scholarly journals Negative regulation of nuclear factor-kappaB activation and function by glucocorticoids

2002 ◽  
Vol 28 (2) ◽  
pp. 69-78 ◽  
Author(s):  
WY Almawi ◽  
OK Melemedjian
Keyword(s):  
Transcription Factors ◽  
Transcriptional Activation ◽  
Promoter Region ◽  
Nuclear Translocation ◽  
Nuclear Factor Kappab ◽  
Nuclear Factor ◽  
Creb Binding Protein ◽  
Transcriptional Initiation ◽  
Nf Kappab ◽  
And Function

Glucocorticoids (GCs) exert their anti-inflammatory and antiproliferative effects principally by inhibiting the expression of cytokines and adhesion molecules. Mechanistically, GCs diffuse through the cell membrane, and bind to their inactive cytosolic receptors (GRs), which then undergo conformational modifications that allow for their nuclear translocation. In the nucleus, activated GRs modulate transcriptional events by directly associating with DNA elements, compatible with the GCs response elements (GRE) motif, and located in variable copy numbers and at variable distances from the TATA box, in the promoter region of GC-responsive genes. In addition, activated GRs also acted by antagonizing the activity of transcription factors, in particular nuclear factor-kappaB (NF-kappaB), by direct and indirect mechanisms. GCs induced gene transcription and protein synthesis of the NF-kappaB inhibitor, IkappaB. Activated GR also antagonized NF-kappaB activity through protein-protein interaction involving direct complexing with, and inhibition of, NF-kappaB binding to DNA (Simple Model), or association with NF-kappaB bound to the kappaB DNA site (Composite Model). In addition, and according to the Transmodulation Model, GRE-bound GR may interact with and inhibit the activity of kappaB-bound NF-kappaB via a mechanism involving cross-talk between the two transcription factors. Lastly, GR may compete with NF-kappaB for nuclear coactivators, including CREB binding protein and p300, thereby reducing and inhibiting transcriptional activation by NF-kappaB. It should be noted that, in exerting its effect, activated GR did not affect the correct assembly of the pre-initiation (DAB) complex, but acted rather more proximally in inhibiting the correct assembly of transcription factors in the promoter region, and thus transcriptional initiation.

scholarly journals The nuclear factor-kappaB (NF-kappaB): from a versatile transcription factor to a ubiquitous therapeutic target.

2006 ◽  
Vol 53 (4) ◽  
pp. 651-662 ◽  
Author(s):  
Laura L Yates ◽  
Dariusz C Górecki
Keyword(s):  
Nuclear Factor Kappab ◽  
Specific Response ◽  
Nuclear Factor ◽  
Therapeutic Approaches ◽  
Altered Regulation ◽  
Nf Kappab ◽  
Novel Therapeutic Strategies ◽  
And Function

The nuclear factor-kappaB (NF-kappaB) transcription factors regulate a plethora of cellular pathways and processes including the immune response, inflammation, proliferation, apoptosis and calcium homeostasis. In addition to the complexity of its physiological roles, the composition and function of this family of proteins is very complicated. While the basic understanding of NF-kappaB signalling is extensive, relatively little is know of the in vivo dynamics of this pathway or what controls the balance between various outcomes. Although we know a large number of NF-kappaB-responsive genes, the contribution of these genes to a specific response is not always clear. Finally, the involvement of NF-kappaB in pathological processes is only now beginning to be unravelled. In addition to cancer and immunodeficiency disorders, altered regulation of NF-kappaB has been associated with several inherited diseases. These findings indicate that modulation of the NF-kappaB pathways may be beneficial. However, our limited knowledge of NF-kappaB signalling hinders therapeutic approaches: in many situations it is not clear whether the enhancement or inhibition of NF-kappaB activity would be beneficial or which pathways to interfere with and what the required level of activation is. Further studies of the role of NF-kappaB are needed as these may result in novel therapeutic strategies for a wide variety of diseases.

scholarly journals PRV UL13 inhibits cGAS–STING-mediated IFN-β production by phosphorylating IRF3

2020 ◽  
Vol 51 (1) ◽  
Author(s):  
Zongyi Bo ◽  
Yurun Miao ◽  
Rui Xi ◽  
Qiuping Zhong ◽  
Chenyi Bao ◽  
...  
Keyword(s):  
Transcriptional Activation ◽  
Pseudorabies Virus ◽  
Nuclear Translocation ◽  
Economic Loss ◽  
Inhibitory Effect ◽  
Poly I:C ◽  
Interferon Response ◽  
Type I ◽  
Creb Binding Protein ◽  
Swine Industry

Abstract Cyclic GMP-AMP (cGAMP) synthase (cGAS) is an intracellular sensor of cytoplasmic viral DNA created during virus infection, which subsequently activates the stimulator of interferon gene (STING)-dependent type I interferon response to eliminate pathogens. In contrast, viruses have developed different strategies to modulate this signalling pathway. Pseudorabies virus (PRV), an alphaherpesvirus, is the causative agent of Aujeszky’s disease (AD), a notable disease that causes substantial economic loss to the swine industry globally. Previous reports have shown that PRV infection induces cGAS-dependent IFN-β production, conversely hydrolysing cGAMP, a second messenger synthesized by cGAS, and attenuates PRV-induced IRF3 activation and IFN-β secretion. However, it is not clear whether PRV open reading frames (ORFs) modulate the cGAS–STING-IRF3 pathway. Here, 50 PRV ORFs were screened, showing that PRV UL13 serine/threonine kinase blocks the cGAS–STING-IRF3-, poly(I:C)- or VSV-mediated transcriptional activation of the IFN-β gene. Importantly, it was discovered that UL13 phosphorylates IRF3, and its kinase activity is indispensable for such an inhibitory effect. Moreover, UL13 does not affect IRF3 dimerization, nuclear translocation or association with CREB-binding protein (CBP) but attenuates the binding of IRF3 to the IRF3-responsive promoter. Consistent with this, it was discovered that UL13 inhibits the expression of multiple interferon-stimulated genes (ISGs) induced by cGAS–STING or poly(I:C). Finally, it was determined that PRV infection can activate IRF3 by recruiting it to the nucleus, and PRVΔUL13 mutants enhance the transactivation level of the IFN-β gene. Taken together, the data from the present study demonstrated that PRV UL13 inhibits cGAS–STING-mediated IFN-β production by phosphorylating IRF3.

Myocyte nuclear factor, a novel winged-helix transcription factor under both developmental and neural regulation in striated myocytes

1994 ◽  
Vol 14 (7) ◽  
pp. 4596-4605
Author(s):  
R Bassel-Duby ◽  
M D Hernandez ◽  
Q Yang ◽  
J M Rochelle ◽  
M F Seldin ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Transcriptional Activation ◽  
Myogenic Differentiation ◽  
Specific Binding ◽  
Motor Nerve ◽  
Sequence Motif ◽  
Nuclear Factor ◽  
Winged Helix ◽  
Amino Terminal ◽  
Myocyte Nuclear Factor

A sequence motif (CCAC box) within an upstream enhancer region of the human myoglobin gene is essential for transcriptional activity in both cardiac and skeletal muscle. A cDNA clone, myocyte nuclear factor (MNF), was isolated from a murine expression library on the basis of sequence-specific binding to the myoglobin CCAC box motif and was found to encode a novel member of the winged-helix or HNF-3/fork head family of transcription factors. Probes based on this sequence identify two mRNA species that are upregulated during myocyte differentiation, and antibodies raised against recombinant MNF identify proteins of approximately 90, 68, and 65 kDa whose expression is regulated following differentiation of myogenic cells in culture. In addition, the 90-kDa form of MNF is phosphorylated and is upregulated in intact muscles subjected to chronic motor nerve stimulation, a potent stimulus to myoglobin gene regulation. Amino acid residues 280 to 389 of MNF demonstrate 35 to 89% sequence identity to the winged-helix domain from other known members of this family, but MNF is otherwise divergent. A proline-rich amino-terminal region (residues 1 to 206) of MNF functions as a transcriptional activation domain. These studies provide the first evidence that members of the winged-helix family of transcription factors have a role in myogenic differentiation and in remodeling processes of adult muscles that occur in response to physiological stimuli.

scholarly journals Neisseria gonorrhoeae Epithelial Cell Interaction Leads to the Activation of the Transcription Factors Nuclear Factor κB and Activator Protein 1 and the Induction of Inflammatory Cytokines

1997 ◽  
Vol 186 (2) ◽  
pp. 247-258 ◽  
Author(s):  
Michael Naumann ◽  
Silja Weßler ◽  
Cornelia Bartsch ◽  
Björn Wieland ◽  
Thomas F. Meyer
Keyword(s):  
Transcription Factors ◽  
Epithelial Cells ◽  
Neisseria Gonorrhoeae ◽  
Transcriptional Activation ◽  
Inflammatory Cytokine ◽  
Nuclear Factor ◽  
Activator Protein 1 ◽  
Messenger Rnas ◽  
Basic Leucine Zipper ◽  
Activator Protein

We have studied the effect of human bacterial pathogen Neisseria gonorrhoeae (Ngo) on the activation of nuclear factor (NF)-κB and the transcriptional activation of inflammatory cytokine genes upon infection of epithelial cells. During the course of infection, Ngo, the etiologic agent of gonorrhea, adheres to and penetrates mucosal epithelial cells. In vivo, localized gonococcal infections are often associated with a massive inflammatory response. We observed upregulation of several inflammatory cytokine messenger RNAs (mRNAs) and the release of the proteins in Ngo-infected epithelial cells. Moreover, infection with Ngo induced the formation of a NF-κB DNA–protein complex and, with a delay in time, the activation of activator protein 1, whereas basic leucine zipper transcription factors binding to the cAMP-responsive element or CAAT/enhancer-binding protein DNA-binding sites were not activated. In supershift assays using NF-κB–specific antibodies, we identified a NF-κB p50/p65 heterodimer. The NF-κB complex was formed within 10 min after infection and decreased 90 min after infection. Synthesis of tumor necrosis factor α and interluekin (IL)-1β occurred at later times and therefore did not account for NF-κB activation. An analysis of transiently transfected IL-6 promoter deletion constructs suggests that NF-κB plays a crucial role for the transcriptional activation of the IL-6 promoter upon Ngo infection. Inactivation of NF-κB conferred by the protease inhibitor N-tosyl-l-phenylalanine chloromethyl ketone inhibited mRNA upregulation of most, but not all, studied cyctokine genes. Activation of NF-κB and cytokine mRNA upregulation also occur in Ngo-infected epithelial cells that were treated with cytochalasin D, indicating an extracellular signaling induced before invasion.

Requirement of nuclear factor kappaB for the constitutive expression of nitric oxide synthase-2 and cyclooxygenase-2 in rat trophoblasts

1999 ◽  
Vol 112 (18) ◽  
pp. 3147-3155
Author(s):  
N.A. Callejas ◽  
M. Casado ◽  
L. Bosca ◽  
P. Martin-Sanz
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Cyclooxygenase 2 ◽  
Nuclear Factor Kappab ◽  
Mrna Levels ◽  
Nuclear Factor ◽  
Cox 2 ◽  
Nf Kappab ◽  
Nitric Oxide Synthase 2 ◽  
Oxide Synthase

Recently isolated trophoblasts express nitric oxide synthase 2 (NOS-2) and cyclooxygenase 2 (COX-2), decreasing the levels of the corresponding mRNAs when the cells were maintained in culture. The sustained expression of COX-2 and NOS-2 in trophoblasts was dependent on the activation of nuclear factor kappaB (NF-kappaB) since proteasome inhibitors and antioxidants that abrogated NF-kappaB activity suppressed the induction of both genes. The time-dependent fall of the mRNA levels of NOS-2 and COX-2 paralleled the inhibition of NF-kappaB, determined by electrophoretic mobility shift assays, and the increase of the IkappaBalpha and IkappaBbeta inhibitory proteins. Isolated trophoblasts synthesized reactive oxygen intermediates (ROI), a process impaired after culturing the cells, and that might be involved in the NF-kappaB activation process. Moreover, treatment of recently isolated cells with ROI scavengers suppressed the expression of COX-2 and NOS-2. Challenge of trophoblasts with interleukin-1beta up-regulated the expression of both proteins, an effect that was potentiated by lipopolysaccharide. These results indicate that the physiological expression of NOS-2 and COX-2 in trophoblasts involves a sustained activation of NF-kappaB which inhibition abrogates the inducibility of both genes.

Jurkat Cells Respond to Biotin Deficiency with Increased Nuclear Translocation of NF-kB, Mediating Cell Survival

2004 ◽  
Vol 74 (3) ◽  
pp. 209-216 ◽  
Author(s):  
Rodriguez-Melendez ◽  
Schwab ◽  
Zempleni
Keyword(s):  
Transcriptional Activation ◽  
Nuclear Translocation ◽  
Suppressor Gene ◽  
Jurkat Cells ◽  
Response To Treatment ◽  
Serum Starvation ◽  
Biotin Deficiency ◽  
Necrosis Factor Alpha ◽  
Nuclear Abundance ◽  
Nf Kappab

Members of the NF-kappaB family of transcription factors cause transcriptional activation of anti-apoptotic genes. Here we determined whether survival of biotin-deficient cells is mediated by nuclear translocation of NF-kappaB. Human T (Jurkat) cells were cultured in biotin-deficient or biotin-supplemented media; nuclear translocation of NF-kappaB was stimulated with phytohemagglutinin and phorbol-12-myristate-13-acetate. Nuclear abundance of two members (p50 and p65) of the NF-kappaB family was greater in biotin-deficient compared to biotin-supplemented cells; this effect was mediated by phosphorylation of IkappaBalpha. The nuclear enrichment of p50 and p65 in biotin-deficient cells was associated with transcriptional activation of NF-kappaB-dependent genes such as the tumor suppressor gene p53 and the anti-apoptotic gene Bfl-1/A1. Biotin-deficient cells exhibited smaller activities of the apoptotic enzyme caspase-3 in response to treatment with tumor necrosis factor alpha, and decreased cell death in response to serum starvation compared to biotin-supplemented cells. These findings suggest that NF-kappaB mediates survival of biotin-deficient cells.

scholarly journals Peroxisome Proliferator-Activated Receptor-γ Antagonizes LOX-1-Mediated Endothelial Injury by Transcriptional Activation of miR-590-5p

PPAR Research ◽  
2019 ◽  
Vol 2019 ◽  
pp. 1-9
Author(s):  
Lei Xu ◽  
Gang Zhao ◽  
Hong Zhu ◽  
Shijun Wang ◽  
Aijun Sun ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Transcriptional Activation ◽  
Promoter Region ◽  
Nuclear Translocation ◽  
Therapeutic Potential ◽  
Umbilical Vein ◽  
Density Lipoprotein ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor

Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is one of the major receptors expressed on the endothelium of arterial wall with a key role in endothelial dysfunction and the development of atherosclerosis. Recent evidence suggested that LOX-1 is upregulated under the condition of insulin resistance and could be suppressed by the antidiabetic drugs. We previously also confirmed that Thiazolidinedione (TZD) has the inhibitory effect on LOX-1 in ox-LDL-induced endothelial cells. However, the underlying mechanism is unclear. Here we showed that Rosiglitazone treatment significantly attenuated the expressions of LOX-1, ICAM-1, VCAM-1, p47phox, and the atherosclerotic lesions in ApoE-/- mice with high-fat diet. In vitro, we revealed that Rosiglitazone inhibited LOX-1 by regulating miR-590-5p. Ox-LDL-mediated ICAM-1, VCAM-1, and p47phox were significantly reduced by Rosiglitazone, but all reversed after pretreating the cells with antagomiR-590-5p. Induction with Rosiglitazone activated PPAR-γ and promoted its nuclear translocation in cultured human umbilical vein endothelial cells (HUVECs). The nuclear PPAR-γ upregulated the miR-590-5p level through binding to its transcriptional promoter region. Retaining PPAR-γ in cytoplasm by transfecting with PPAR-γ⊿NLS plasmid in HUVECs failed to activate miR-590-5p. Mutation of the promoter region of PPAR-γ also reduced the miR-590-5p promoter luciferase activity. Collectively, these data indicated that PPAR-γ may have the therapeutic potential in atherosclerosis via the transcriptional regulation of miR-590-5p in endothelial cells.

NF-κB Transcription Factors Are Involved in Normal Erythropoiesis

Blood ◽  
1998 ◽  
Vol 91 (11) ◽  
pp. 4136-4144 ◽  
Author(s):  
Min-Ying Zhang ◽  
Shao-Cong Sun ◽  
Laurie Bell ◽  
Barbara A. Miller
Keyword(s):  
Transcription Factors ◽  
Nuclear Translocation ◽  
Luciferase Reporter ◽  
Erythroid Cells ◽  
Gm Csf ◽  
Luciferase Reporter Plasmid ◽  
Nuclear Extracts ◽  
Nuclear Levels ◽  
And Function

Abstract NF-κB/Rel designates a widely distributed family of transcription factors involved in immune and acute phase responses. Here, the expression and function of NF-κB factors in erythroid proliferation and differentiation were explored. In an erythroleukemia cell line, TF-1, high levels of p105/p50, p100/p52, p65, and IκBα were detected 24 hours after growth factor deprivation. In response to granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulation, significant induction of p52 expression was observed. GM-CSF also induced nuclear translocation of both p52 and p65. No induction of NF-κB factors was observed with erythropoietin stimulation of TF-1 cells. Overexpression of p52 and p65 in TF-1 cells by transient transfection resulted in significant induction of a κB-TATA-luciferase reporter plasmid, showing that these factors are functional in vivo in erythroid cells. To determine whether NF-κB factors may play a role in normal erythropoiesis, levels of these factors were determined in burst-forming unit-erythroid (BFU-E)–derived cells at different stages of differentiation. The NF-κB factors p105/p50, p100/p52, and p65 were highly expressed in early BFU-E–derived precursors, which are rapidly proliferating, and declined during maturation. Furthermore, nuclear levels of NF-κB factors p50, p52, and p65 were higher in less mature precursors (day 10 BFU-E–derived cells) compared with more differentiated (day 14) erythroblasts. In nuclear extracts from day 10 BFU-E–derived cells, p50, p52, and p65 were able to form complexes, which bound to κB sites in the promoters of both the c-myb and c-mycgenes, suggesting that c-myb and c-myc may be among the κB-containing genes regulated by NF-κB factors in normal erythroid cells. Taken together, these data show that NF-κB factors are modulated by GM-CSF and suggest they function to regulate specific κB containing genes involved in erythropoiesis.

scholarly journals Transcriptional activation of the chicken lysozyme gene by NF-κ Bp65 (RelA) and c-Rel, but not by NF-κ Bp50

1996 ◽  
Vol 313 (1) ◽  
pp. 39-44 ◽  
Author(s):  
Loc VAN PHI
Keyword(s):  
Transcription Factors ◽  
Transcriptional Activation ◽  
Nuclear Factor Kappa B ◽  
Protein Complexes ◽  
Terminal Differentiation ◽  
Binding Activity ◽  
Nuclear Factor ◽  
Lysozyme Gene ◽  
Chloramphenicol Acetyltransferase Gene ◽  
Chicken Lysozyme

The lysozyme gene is expressed at a low level in myeloblasts and is progressively activated to constitutively high expression in mature macrophages. The binding activity of the newly defined NF-ĸB/Rel family of transcription factors increases during the terminal differentiation of macrophages. In this study, I show that NF-ĸB/Rel-like proteins bind to the nuclear factor kappa B (ĸB)-like sequence of the lysozyme promoter. These binding activities were induced by treatment of HD11 cells with lipopolysaccharide. Immunomobility shift assays show that c-Rel is possibly a factor in the complexes that bind to the ĸB-like sequence lysĸB. Binding activity to one of the protein complexes seems to be regulated by phosphorylation. In fact, overexpression of p65 and c-Rel stimulates expression of the chloramphenicol acetyltransferase gene controlled by the lysozyme promoter. Furthermore, co-transfection experiments reveal that the ĸB-like sequence within the lysozyme promoter mediates the transactivation by p65 and c-Rel. These results indicate that the p65 and c-Rel could be components of the protein complexes that bind to the ĸB-like sequence and this binding could contribute to the progressively activated expression of the lysozyme gene during the terminal differentiation of macrophages.

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