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)

CD40 is a member of the tumor necrosis factor receptor superfamily and is a key signaling molecule expressed by antigen-presenting cells of the immune system. In a previous paper, we demonstrated that the expression of CD40 is regulated by both post-transcriptional and post-translational processes. In this paper, we show that basal (constitutive) CD40 gene expression is regulated by a TATA-less promoter, with Sp1 as a key transcription factor. Two Sp1 binding regions were identified in the mouse CD40 promoter at positions -59 to -50 and -74 to -66. Surprisingly, Sp1-mediated CD40 transcription was reduced following lipopolysaccharide stimulation and was associated with a time-dependent reduction in Sp1 DNA binding activity. This reduction seemed to be mediated by phosphorylation of the Sp1 molecule. We also show here that CD40 expression in lipopolysaccharide-stimulated cells is up-regulated by NF-kappaB through two distinct sites. One of these sites (-128 to -119) was shown to bind p50 and p65 members of the NF-kappaB family, while the other site (-562 to -553) bound only p65. Transfectants of p65 were generated using RAW 264 cells, and it was shown that the up-regulation of CD40 mRNA expression was dependent on the presence of the p65 molecule.
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PMID:The role of Sp1 and NF-kappa B in regulating CD40 gene expression. 1175 10

We examined the in vivo effect of lipopolysaccharide (LPS) on Sp1 (promoter-selective transcription factor 1) DNA binding activity and studied the mechanisms involved in mouse lungs. The Sp1 DNA complex displayed a major band composed of Sp1, Sp2, and Sp3 trimer and a minor band composed of Sp3 homodimer. Compared with control, nuclear proteins from lungs challenged with LPS for 60, 90, 120, 150, 180, and 240 min, respectively, showed a markedly reduced Sp1 binding activity. Down-regulation of Sp1 binding activity was accompanied by a reduced expression of two Sp1-dependent genes (endothelial nitric oxide synthase and cyclooxygenase-1). Immunoprecipitation-Western blot experiments demonstrated that LPS dephosphorylated Sp1 protein at serine and threonine residues but not at the tyrosine residue. Dephosphorylation of Sp1 protein in vitro significantly reduced Sp1 DNA binding activity. Deglycosylation of Sp1 protein also reduced Sp1 binding activity. However, LPS did not cause Sp1 deglycosylation. LPS markedly reduced nuclear Sp1 protein level but had no significant effect on Sp1 mRNA abundance and on Sp1 protein nuclear translocation. Both Sp1 protein dephosphorylation and Sp1 protein degradation are temporally correlated to the reduced Sp1 binding activity. Our results demonstrate that challenge of mice with LPS in vivo down-regulates Sp1 DNA binding activity through promoting Sp1 protein dephosphorylation and degradation.
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PMID:Lipopolysaccharide down-regulates Sp1 binding activity by promoting Sp1 protein dephosphorylation and degradation. 1208 57

Serum response factor (SRF) is a transcription factor, which binds to a serum response element (SRE) associated with a variety of genes including immediate early genes such as c-fos, fosB, junB, egr-1 and -2, neuronal genes such as nurr1 and nur77 and muscle genes such as actins and myosins. By regulating expression of these genes, SRF controls cell growth and differentiation, neuronal transmission as well as muscle development and function. SRF can be activated by a variety of agents, including serum, lysophosphatidic acid (LPA), lipopolysaccharide (LPS), 12-O-tetradecanoylphorbol-13-acetate (TPA), cytokines, tumor necrosis factor-alpha (TNFalpha), agents that increase intracellular Ca2+, T-cell virus1 activator protein, hepatitis B virus activator proteins pX, activated oncogenes and protooncogenes as well as extracellular stimuli such as antioxidant and UV light. SRF itself is regulated by both cellular signal transduction pathways and interaction with other transcription factors e.g. Sp1, ATF6 and myogenic regulatory factors. Its biological function is best elucidated for myocardium. Specific cardiac SRF transgenesis demonstrated that overexpression of SRF caused hypertrophic cardiomyopathy in mouse and the mouse died of heart failure within 6 months after birth. Other transgenic data suggested that sufficient SRF was needed for embryogenesis and early development. Since SRF is important regulator of numerous genes involved in cell growth and differentiation, including muscle and neural components, SRF may also play a crucial role in tissue injury and ulcer healing, e.g. healing of gastrointestinal ulcers.
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PMID:Serum response factor: discovery, biochemistry, biological roles and implications for tissue injury healing. 1212 Aug 92

The expression of CD14, a monocyte receptor for the bacterial lipopolysaccharide (LPS), is upregulated during monocytic cell differentiation. Although a Sp1 site at -110bp of the CD14 promoter was shown to be critical for activation of the promoter during the differentiation, how the Sp1 site is regulated has not been well understood. We have recently reported that expression of MEF2D protein increases during the differentiation of HL60 promyeloid cells to monocyte and that the upregulation of the protein is required for CD14 expression during the differentiation [Mol. Immunol. 36 (1999) 1209]. However, there is no obvious MEF2 binding site in the critical region of the CD14 promoter. In this study, which aimed to determine the regulatory role of MEF2D in monocytic cell differentiation, MEF2D was found to form a complex with Sp1 in U937 promyeloid cells. Transient transfection experiments showed that co-expression of MEF2D and Sp1 synergistically activated the CD14 promoter. The results support a model in which increased MEF2D protein during monocytic cell differentiation activates the CD14 promoter through interaction with Sp1.
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PMID:Synergistic interaction of MEF2D and Sp1 in activation of the CD14 promoter. 1221 24

Interleukin (IL)-4, IL-10, and IL-13 affect monocyte/macrophage functions including regulation of cytokine production. We analyzed the regulatory effects of these cytokines on cytokine production using a human monoblastic cell line, UG3. It is interesting that IL-10 up-regulated, whereas IL-4 and IL-13 down-regulated monocyte chemoattractant protein-1 (MCP-1) production by unstimulated UG3 cells. IL-10-induced expression of MCP-1 mRNA occurred without de novo protein synthesis at transcriptional and post-transcriptional levels. The enhancement of binding activity of nuclear factor Sp1 (Sp-1) and signal transducer and activators of transcription (STAT)1 and 3 but not nuclear factor kappaB (NF-kappaB) was associated with this IL-10-induced MCP-1 expression. Furthermore, IL-10 suppressed lipopolysaccharide (LPS)-induced NF-kappaB binding but not Sp-1. The present results suggest IL-10 has two contrasting actions on the MCP-1 production of monocytes/macrophages, between the resting and activated conditions. The combination of activated Sp-1 and STATs is important for IL-10-induced MCP-1 expression in resting monocytes/macrophages, and the inhibition of LPS-induced NF-kappaB binding is crucial for down-regulation of MCP-1 by IL-10 in stimulated monocytes/macrophages.
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PMID:Interleukin-10 differently regulates monocyte chemoattractant protein-1 gene expression depending on the environment in a human monoblastic cell line, UG3. 1248 2

To get insight into the regulation of human interleukin-12 (IL-12) synthesis, we determined the chromatin organization of the IL-12(p35) promoter region. First, we determined positioning of nucleosomes within the IL-12(p35) promoter using the indirect end-labeling technique in the THP-1 monocytic cell line. On stimulation with bacterial lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma), hypersensitivity to digestion with DNase I, micrococcal nuclease, and specific restriction enzymes was detected in the region encompassing nucleotide (nt) -310 to -160, indicating selective inducible chromatin remodeling involving disruption of a single nucleosome (named nuc-2). Using p35 promoter deletion mutants and reporter gene assays, we demonstrated that the -396/-241 region contained critical cis-acting elements. Within this latter region, we characterized physically and functionally 2 Sp1-binding sites, which were acting as key regulatory elements for both basal and LPS/IFN-gamma-inducible p35 gene expression: Sp1#1 lies within the remodeled nuc-2 region and Sp1#2 is located in the nucleosome-free region immediately upstream of nuc-2. Finally, we extended the chromatin structure analysis to dendritic cells (DCs) derived from human monocytes and observed the same nucleosomal organization and remodeling as in the THP-1 cell line. Moreover, we found that in DCs, LPS and IFN-gamma synergized in the induction of nucleosomal remodeling and that chromatin remodeling at the p35 locus immediately preceded IL-12(p35) mRNA synthesis. Taken together, our results demonstrate that IL-12(p35) gene activation in the course of DC maturation involves selective and rapid remodeling of a single positioned nucleosome within a region of the promoter containing critical Sp1-binding sites.
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PMID:Human IL-12(p35) gene activation involves selective remodeling of a single nucleosome within a region of the promoter containing critical Sp1-binding sites. 1257 36

RAW 264.7 macrophages express nonmuscle myosin heavy chain II-A as the only significant nonmuscle myosin heavy chain isoform, with expression of nonmuscle myosin heavy chain II-B and II-C low or absent. Treatment of the cells with sodium butyrate, an inhibitor of histone deacetylase, led to the dose-dependent induction of nonmuscle myosin heavy chain II-C. Trichostatin A, another inhibitor of histone deacetylase, also induced nonmuscle myosin heavy chain II-C. Induction of nonmuscle myosin heavy chain II-C in response to these histone deacetylase inhibitors was attenuated by mithramycin, an inhibitor of Sp1 binding to GC-rich DNA sequences. Bacterial lipopolysaccharide alone had no effect on basal nonmuscle myosin heavy chain II-C expression, but attenuated butyrate-mediated induction of nonmuscle myosin heavy chain II-C. The effects of lipopolysaccharide were mimicked by the nitric oxide donors sodium nitroprusside and spermine NONOate, suggesting a role for nitric oxide in the lipopolysaccharide-mediated down-regulation of nonmuscle myosin heavy chain II-C induction. This was supported by experiments with the inducible nitric-oxide synthase inhibitor 1400W, which partially blocked the lipopolysaccharide-mediated attenuation of nonmuscle myosin heavy chain induction. 8-Bromo-cGMP had no effect on nonmuscle myosin heavy chain induction, consistent with a cGMP-independent mechanism for nitric oxide-mediated inhibition of nonmuscle myosin heavy chain II-C induction.
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PMID:Induction of nonmuscle myosin heavy chain II-C by butyrate in RAW 264.7 mouse macrophages. 1259 34

Bacterial lipopolysaccharide (LPS) elicits inflammation and endotoxic shock by inducing proinflammatory cytokine gene expression. The purpose of this study was to test the hypothesis that differential activation of transcription factor binding in the spleen correlates with proinflammatory cytokine gene expression in mice exposed to LPS. When proinflammatory cytokine expression in spleen was evaluated in mice injected ip with 4 mg/kg LPS over an 8-h period, tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta, and IL-6 mRNAs were elevated up to 5-, 6-, and 300-fold, respectively, over vehicle controls. Both TNF- alpha and IL-6 mRNA peaked at 2 h and begin to decline thereafter, whereas IL-1beta mRNA remained elevated from 2 to 8 h. The capacities of splenic nuclear proteins to bind to six different consensus transcriptional control motifs associated with proinflammatory cytokine promoters were also measured over 8 h. Electrophoretic mobility shift assay (EMSA) revealed that binding activity was markedly increased at 0.5 to 8 h for activator protein-1 (AP-1) as were CCAAT enhancer-binding protein (C/EBP) and nuclear factor kappaB (NF-kappaB) at 0.5 to 1.5 h. At 0.5 h, cyclic AMP response element (CRE)-binding protein (CREB) and binding was slightly elevated, whereas activator protein- 2 (AP-2) and specificity protein 1 (Sp1) binding were not affected. Antibody supershift EMSA and Western blot analysis confirmed that increased binding of these factors correlated with LPS-induced increases in nuclear concentrations of AP-1 (c-Jun, phosphorylated c-Jun, Jun D, and Jun B), C/EBPbeta, NF-kappaB (p50, p65, and c-Rel), CREB (CREB-1, CREB-2, and ATF-2), and AP-2alpha proteins. Remarkably, after 8 h, C/EBP, CREB, AP-2, and Sp1 binding activities were greatly depleted relative to both naive and corresponding vehicle controls. When mice were exposed to a second dose of LPS, 8 h after a 4 mg/kg priming dose, TNF-alpha and IL-6 mRNA responses were markedly impaired, suggesting that the mice were endotoxin tolerant at this time point. Taken together, the quiescent, active, and suppressive phases of transcription factor binding observed in this model were highly consistent with the rapid transient nature of LPS-induced proinflammatory cytokine expression in vivo as well as tolerance to secondary LPS exposure.
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PMID:Kinetics of lipopolysaccharide-induced transcription factor activation/inactivation and relation to proinflammatory gene expression in the murine spleen. 1266 98

Murine Nramp1 encodes a divalent cation transporter that is expressed in late endosomes/lysosomes of macrophages, and the transported cations facilitate intracellular pathogen growth control. The Nramp1 promoter is TATA box-deficient, has two initiator elements, and is repressed by c-Myc, in accordance with the notion that genes that deplete the iron content of the cell cytosol antagonize cell growth. Repression via c-Myc occurs at the initiator elements, whereas a c-Myc-interacting protein (Miz-1) stimulates transcription. Here we demonstrate that a non-canonical E box (CAACTG) inhibits basal promoter activity and activation by Miz-1. A consensus Sp1-binding site or GC box is also necessary for Miz-1-dependent transactivation, but not repression. Repression occurs by c-Myc competing with p300/CBP for binding Miz-1. Our results show that an Sp1 site mutant inhibits coactivation by p300 and that the murine Nramp1 promoter is preferentially expressed within macrophages (relative to a beta-actin control) compared with non-macrophage cells. The effect of the Sp1 site mutation on promoter function shows cell-type specificity: stimulation in COS-1 and inhibition in RAW264.7 cells. Miz-1-directed RNA interference confirms a stimulatory role for Miz-1 in Nramp1 promoter function. c-Myc, Miz-1, and Sp1 were identified as binding to the Nramp1 core promoter in control cells and following acute stimulation with interferon-gamma and lipopolysaccharide. These results provide a description of sites that modulate the activity of the initiator-binding protein Miz-1 and indicate a stimulatory role for GC box-binding factors in macrophages and a inhibitory role for E box elements in proliferating cells.
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PMID:Characterization of the murine Nramp1 promoter: requirements for transactivation by Miz-1. 1284 21

We recently showed that angiotensin (ANG) II as well as mechanical stretch stimulated production of tumor necrosis factor (TNF) in cardiac fibroblasts. Presently, we examined the molecular mechanisms by which ANGII and lipopolysaccharide (LPS) upregulate TNF-alpha gene expression. In neonatal rat cardiac fibroblasts, increased transcription of TNF-alpha mRNA was detected as luciferase activity associated with activity of the TNF-alpha promoter. Progressive deletion from this promoter located the LPS-responsive region between -200 and -120 bp from the transcription initiation site, while the sequence between -120 and -70 bp was required for ANGII-induced expression. Next, we examined which cis-acting sequences in the TNF-alpha promoter region were essential for induction of TNF-alpha transcription. Competition analysis by electrophoretic mobility shift assay with and without specific antibodies showed that LPS increased binding of Sp1 and Sp3 to the Sp1-binding site, while Egr-1 was unimportant. With ANGII, binding of ATF-2/c-jun to the CRE site was required for TNF-alpha gene induction; neither Ets nor NF-kappaB was essential. Mutation analysis confirmed that response to LPS relied upon the Sp1 site in the TNF-alpha promoter, while the CRE-binding site was essential for stimulation by ANGII. We concluded that since TNF-alpha gene expression is transcriptionally activated by ANGII or LPS in cardiac fibroblasts via different cis-acting sequences in the TNF-alpha promoter and different transcriptional factors, mechanisms inducing TNF production differ between heart failure or cardiac hypertrophy and infectious disease.
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PMID:Regulation of the human tumor necrosis factor-alpha promoter by angiotensin II and lipopolysaccharide in cardiac fibroblasts: different cis-acting promoter sequences and transcriptional factors. 1451 26


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