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

The peroxisome proliferator-activated receptor gamma (PPARgamma) is a member of the nuclear receptor superfamily that activates target gene transcription in a ligand-dependent manner. In addition, liganded PPARgamma can inhibit transcription of genes induced by gamma interferon (IFN-gamma) and/or lipopolysaccharides (LPSs), including the inducible nitric oxide synthase (iNOS) gene. Inhibition of the iNOS promoter is achieved partially through antagonizing the activities of NF-kappaB, AP-1, and STAT1, which are known to mediate effects of LPS and IFN-gamma. Previous studies have suggested that transrepression of these factors by nuclear receptors involves competition for limiting amounts of the general coactivators CREB-binding protein (CBP) and p300. CBP and p300 are thought to be recruited to nuclear receptors through bridging factors that include SRC-1, although CBP also interacts directly with PPARgamma through its amino terminus. These observations have raised questions concerning the involvement of SRC-1-like factors in CBP recruitment and transrepression. We here provide evidence that PPARgamma's ability to repress iNOS transcription requires the ligand-dependent charge clamp that mediates interactions with CBP and SRC-1. Single amino acid mutations in PPARgamma that abolished ligand-dependent interactions with SRC-1 and CBP not only resulted in complete loss of transactivation activity but also abolished transrepression. Conversely, a CBP deletion mutant containing the SRC-1 interaction domain but lacking the N-terminal PPARgamma interaction domain was inactive as a PPARgamma coactivator and failed to rescue transrepression. Together, these findings are consistent with a model in which transrepression by PPARgamma is achieved by targeting CBP through direct interaction with its N-terminal domain and via SRC-1-like bridge factors.
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PMID:Peroxisome proliferator-activated receptor gamma-dependent repression of the inducible nitric oxide synthase gene. 1084 96

The tumor necrosis factor alpha (TNF-alpha) gene is rapidly activated by lipopolysaccharide (LPS). Here, we show that extracellular signal-regulated kinase (ERK) kinase activity but not calcineurin phosphatase activity is required for LPS-stimulated TNF-alpha gene expression. In LPS-stimulated macrophages, the ERK substrates Ets and Elk-1 bind to the TNF-alpha promoter in vivo. Strikingly, Ets and Elk-1 bind to two TNF-alpha nuclear factor of activated T cells (NFAT)-binding sites, which are required for calcineurin and NFAT-dependent TNF-alpha gene expression in lymphocytes. The transcription factors ATF-2, c-jun, Egr-1, and Sp1 are also inducibly recruited to the TNF-alpha promoter in vivo, and the binding sites for each of these activators are required for LPS-stimulated TNF-alpha gene expression. Furthermore, assembly of the LPS-stimulated TNF-alpha enhancer complex is dependent upon the coactivator proteins CREB binding protein and p300. The finding that a distinct set of transcription factors associates with a fixed set of binding sites on the TNF-alpha promoter in response to LPS stimulation lends new insights into the mechanisms by which complex patterns of gene regulation are achieved.
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PMID:A lipopolysaccharide-specific enhancer complex involving Ets, Elk-1, Sp1, and CREB binding protein and p300 is recruited to the tumor necrosis factor alpha promoter in vivo. 1091 90

Activated macrophages are critical cellular participants in inflammatory disease states. Transforming growth factor (TGF)-beta1 is a growth factor with pleiotropic effects including inhibition of immune cell activation. Although the pathway of gene activation by TGF-beta1 via Smad proteins has recently been elucidated, suppression of gene expression by TGF-beta1 remains poorly understood. We found that of Smad1-Smad7, Smad3 alone was able to inhibit expression of markers of macrophage activation (inducible nitric-oxide synthase and matrix metalloproteinase-12) following lipopolysaccharide treatment in gene reporter assays. Transient and constitutive overexpression of a dominant negative Smad3 opposed the inhibitory effect of TGF-beta1. Domain swapping experiments suggest that both the Smad MH-1 and MH-2 domains are required for inhibition. Mutation of a critical amino acid residue required for DNA binding in the MH-1 of Smad3 (R74A) resulted in the loss of inhibition. Transient overexpression of p300, an interactor of the Smad MH-2 domain, partially alleviated the inhibition by TGF-beta1/Smad3, suggesting that inhibition of gene expression may be due to increased competition for limiting amounts of this coactivator. Our results have implications for the understanding of gene suppression by TGF-beta1 and for the regulation of activated macrophages by TGF-beta1.
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PMID:Transforming growth factor-beta 1 inhibition of macrophage activation is mediated via Smad3. 1097 58

The proto-oncogene c-myb is essential for a controlled balance between cell growth and differentiation. Aberrant c-Myb activity has been reported for numerous human cancers, and enforced c-Myb transcription can transform cells of lymphoid origin by stimulating cellular proliferation and inhibiting apoptotic pathways. Here we demonstrate that activation of the NF-kappaB pathway by the HTLV-1 Tax protein leads to transcriptional inactivation of c-Myb. This conclusion was supported by the fact that Tax mutants unable to stimulate the NF-kappaB pathway could not inhibit c-Myb transactivating functions. In addition, inhibition of Tax-mediated NF-kappaB activation by coexpression of IkappaBalpha restored c-Myb transcription, and Tax was unable to block c-Myb transcription in a NEMO knockout cell line. Importantly, physiological stimuli, such as signaling with the cellular cytokines tumor necrosis factor alpha, interleukin 1 beta (IL-1beta), and lipopolysaccharide, also inhibited c-Myb transcription. These results uncover a new link between extracellular signaling and c-Myb-dependent transcription. The mechanism underlying NF-kappaB-mediated repression was identified as sequestration of the coactivators CBP/p300 by RelA. Interestingly, an amino-terminal deletion form of p300 lacking the C/H1 and KIX domains and unable to bind RelA retained the ability to stimulate c-Myb transcription and prevented NF-kappaB-mediated repression.
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PMID:Human T-cell lymphotropic virus type 1 Tax represses c-Myb-dependent transcription through activation of the NF-kappaB pathway and modulation of coactivator usage. 1158 20

Bisphenol A diglycidyl ether (BADGE) is a newly described peroxisome proliferator-activated receptor gamma (PPARgamma) antagonist in adipogenic cells. In contrast, in the macrophage-like cell line RAW 264.7, BADGE, like the PPARgamma agonist pioglitazone hydrochloride, not only increased promoter activity of the PPARgamma-luciferase reporter gene, but also suppressed lipopolysaccharide (LPS)-induced tumor necrosis factor-alpha (TNF-alpha) production. These results suggest that BADGE is a PPARgamma agonist in RAW 264.7 cells. Furthermore, overexpression of the coactivator p300 restored BADGE- or pioglitazone hydrochloride-suppressed promoter activity of the nuclear factor-kappa B (NF-kappaB)-luciferase reporter gene, suggesting that PPARgamma may interfere with NF-kappaB transcriptional activity via coactivator competition.
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PMID:Bisphenol a diglycidyl ether (BADGE) suppresses tumor necrosis factor-alpha production as a PPARgamma agonist in the murine macrophage-like cell line, RAW 264.7. 1199 51

Estrogens have been suggested to modulate several inflammatory processes. Here, we show that IL-1beta treatment induced the expression of approximately 75 genes in the liver of ovariectomized mice. 17alpha-Ethinyl estradiol (EE) pretreatment reduced the IL-1beta induction of approximately one third of these genes. Estrogen receptor alpha (ERalpha) was required for this inhibitory activity, because EE inhibition of IL-1beta-stimulated gene expression occurred in ERbeta knockout mice, but not in ERalpha knockout mice. EE treatment induced expression of 40 genes, including the transcriptional repressor short heterodimer partner and prostaglandin D synthase, known modulators of nuclear factor-kappaB signaling. However, the ER agonists genistein and raloxifene both inhibited IL-1beta gene induction without stimulating the expression of prostaglandin D synthase, short heterodimer partner, or other ER-inducible genes, indicating that induction of gene expression was not required for ER inhibition of IL-1beta signaling. Finally, the ability of EE to repress IL-1beta gene induction varied among tissues. For example, EE inhibited IL-1beta induction of lipopolysaccharide-induced c-x-c chemokine (LIX) in the liver, but not in the spleen or lung. The degree of EE repression did not correlate with ER expression. cAMP response element binding protein-binding protein (CBP)/p300 levels also varied between tissues. Together, these results are consistent with a model of in vivo ER interference with IL-1beta signaling through a coactivator-based mechanism.
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PMID:Estrogen receptor alpha inhibits IL-1beta induction of gene expression in the mouse liver. 1207 88

It is well established that p300 plays an important role in mediating gene expressions. However, it is less clear how its binding is influenced by physiological stimuli and how its altered binding affects transactivator acetylation and binding. In this study, we determined p300 binding to a core cyclooxygenase-2 (COX-2) promoter region by chromatin immunoprecipitation and streptavidin-agarose pull-down assays in basal and tumor necrosis factor-alpha (TNFalpha)-treated human foreskin fibroblasts. We found basal binding of p300, p50/p65 NF-kappaB, cyclic AMP regulatory element-binding protein-2, CCAAT/enhancer-binding protein beta, and c-Jun. p50/p65 and p300 binding was selectively increased by TNFalpha. Immunoprecipitation confirmed direct interaction of p300 with NF-kappaB and the other involved transactivators. p50 acetylation was detected in resting cells and was increased by TNFalpha or lipopolysaccharide. Overexpression of p300 augmented p50 acetylation, which was attenuated by deletion of its histone acetyltransferase domain. Enhanced p50 acetylation correlated with increased p50 binding to COX-2 promoter and transcriptional activation. Co-transfection of E1A with p300 abrogated p50 acetylation and p50 binding. These findings suggest that up-regulation of p300 binding and its acetylation of NF-kappaB occupies a central position in COX-2 promoter activation.
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PMID:Up-regulation of p300 binding and p50 acetylation in tumor necrosis factor-alpha-induced cyclooxygenase-2 promoter activation. 1247 Oct 36

The ubiquitously expressed latent interferon regulatory factor (IRF) 3 transcription factor is activated in response to virus infection by phosphorylation events that target a cluster of Ser/Thr residues, (382)GGASSLENTVDLHISNSHPLSLTSDQY(408) at the C-terminal end of the protein. To delineate the minimal phosphoacceptor sites required for IRF-3 activation, several point mutations were generated and tested for transactivation potential and cAMP-response element-binding protein-binding protein/p300 coactivator association. Expression of the IRF-3 S396D mutant alone was sufficient to induce type I IFN beta, IFNalpha1, RANTES, and the interferon-stimulated gene 561 promoters. Using SDS-PAGE and immunoblotting with a novel phosphospecific antibody, we show for the first time that, in vivo, IRF-3 is phosphorylated on Ser(396) following Sendai virus infection, expression of viral nucleocapsid, and double-stranded RNA treatment. These results demonstrate that Ser(396) within the C-terminal Ser/Thr cluster is targeted in vivo for phosphorylation following virus infection and plays an essential role in IRF-3 activation. The inability of the phosphospecific antibody to detect Ser(396) phosphorylation in lipopolysaccharide-treated cells suggests that other major pathways may be involved in IRF-3 activation following Toll-like receptor 4 stimulation.
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PMID:Identification of the minimal phosphoacceptor site required for in vivo activation of interferon regulatory factor 3 in response to virus and double-stranded RNA. 1252 42

Ceramide, formed by sphingomyelinase, is involved in the expression of cyclooxygenase-2 (COX-2). This study examines the effect of C2-ceramide (C2), a cell-permeable ceramide analog, on the lipopolysaccharide (LPS)-inducible COX-2 expression and signaling pathways. C2 did not induce COX-2 but potentiated LPS-inducible COX-2 expression in Raw264.7 cells, whereas dihydro-C2 was inactive. Treatment of cells with C2 notably increased LPS-inducible CCAAT/enhancer binding protein (C/EBP) DNA binding. Antibody supershift experiments revealed that LPS-induced C/EBP DNA binding activity depended on C/EBP beta and C/EBP delta but not C/EBP alpha, C/EBP epsilon or CBP/p300. C/EBP beta contributed to C2-enhanced DNA binding activity. 4-(4-Fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl) 1H-imidazole (SB203580), a p38 kinase inhibitor, completely inhibited LPS-inducible and C2-potentiated LPS-inducible COX-2 expression. Enhancement of LPS-inducible COX-2 expression and C/EBP DNA binding by C2 was abrogated in dominant-negative mutant of JNK1 [JNK1(-)] cells. 2'-Amino-3'-methoxyflavone (PD98059) or stable transfection with dominant-negative mutant of MKK1 decreased COX-2 induction by LPS but failed to inhibit C2-enhanced LPS induction of COX-2. Transfection with dominant-negative mutant of C/EBP inhibited the ability of C2 to potentiate the induction of COX-2 by LPS. In LPS-treated cells, C2 enhanced both the nuclear translocation and the expression of LPS-inducible C/EBP beta with an increase in AP-1 DNA binding activity. These enhancements were abolished by JNK1(-) transfection. AP-1 decoy oligonucleotide suppressed C2-potentiated C/EBP beta expression, indicating that AP-1 was responsible for C2-mediated C/EBP beta expression. These results demonstrate that C2 increases C/EBP beta-mediated COX-2 induction by LPS and that the pathway of JNK1 but not ERK1/2 is responsible for C/EBP beta activation involving activator protein-1-mediated enhanced C/EBP beta expression.
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PMID:Potentiation of lipopolysaccharide-inducible cyclooxygenase 2 expression by C2-ceramide via c-Jun N-terminal kinase-mediated activation of CCAAT/enhancer binding protein beta in macrophages. 1260 57

We have shown that non-pathogenic enteric Gram-negative Bacteroides vulgatus induces RelA phosphorylation, NF-kappaB activation, and proinflammatory gene expression in primary and intestinal epithelial cell (IEC) lines. We now demonstrate the transient induction of nuclear phospho-RelA (day 3) followed by persistent activation of phospho-Smad2 (days 3 and 7) in IEC from mucosal tissue sections of B. vulgatus-monoassociated rats, indicating that both NF-kappaB and transforming growth factor-beta1 (TGF-beta1) signaling are induced in vivo following bacterial colonization. Interestingly, TGF-beta1 inhibited B. vulgatus- and lipopolysaccharide (LPS)-induced NF-kappaB transcriptional activity as well as interleukin-6 (IL-6) mRNA accumulation and protein secretion in IEC. The inhibitory effect of TGF-beta1 is mediated independently of B. vulgatus/LPS-induced IkappaBalpha, Akt, and RelA phosphorylation as well as NF-kappaB DNA binding activity. Moreover, the specific histone deacetylase inhibitor trichostatin A blocked B. vulgatus/LPS-induced histone acetylation/phosphorylation (Lys-9/Ser-10) and reversed TGF-beta1-mediated inhibition of IL-6 gene expression. Chromatin immunoprecipitation analysis revealed that B. vulgatus/LPS-induced RelA recruitment to the IL-6 promoter is inhibited by TGF-beta1 treatment. Adenoviral delivery of Smad7 and dominant negative Smad3 (SmadDelta3) reversed the TGF-beta1-mediated inhibition of NF-kappaB transcriptional activity and NF-kappaB recruitment to the IL-6 promoter. In addition, TGF-beta1 and Ad5Smad3/4 prevent B. vulgatus/LPS-induced CBP/p300 and p65 nuclear co-association. We concluded that the TGF-beta1/Smad signaling pathway helps maintain normal intestinal homeostasis to commensal luminal enteric bacteria by regulating NF-kappaB signaling in IEC through altered histone acetylation.
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PMID:Transforming growth factor-beta 1 inhibits non-pathogenic Gram negative bacteria-induced NF-kappa B recruitment to the interleukin-6 gene promoter in intestinal epithelial cells through modulation of histone acetylation. 1267 95


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