha on kappaB-dependent gene expression. The stimulatory effect of PDTC with TNF-alpha was not observed with an HIV-1 LTR reporter construct containing two mutated kappaB binding sites or with a construct with a mutation of the activating protein (AP)-2 binding site located between the two kappaB elements. Two distinct signalling pathways, one mediated by TPA and the other by TNF-alpha, were shown to interact, functionally defining a threshold important in the inhibitory or stimulatory effect of PDTC on kappaB-dependent gene expression. Evidence that PDTC induced AP-1 DNA binding and AP-1 reporter gene activity, raised the hypothesis that the effect of PDTC was mediated by an interaction between the AP-1 pathway and p65(RelA). Co-transfection with expression vectors for p65(RelA) and the AP-1 subunits c-Fos and c-Jun resulted in a decrease in the stimulatory effect of PDTC on HIV-1 LTR activity. Co-transfection of p65(RelA) with Tam67, a dominant negative mutant of c-Jun defective in transactivation, stimulated the effect of PDTC on HIV-1 LTR activity. Evidence that the stimulatory effect of Tam67 with PDTC was reduced with c-Jun is consistent with the hypothesis.
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PMID:Dual activity of pyrrolidine dithiocarbamate on kappaB-dependent gene expression in U937 cells: II. Regulation by tumour necrosis factor-alpha. 1037 11

To study the role of MAPK cascades in the regulation of naturally occurring human immunodeficiency virus type 1 long terminal repeats (HIV-1 LTRs), we analyzed several HIV-1 LTRs from patients at different stages of disease progression. One of these naturally occurring HIV-1 LTRs contains an insertion termed the most frequent naturally occurring length polymorphism (MFNLP) and exhibited high inducibility upon T cell activation. We found that the protein kinase mixed lineage kinase 3/src-homology 3 domain-containing proline-rich kinase, a specific activator of the stress-activated protein kinase (SAPK)/JNK signaling pathway in T lymphocytes, induces high transcriptional activation of this promoter. Promoter inducibility is inhibited by the SAPK/JNK inhibitor, the JNK binding domain of the JNK interacting protein 1, and Tam-67 (N-terminal deletion mutant of c-Jun). In electrophoretic mobility shift assay, several protein complexes were found to bind to the MFNLP sequence in T cells. We identified AP-1 factors c-Fos and JunB as MFNLP-binding proteins, whose binding is abolished by introducing point mutations in the 3'-half of the MFNLP sequence. Introduction of these point mutations into the MFNLP containing HIV-1 LTR reduced src-homology 3 domain-containing proline-rich kinase -mediated transactivation. These data indicate that the AP-1-like binding site in the MFNLP sequence gives rise to a higher inducibility of natural HIV-LTRs by the SAPK/JNK signaling pathway.
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PMID:Transactivation of naturally occurring HIV-1 long terminal repeats by the JNK signaling pathway. The most frequent naturally occurring length polymorphism sequence introduces a novel binding site for AP-1 factors. 1076 60

The X protein of hepatitis B virus or HBx is a multifunctional regulatory protein that carries the fame of a promiscuous transactivator. Although, the N-terminal 'A' region of HBx (amino acids 1-20) is the most conserved region among mammalian hepadnavirus genomes, it has been found to be dispensable for transactivation function [Proc. Natl. Acad. Sci. U.S.A. 93, 1996, 5647]. To elucidate its biological role, DNA sequence corresponding to the A region of X gene was amplified by polymerase chain reaction and cloned as a 72 base pair HBx mutant X17. In order to augment the intracellular biochemical stability of the expressed protein, the monomeric X17 was multimerized and 2-10 units long tandem repeats of the A region (X17-n) were cloned in a mammalian expression vector. Expression of the X17 constructs was confirmed by in vitro transcription and translation, as well as by RT-PCR after transfection in hepatoma cells. The function of X17 was investigated using the chloramphenicol acetyl transferase reporter constructs of viral (RSV-LTR, HIV1-LTR and HBx) and cellular gene promoters (c-Jun and epidermal growth receptor). Not only did the X17 multimers inhibit the HBx-mediated transactivation of all the reporter genes, but also their basal activities. The inhibition was dependent on the amount of X17 plasmid transfected in cells as well as on the number of repeat units present in the X17 expression vectors. Further, the X17-related inhibition of transactivation was not a cytotoxic effect. Thus, our data suggests that the N-terminal 'A' domain of HBx has a negative regulatory function.
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PMID:The conserved amino-terminal region (amino acids 1-20) of the hepatitis B virus X protein shows a transrepression function. 1535 89

Mild doses of oxidative stress in the heart correlate with the induction of apoptosis or hypertrophy in cardiomyocytes (CMCs) and fibrosis or proliferation of fibroblasts. Three branches of mitogen-activated protein kinases (MAPKs), i.e., c-Jun N-terminal kinases (JNKs), extracellular signal-related kinases 1 and 2 (ERK1/2), and p38, are activated by oxidants in a variety of cell types, including CMCs. However, the initiation process of these signaling pathways remains unsolved. We explored the role of the epidermal growth factor (EGF) receptor in H(2)O(2)-induced MAPK activation using two different cell types from the same organ: CMCs and heart fibroblasts (HFs). Pretreatment of each cell type with EGF revealed differences in how CMCs and HFs responded to subsequent treatment with H(2)O(2): in CMCs, the second treatment resulted in little further activation of JNKs and ERK1/2, whereas HFs retained the full response of JNKs and ERK1/2 activation by H(2)O(2) regardless of EGF pretreatment. AG-1478 [4-(3'-chloroanilino)-6,7-dimethoxy-quinazoline], a pharmacologic inhibitor of the EGF receptor tyrosine kinase, inhibited JNK and ERK1/2 activations but not p38 in both cell types. The data using the Src inhibitor PP2 [4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine] resemble those found when using AG-1478 in either cell type. Pharmacologic inhibitors of matrix metalloproteinases (MMPs) further illustrated the difference between the two cell types. In HFs, MMP inhibitors GM6001 [N-[(2R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl]-l-tryptophan methylamide] and BB2516 [[2S-[N4(R(*)),2R(*),3S(*)]]-N4-[2,2-dimethyl-1-[(methylamino)carbonyl]propyl]-N1,2-dihydroxy-3-(2-methylpropyl)butanediamide, marimastat] inhibited JNKs and ERK1/2 activation without affecting p38 activation by H(2)O(2) inhibitors. In contrast, these MMP failed to significantly inhibit the activation of JNKs, ERKs, or p38 in CMCs. These data suggest the complexity of the cell type-dependent signaling web initiated by oxidants in the heart.
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PMID:Epidermal growth factor receptor-dependent and -independent pathways in hydrogen peroxide-induced mitogen-activated protein kinase activation in cardiomyocytes and heart fibroblasts. 1557 83

Tetrahydrobiopterin is an essential cofactor for the phenylalanine, tyrosine and tryptophan hydroxylases, and the family of nitric oxide synthases. The initial and rate-limiting enzyme in the biosynthesis of tetrahydrobiopterin is GTP cyclohydrolase I. The proximal promoter of the human GTP cyclohydrolase I gene contains the sequence motif 5'-TGACGCGA-3', resembling a cAMP response element (CRE). The objective of this study was to analyze the regulation of GTP cyclohydrolase I gene transcription by basic region leucine zipper (bZIP) transcription factors. A constitutively active mutant of the cAMP response element binding (CREB) protein strongly stimulated GTP cyclohydrolase I promoter activity, indicating that the CRE in the context of the GTP cyclohydrolase I gene is functional. Likewise, GTP cyclohydrolase I promoter/luciferase gene transcription was stimulated following nuclear expression of the catalytic subunit of cAMP-dependent protein kinase. Constitutively active mutants of activating transcription factor 2 (ATF2) and c-Jun additionally stimulated GTP cyclohydrolase I promoter activity, but to a lesser extent than the constitutively active CREB mutant. The fact that stress-activated protein kinases target the GTP cyclohydrolase I gene was corroborated by expression experiments involving p38 and MEKK1 protein kinases. We conclude that signaling pathways involving either the cAMP-dependent protein kinase or stress-activated protein kinases converge to the GTP cyclohydrolase I gene. Hence, enzymatic reactions that require tetrahydrobiopterin as cofactor are therefore indirectly controlled by signaling cascades involving the signal-responsive transcription factors CREB, c-Jun, and ATF2.
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PMID:Regulation of GTP cyclohydrolase I gene transcription by basic region leucine zipper transcription factors. 1614 46

Human immunodeficiency virus type 1 (HIV-1) Tat affects cellular gene expression through modulation of the activity of different transcription factors. Here, the role of Tat in the cooperation between nuclear factor of activated T cells (NFAT) and activator protein 1 (AP-1) transcription factors was investigated. Constitutive or transient Tat expression in Jurkat T cells enhanced cooperative NFAT/AP-1- but not AP-1-dependent transcription independent of its ability to transactivate the HIV-1 LTR. The enhancing effect of Tat took place after nuclear translocation of NFAT. Furthermore, transactivation of an NFAT/AP-1 reporter by transfection of NFAT and c-Jun was strongly enhanced by simultaneous Tat transfection. Moreover, intracellular Tat expression increased the binding of NFAT/AP-1 complexes to the interleukin 2 promoter without significantly altering NFAT- and AP-1-independent binding. HIV-1 Tat interacted with NFAT but not c-Jun. These results indicate that Tat interacts with NFAT, affecting its cooperation with AP-1, without altering independent binding of these transcription factors to DNA.
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PMID:Human immunodeficiency virus type 1 Tat increases cooperation between AP-1 and NFAT transcription factors in T cells. 1669 Sep 25

Inflammation-induced activation of the tryptophan catabolizing enzyme indoleamine 2,3-dioxygenase (IDO) causes depressive-like behavior in mice following acute activation of the innate immune system by lipopolysaccharide (LPS). Here we investigated the mechanism of IDO expression induced by LPS in primary cultures of microglia derived from neonatal C57BL/6J mice. LPS (10 ng/ml) induced IDO transcripts that peaked at 8h and enzymatic activity at 24h, resulting in an increase in extracellular kynurenine, the catabolic product of IDO-induced tryptophan catabolism. This IDO induction by LPS was accompanied by synthesis and secretion of the proinflammatory cytokines TNFalpha and IL-6, but without detectable IFNgamma expression. To explore the mechanism of LPS-induced IDO expression, microglia were pretreated with the c-Jun-N-terminal kinase (JNK) inhibitor SP600125 for 30 min before LPS treatment. We found that SP600125 blocked JNK phosphorylation and significantly decreased IDO expression induced by LPS, which was accompanied by a reduction of LPS-induced expression of TNFalpha and IL-6. Collectively, these data extend to microglia the property that LPS induces IDO expression via an IFNgamma-independent mechanism that depends upon activation of JNK. Inhibition of the JNK pathway may provide a new therapy for inflammatory depression.
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PMID:LPS-induced indoleamine 2,3-dioxygenase is regulated in an interferon-gamma-independent manner by a JNK signaling pathway in primary murine microglia. 1957 30

Investigation of the nucleotide sequence of the HIV-1 LTR showed the presence of four novel short DNA regions which are homologous to the recognition site for the cellular transcription factor AP-1. Four short oligonucleotide hybrids containing these potential AP-1 sites were constructed and used in gel retardation assays and in competition experiments in order to determine the role of the AP-L protein in the regulation of HIV-1 expression. The breast MDA MB 468 and cervical HeLa turner cell lines, which are known to overexpress the AP-1 protein were used in a gel retardation assay as a control to study the affinity of the AP-1 to synthesized oligonucleotide sequences. We have observed specific binding of nuclear factor AP-1 to three of these oligonucleotide hybrids. These results demonstrate the presence of three novel AP-1 binding sites on HIV-1 LTR, one of which was found within the TAR element and in the Tat protein binding region. Moreover, they suggest that AP-1 could be contributing to HIV-1 transcriptional regulation through its interaction with the AP-1 binding sites of HIV-1 LTR.
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PMID:Ap-1 recognizes sequence elements on hiv-1 LTR in human epithelial tumor-cell lines. 2160 73


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