scholarly journals Osmoprotective Transcription Factor NFAT5/TonEBP Modulates Nuclear Factor-κB Activity

2010 ◽  
Vol 21 (19) ◽  
pp. 3459-3474 ◽  
Author(s):  
Isabelle Roth ◽  
Valérie Leroy ◽  
H. Moo Kwon ◽  
Pierre-Yves Martin ◽  
Eric Féraille ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Transforming Growth Factor ◽  
Nuclear Translocation ◽  
Collecting Duct ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Transforming Growth Factor Α ◽  
Osmotic Response ◽  
Dependent Signal ◽  
Factor Α

Tonicity-responsive binding-protein (TonEBP or NFAT5) is a widely expressed transcription factor whose activity is regulated by extracellular tonicity. TonEBP plays a key role in osmoprotection by binding to osmotic response element/TonE elements of genes that counteract the deleterious effects of cell shrinkage. Here, we show that in addition to this “classical” stimulation, TonEBP protects cells against hypertonicity by enhancing nuclear factor-κB (NF-κB) activity. We show that hypertonicity enhances NF-κB stimulation by lipopolysaccharide but not tumor necrosis factor-α, and we demonstrate overlapping protein kinase B (Akt)-dependent signal transduction pathways elicited by hypertonicity and transforming growth factor-α. Activation of p38 kinase by hypertonicity and downstream activation of Akt play key roles in TonEBP activity, IκBα degradation, and p65 nuclear translocation. TonEBP affects neither of these latter events and is itself insensitive to NF-κB signaling. Rather, we reveal a tonicity-dependent interaction between TonEBP and p65 and show that NF-κB activity is considerably enhanced after binding of NF-κB-TonEBP complexes to κB elements of NF-κB–responsive genes. We demonstrate the key roles of TonEBP and Akt in renal collecting duct epithelial cells and in macrophages. These findings reveal a novel role for TonEBP and Akt in NF-κB activation on the onset of hypertonic challenge.

scholarly journals Transforming Growth Factor-α Mediates Nuclear Factor κB Activation in Strained Arteries

2006 ◽  
Vol 99 (4) ◽  
pp. 434-441 ◽  
Author(s):  
Catherine A. Lemarié ◽  
Pierre-Louis Tharaux ◽  
Bruno Esposito ◽  
Alain Tedgui ◽  
Stéphanie Lehoux
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Transforming Growth Factor Α ◽  
Factor Α

scholarly journals A mechanism of suppression of TGF–β/SMAD signaling by NF-κB/RelA

2000 ◽  
Vol 14 (2) ◽  
pp. 187-197 ◽  
Author(s):  
Markus Bitzer ◽  
Gero von Gersdorff ◽  
Dan Liang ◽  
Alfredo Dominguez-Rosales ◽  
Amer A. Beg ◽  
...  
Keyword(s):  
Transforming Growth Factor ◽  
Nuclear Translocation ◽  
Transforming Growth Factor Β ◽  
Nuclear Factor Κb ◽  
Transcriptional Responses ◽  
Smad Signaling ◽  
Antisense Mrna ◽  
Tnf Α ◽  
Factor Α ◽  
Necrosis Factor

A number of pathogenic and proinflammatory stimuli, and the transforming growth factor-β (TGF-β) exert opposing activities in cellular and immune responses. Here we show that the RelA subunit of nuclear factor κB (NF-κB/RelA) is necessary for the inhibition of TGF-β-induced phosphorylation, nuclear translocation, and DNA binding of SMAD signaling complexes by tumor necrosis factor-α (TNF-α). The antagonism is mediated through up-regulation of Smad7 synthesis and induction of stable associations between ligand-activated TGF-β receptors and inhibitory Smad7. Down-regulation of endogenous Smad7 by expression of antisense mRNA releases TGF-β/SMAD-induced transcriptional responses from suppression by cytokine-activated NF-κB/RelA. Following stimulation with bacterial lipopolysaccharide (LPS), or the proinflammatory cytokines TNF-α and interleukin-1β (IL-1β, NF-κB/RelA induces Smad7 synthesis through activation of Smad7 gene transcription. These results suggest a mechanism of suppression of TGF-β/SMAD signaling by opposing stimuli mediated through the activation of inhibitory Smad7 by NF-κB/RelA.

scholarly journals Transcription factor AP2 is required for expression of the rat transforming growth factor-α gene

Oncogene ◽  
1997 ◽  
Vol 14 (18) ◽  
pp. 2229-2238 ◽  
Author(s):  
Eugene A Berkowitz ◽  
Charles P Hecht ◽  
Jane C Azizkhan ◽  
Xiaorong Chen ◽  
David C Lee
Keyword(s):  
Transcription Factor ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Α ◽  
Factor Α

β-Adrenergic agonists exert their “anti-inflammatory” effects in monocytic cells through the IκB/NF-κB pathway

2000 ◽  
Vol 279 (4) ◽  
pp. L675-L682 ◽  
Author(s):  
Pierre Farmer ◽  
Jérôme Pugin
Keyword(s):  
Mononuclear Cells ◽  
Nuclear Translocation ◽  
Nuclear Factor Κb ◽  
Late Time ◽  
Nuclear Factor ◽  
Adrenergic Agonists ◽  
Time Points ◽  
Human Mononuclear Cells ◽  
Anti Inflammatory ◽  
Factor Α

In addition to their well-studied bronchodilatory and cardiotonic effects, β-adrenergic agonists carry anti-inflammatory properties by inhibiting cytokine production by human mononuclear cells. In a model of human promonocytic THP-1 cells stimulated with lipopolysaccharide (LPS), we showed that β-agonists inhibited tumor necrosis factor-α and interleukin-8 production predominantly via the β2-adrenergic receptor through the generation of cAMP and activation of protein kinase A. This effect was reproduced by other cAMP-elevating agents such as prostaglandins and cAMP analogs. Activation and nuclear translocation of the transcription factor nuclear factor-κB induced by LPS were inhibited with treatment with β-agonists, an effect that was prominent at late time points (>1 h). Although the initial IκB-α degradation induced by LPS was minimally affected by β-agonists, the latter induced a marked rebound of the cytosolic IκB-α levels at later time points (>1 h), accompanied by an increased IκB-α cytoplasmic half-life. This potentially accounts for the observed nuclear factor-κB sequestration in the cytoplasmic compartment. We postulate that the anti-inflammatory effects of β-agonists reside in their capacity to increase cytoplasmic concentrations of IκB-α, possibly by decreasing its degradation.

scholarly journals Development of a Gene Delivery System of Oligonucleotides for Fibroses by Targeting Cell-Surface Vimentin-Expressing Cells with N-Acetylglucosamine-Bearing Polymer-Conjugated Polyethyleneimine

Polymers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1508
Author(s):  
Inu Song ◽  
Hirohiko Ise
Keyword(s):  
Cell Surface ◽  
Transforming Growth Factor ◽  
Stellate Cells ◽  
Nuclear Factor Κb ◽  
Transforming Growth Factor Β1 ◽  
Binding Activity ◽  
Dermal Fibroblasts ◽  
Cytoskeletal Proteins ◽  
Nuclear Factor ◽  
Factor Α

Targeting myofibroblasts and activated stellate cells in lesion sites of fibrotic tissues is an important approach to treat fibroses. Herein, we focused on targeting the cytoskeletal proteins vimentin, which are reportedly highly expressed on the surface of these cells and have N-acetylglucosamine (GlcNAc)-binding activity. A GlcNAc-bearing polymer synthesized via radical polymerization with a reversible addition-fragmentation chain transfer reagent has been previously found to interact with cell-surface vimentin-expressing cells. We designed a GlcNAc-bearing polymer-conjugated polyethyleneimine (PEI), as the gene carrier to target cell-surface vimentin-expressing cells and specifically deliver nuclear factor-κB decoy oligonucleotides (ODNs) and heat shock protein 47 (HSP47)-small interfering RNA (siRNA) to normal human dermal fibroblasts (NHDFs) that express cell-surface vimentin. The results showed that the expression of tumor necrosis factor-α in lipopolysaccharide-stimulated NHDFs and HSP47 in transforming growth factor-β1-stimulated NHDFs was suppressed by cellular uptake of the GlcNAc-bearing polymer-conjugated PEI/nuclear factor (NF)-κB decoy ODNs and HSP47-siRNA complexes through cell-surface vimentin, respectively. These findings suggest that the effective and specific delivery of ODNs and siRNA for cell-surface vimentin-expressing cells such as myofibroblasts and activated stellate cells can be achieved using GlcNAc-bearing polymer-conjugated PEI. This therapeutic approach could prove advantageous to prevent the promotion of various fibroses.

Understanding life and death decisions in human leukaemias

2014 ◽  
Vol 42 (4) ◽  
pp. 747-751
Author(s):  
David J. MacEwan ◽  
Lawrence N. Barrera ◽  
Sujitra Keadsanti ◽  
Stuart A. Rushworth ◽  
Niraj M. Shah ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Apoptotic Cell ◽  
Chemotherapy Resistance ◽  
Nuclear Factor Κb ◽  
Related Factor ◽  
Nuclear Factor ◽  
Cellular Processes ◽  
Cell Death Mechanisms ◽  
Factor Α ◽  
Human Leukaemia

Human leukaemia cells have an often unique ability to either undergo apoptotic cell death mechanisms or, at other times, undergo proliferative expansion, sometimes to the same stimulus such as the pluripotent cytokine TNFα (tumour necrosis factor α). This potential for life/death switching helps us to understand the molecular signalling machinery that underlies these cellular processes. Furthermore, looking at the involvement of these switching signalling pathways that may be aberrant in leukaemia informs us of their importance in cancer tumorigenesis and how they may be targeted pharmacologically to treat various types of human leukaemias. Furthermore, these important pathways may play a crucial role in acquired chemotherapy resistance and should be studied further to overcome in the clinic many drug-resistant forms of blood cancers. In the present article, we uncover the relationship that exists in human leukaemia life/death switching between the anti-apoptotic pro-inflammatory transcription factor NF-κB (nuclear factor κB) and the cytoprotective antioxidant-responsive transcription factor Nrf2 (nuclear factor-erythroid 2-related factor 2). We also discuss recent findings that reveal a major role for Btk (Bruton's tyrosine kinase) in both lymphocytic and myeloid forms of human leukaemias and lymphomas.

scholarly journals Transforming Growth Factor α Binds to Trypanosoma cruzi Amastigotes To Induce Signaling and Cellular Proliferation

2003 ◽  
Vol 71 (7) ◽  
pp. 4201-4205 ◽  
Author(s):  
A. Deloris Alexander ◽  
Fernando Villalta ◽  
Maria F. Lima
Keyword(s):  
Growth Factor ◽  
Trypanosoma Cruzi ◽  
Cellular Proliferation ◽  
Transforming Growth Factor ◽  
Signal Transduction Pathway ◽  
Binding Affinities ◽  
Transforming Growth Factor Α ◽  
Dependent Signal ◽  
Epidermal Growth ◽  
Factor Α

ABSTRACT Macrophages secrete transforming growth factor α (TGF-α) to trigger proliferation of cancer cells. Here, we report a new role for TGF-α in modulating the direct cellular proliferation of a parasitic protozoan, Trypanosoma cruzi. Amastigotes present two classes of receptors for TGF-α with different binding affinities. 125I-TGF-α binding was competed by an excess of cold epidermal growth factor and TGF-α but not by an irrelevant molecule. Upon binding of TGF-α to amastigotes, the ligand is internalized, inducing trypanosome tyrosine phosphorylation of 90- and 87-kDa proteins and increasing DNA synthesis and proliferation of amastigotes. Furthermore, exposure of macrophages to TGF-α induced increased amastigote proliferation. These results describe a novel mechanism used by amastigotes to regulate their proliferation mediated by a TGF-α-dependent signal transduction pathway.

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