Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tissue factor (TF) is a transmembrane glycoprotein that mediates cellular initiation of the coagulation serine protease cascades. Moreover, expression of TF in human atherosclerotic plaques is likely to play a significant role in the thrombotic complications associated with plaque rupture. In this study the complete murine TF gene, Cf-3, was isolated from mouse NIH 3T3 cells and was found to consist of six exons spanning about 11 kilobase pairs (kbp) of DNA. A major transcriptional start site was located 24 bp downstream of a TATA box. Cf-3 was mapped to chromosome 3 by analysis of an intersubspecies test cross. Conserved transcription factor-binding sites were identified by comparison of 5' flanking regions of the murine and human TF genes. A region of the TF promoter required for constitutive expression exhibited 85% identity in DNA sequence and included two conserved binding sites for Sp1. Furthermore, two AP-1 sites and an NF-kappa B site were conserved in a 56-bp region necessary for transcriptional activation in response to bacterial lipopolysaccharide. These highly conserved regions of the TF promoter, which contain several binding sites for well-characterized transcription factors, are likely to be functionally important in the complex pattern of TF gene expression observed in a variety of cell types.
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PMID:Structure of the murine tissue factor gene. Chromosome location and conservation of regulatory elements in the promoter. 134 27

We investigated the molecular basis of the synergistic induction by interferon-gamma (IFN-gamma)/tumor necrosis factor-alpha (TNF-alpha) of human interleukin-6 (IL-6) gene in THP-1 monocytic cells, and compared it with the basis of this induction by lipopolysaccharide (LPS). Functional studies with IL-6 promoter demonstrated that three regions are the targets of the IFN-gamma and/or TNF-alpha action, whereas only one of these regions seemed to be implicated in LPS activation. The three regions concerned are: 1) a region between -73 and -36, which is the minimal element inducible by LPS or TNF-alpha; 2) an element located between -181 and -73, which appeared to regulate the response to IFN-gamma and TNF-alpha negatively; and 3) a distal element upstream of -224, which was inducible by IFN-gamma alone. LPS signaling was found to involve NF kappa B activation by the p50/p65 heterodimers. Synergistic induction of the IL-6 gene by IFN-gamma and TNF-alpha, in monocytic cells, involved cooperation between the IRF-1 and NF kappa B p65 homodimers with concomitant removal of the negative effect of the retinoblastoma control element present in the IL-6 promoter. This removal occurred by activation of the constitutive Sp1 factor, whose increased binding activity and phosphorylation were mediated by IFN-gamma.
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PMID:Triggering of the human interleukin-6 gene by interferon-gamma and tumor necrosis factor-alpha in monocytic cells involves cooperation between interferon regulatory factor-1, NF kappa B, and Sp1 transcription factors. 749 67

Transcription of the vascular cell adhesion molecule-1 (VCAM-1) gene in endothelial cells is induced by the inflammatory cytokines interleukin-1 beta, tumor necrosis factor-alpha, and lipopolysaccharide. Previous studies demonstrated that the cytokine-response region in the VCAM1 promoter contains binding sites for the transcription factors nuclear factor-kappa B (NF-kappa B) and interferon regulatory factor-1. Using a saturation mutagenesis approach, we report that the cytokine-inducible enhancer consists of these previously characterized elements and a novel region located 3' of the NF-kappa B sites. Electrophoretic mobility shift assays and DNase I footprint studies with endothelial nuclear extracts and recombinant protein revealed that the transcriptional activator Sp1 interacts with this novel element in a specific manner. Transient transfection assays using vascular endothelial cells revealed that site-directed mutations in the Sp1 binding element decreased tumor necrosis factor-alpha-induced activity of the VCAM1 promoter. The cytokine-induced enhancer of the VCAM1 gene requires constitutively bound Sp1 and induced heterodimeric NF-kappa B for maximal promoter activity.
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PMID:Sp1 is a component of the cytokine-inducible enhancer in the promoter of vascular cell adhesion molecule-1. 749 19

Human TNF-stimulated gene 14 (TSG-14) encodes a secreted 42-kDa glycoprotein that shows significant homology to proteins of the pentraxin family, which includes the acute phase reactants C-reactive protein and serum amyloid P component. Levels of TSG-14 protein (also termed PTX-3) become elevated in the serum of mice and humans after injection with bacterial lipopolysaccharide, but in contrast to conventional acute phase proteins, the bulk of TSG-14 synthesis in the intact organism occurs outside the liver. In the present study we cloned and partially sequenced murine genomic TSG-14 DNA. Analysis of the coding region predicts a high degree of amino acid sequence homology between murine and human TSG-14 (88 and 75% identity in the first and second exons, respectively). The promoter of the TSG-14 gene lacks consensus sequences for either a TATA box or CCAAT box. Primer extension analysis and S1 nuclease protection assay revealed one major transcription start site, situated within a consensus sequence for an initiator element. Sequence analysis of a approximately 1.4-kilobase pair fragment of the 5'-flanking region of the TSG-14 gene revealed the presence of numerous potential enhancer binding elements, including six NF-IL6-like sites, four AP-1, one AP-2, one NF-kB, two Sp1, two interferon-gamma-activated sites (GAS), one Hox-1.3, and five binding sites for Ets family members. Transfection of BALB/c 3T3 cells with promoter DNA fragments linked to the luciferase reporter gene revealed that the 5'-flanking region of the TSG-14 gene comprises elements that can mediate a basal level of transcription and inducibility by TNF.
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PMID:Promoter structure and transcriptional activation of the murine TSG-14 gene encoding a tumor necrosis factor/interleukin-1-inducible pentraxin protein. 759 30

AGP/EBP (C/EBP beta) is a key transcription factor responsible for transcriptional induction of many acute-phase protein genes. To characterize the regulation of this gene, we have isolated the mouse genomic DNA and sequenced the 5'-regulatory region. Using nuclear extracts from lipopolysaccharide (LPS)-stimulated or unstimulated mouse liver, three protein factor-binding motifs, UF1(-376 to -352), UF2(-254 to -223), and UF3(-220 to -190), as well as two Sp1 motifs (-309 to -277, and -264 to -241) were identified by DNase I footprinting assays. Biochemical analysis has shown that the AGP/EBP protein can bind to UF1 and UF2 sites, whereas an ubiquitous factor of unknown identity can bind to the UF3 site. Functional characterizations indicate that all of these factors play a major role in AGP/EBP induction. Thus, the agp/ebp gene is autoregulated during the acute-phase response.
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PMID:Autoregulated induction of the acute-phase response transcription factor gene, agp/ebp. 759 8

The tissue factor (TF) gene is expressed in a cell type-specific manner in vivo. It is constitutively expressed by several extravascular cell types and inducibly expressed within the vasculature by monocytes and endothelial cells. TF expression initiates thrombotic episodes associated with various diseases, including atherosclerosis, septic shock, and cancer. Regulatory elements within the human TF promoter have been identified by functional analysis of TF promoter-luciferase gene plasmids transiently transfected into various cell types. Transcription factors that control expression of the TF gene were identified using gel shift mobility assays. Induction of the TF gene in human monocytic cells and endothelial cells exposed to bacterial lipopolysaccharide or cytokines is mediated by a distal enhancer (-227 to -172 bp) containing two AP-1 sites and a kappa B site. Functional interactions between Fos-Jun heterodimers and c-Rel-p65 heterodimers are required for transcriptional activation of the TF gene. In contrast, serum and phorbol ester induction of the TF gene in human epithelial cells is controlled by a proximal enhancer (-111 to +14 bp) containing three overlapping Egr-1/Sp1 binding sites. Sp1 is constitutively expressed whereas Egr-1 expression is induced by serum or phorbol ester stimulation. Sp1 also mediates basal promoter activity. Thus, TF gene expression is complex and is regulated by a number of transcription factors that bind to distinct regions of the TF promoter.
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PMID:Regulation of the tissue factor gene. 761 58

Simple tandem repeats of the trinucleotide sequence CAG encode homopolymeric stretches of glutamine. Although polyglutamine has been identified in diverse proteins, it is present predominantly in transcription factors. We observed that oncogene-immortalized mouse macrophages express several genes that contain a CAG repeat motif. Therefore, we attempted to clone a novel gene that contains a CAG repeat and is associated with cytokine activation of macrophages. Screening of a mouse macrophage cDNA library with a probe comprising 12 consecutive CAG triplets identified at least one unique clone. The cDNA encodes a protein (named GRP-1 or glutamine repeat protein-1) with 171 amino acids, a calculated molecular mass of 21.6 kDa, and a predicted pI of 10.67. Greater than two-thirds of GRP-1 are only two amino acids, namely glutamine (50%) and histidine (18%). There are four polyglutamine motifs interspersed with histidine-rich regions. There is also a putative nuclear localization signal flanked by sites for possible serine phosphorylation. GRP-1 mRNA was expressed constitutively in some macrophage cell lines and B and T cell lines. Interferon-gamma or lipopolysaccharide augmented GRP-1 mRNA expression in the mouse macrophage cell line ANA-1. Western blot analyses using an antipeptide serum revealed that GRP-1 was localized in the nucleus of ANA-1 macrophages and transfected 3T3 fibroblasts. Overexpression of GRP-1 decreased Sp1-driven chloramphenicol acetyltransferase gene expression in transient cotransfection experiments. Because polyglutamine motifs can cause protein oligomerization and can function as transcriptional activation domains, we suggest that GRP-1 may be a transcription factor associated with interferon-gamma- or lipopolysaccharide-induced activation of macrophages.
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PMID:Molecular cloning and characterization of a novel mouse macrophage gene that encodes a nuclear protein comprising polyglutamine repeats and interspersing histidines. 881 Mar 23

Tissue factor (TF) expression by peripheral blood monocytes during sepsis initiates intravascular thrombosis. Bacterial lipopolysaccharide (LPS) rapidly induces TF gene transcription in monocytes. The human TF promoter contains binding sites for the transcription factors AP-1, c-Rel/p65, Egr-1, and Sp1. NF-kappa B/Rel proteins have been shown to physically interact with both AP-1 and Sp1 proteins. In this study, we investigated the role of these transcription factors in uninduced and LPS-induced TF gene expression in human monocytic THP-1 cells. Deletional analysis indicated that five Sp1 sites mediated basal expression in uninduced cells. The two AP-1 sites bound c-Fos/c-Jun heterodimers in both unstimulated and LPS-stimulated cells. Maximal LPS induction of the TF promoter required the two AP-1 sites and the kappa B site within the LPS response element. Disruption of the conserved spacing between the proximal AP-1 site and the kappa B site abolished LPS induction. Replacement of the two AP-1 sites with intrinsically bent DNA partially restored LPS induction, suggesting an additional structural role for the AP-1 sites. Synergistic transactivation of the LPS response element in Drosophila Schneider cells by coexpression of c-Fos, c-Jun, c-Rel, and p65 or c-Jun and p65 required the transactivation domains of c-Jun and p65. These data indicated that c-Fos/c-Jun, c-Rel/p65, and Sp1 regulate TF gene expression in human monocytic cells.
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PMID:Regulation of the tissue factor gene in human monocytic cells. Role of AP-1, NF-kappa B/Rel, and Sp1 proteins in uninduced and lipopolysaccharide-induced expression. 908 93

Biosynthesis of tumor necrosis factor-alpha (TNF-alpha) is predominantly by cells of the monocytic lineage. This study examined the role of various cis-acting regulatory elements in the lipopolysaccharide (LPS) induction of the human TNF-alpha promoter in cells of monocytic lineage. Functional analysis of monocytic THP-1 cells transfected with plasmids containing various lengths of TNF-alpha promoter localized enhancer elements in a region (-182 to -37 base pairs (bp)) that were required for optimal transcription of the TNF-alpha gene in response to LPS. Two regions were identified: region I (-182 to -162 bp) contained an overlapping Sp1/Egr-1 site, and region II (-119 to -88) contained CRE and NF-kappaB (designated kappaB3) sites. In unstimulated THP-1, CRE-binding protein and, to a lesser extent, c-Jun complexes were found to bind to the CRE site. LPS stimulation increased the binding of c-Jun-containing complexes. In addition, LPS stimulation induced the binding of cognate nuclear factors to the Egr-1 and kappaB3 sites, which were identified as Egr-1 and p50/p65, respectively. The CRE and kappaB3 sites in region II together conferred strong LPS responsiveness to a heterologous promoter, whereas individually they failed to provide transcriptional activation. Furthermore, increasing the spacing between the CRE and the kappaB3 sites completely abolished LPS induction, suggesting a cooperative interaction between c-Jun complexes and p50/p65. These studies indicate that maximal LPS induction of the TNF-alpha promoter is mediated by concerted participation of at least two separate cis-acting regulatory elements.
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PMID:Lipopolysaccharide induction of the tumor necrosis factor-alpha promoter in human monocytic cells. Regulation by Egr-1, c-Jun, and NF-kappaB transcription factors. 921 33

The nuclear factor-kappaB (NF-kappaB) family of transcription factors have been implicated in the inducible expression of genes involved in inflammatory and immune responses. As such, a specific inhibitor of NF-kappaB would be a useful therapeutic agent in a variety of inflammatory disorders. The marine natural product hymenialdisine was evaluated as an inhibitor of NF-kappaB in U937 cells. U937 cells were transfected with either a luciferase reporter plasmid containing the human immunodeficiency virus long terminal repeat or the interleukin-8 (IL-8) core promoter, both of which are activated by NF-kappaB. Hymenialdisine caused a concentration-dependent decrease in luciferase production from both reporters when the cells were stimulated with tumor necrosis factor-alpha, lipopolysaccharide or phorbol myristate acetate. An electrophoretic mobility shift assay confirmed its activity by inhibiting DNA binding of NF-kappaB. Hymenialdisine was shown to be a selective inhibitor of NF-kappaB in that it had no effect on the binding of other transcription factors to their DNA concensus motifs; these included activator protein-1, CCAAT/enhancer binding protein and Sp1. Functional studies showed hymenialdisine to be an inhibitor of IL-8 production and IL-8 mRNA formation in the U937 cell. Investigation into the mechanism of action of hymenialdisine showed that it was not due to inhibition of protein kinase C because the selective protein kinase C inhibitor RO 32-0432 was inactive against tumor necrosis factor-alpha-stimulated luciferase and IL-8 production. The compound also had no effect on IkappaB alpha or IkappaB beta phosphorylation and degradation. Thus, hymenialdisine is a potent inhibitor of NF-kappaB and IL-8 production in U937 cells.
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PMID:The natural product hymenialdisine inhibits interleukin-8 production in U937 cells by inhibition of nuclear factor-kappaB. 922 88


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