Anthrax lethal toxin represses glucocorticoid receptor (GR) transactivation by inhibiting GR-DNA binding in vivo

2005 ◽  
Vol 241 (1-2) ◽  
pp. 21-31 ◽  
Author(s):  
Jeanette I. Webster ◽  
Esther M. Sternberg
Keyword(s):  
Dna Binding ◽  
Glucocorticoid Receptor ◽  
Lethal Toxin ◽  
Anthrax Lethal Toxin

scholarly journals Mechanism of Histone H1-Stimulated Glucocorticoid Receptor DNA Binding In Vivo

2008 ◽  
Vol 28 (21) ◽  
pp. 6730-6730
Author(s):  
Sergey Belikov ◽  
Carolina Åstrand ◽  
Örjan Wrange
Keyword(s):  
Dna Binding ◽  
Glucocorticoid Receptor ◽  
Histone H1

Novel Repression of the Glucocorticoid Receptor by Anthrax Lethal Toxin

2004 ◽  
Vol 1024 (1) ◽  
pp. 9-23 ◽  
Author(s):  
JEANETTE I. WEBSTER ◽  
MAHTAB MOAYERI ◽  
ESTHER M. STERNBERG
Keyword(s):  
Glucocorticoid Receptor ◽  
Lethal Toxin ◽  
Anthrax Lethal Toxin

Functional interference between the ubiquitous and constitutive octamer transcription factor 1 (OTF-1) and the glucocorticoid receptor by direct protein-protein interaction involving the homeo subdomain of OTF-1

1992 ◽  
Vol 12 (11) ◽  
pp. 4960-4969
Author(s):  
E Kutoh ◽  
P E Strömstedt ◽  
L Poellinger
Keyword(s):  
Transcription Factor ◽  
Dna Binding ◽  
Glucocorticoid Receptor ◽  
Protein Interaction ◽  
Binding Activity ◽  
Dependent Manner ◽  
Protein Protein Interaction ◽  
Dna Binding Activity ◽  
Functional Interference

The ubiquitous and constitutive octamer transcription factor OTF-1 (Oct 1) is the target of positive regulation by the potent herpes simplex virus trans-activator VP16, which forms a complex with the homeodomain of OTF-1. Here we present evidence that the glucocorticoid receptor can negatively regulate OTF-1 function by a mechanism that is independent of DNA binding. In vivo-expressed glucocorticoid receptor inhibited in a hormone-dependent manner activation of a minimal promoter construct carrying a functional octamer site. Moreover, expression of the receptor in vivo resulted in hormone-dependent repression of OTF-1-dependent DNA-binding activity in nuclear extract. In vitro, the DNA-binding activity of partially purified OTF-1 was repressed following incubation with purified glucocorticoid receptor. Cross-linking and immunoprecipitation experiments indicated that the functional interference may be due to a strong association between these two proteins in solution. Finally, preliminary evidence indicates that the homeo subdomain of OTF-1 that directs formation of a complex with VP16 may also be critical for interaction with the glucocorticoid receptor. Thus, OTF-1 is a target for both positive and negative regulation by protein-protein interaction. Moreover, the functional interference between OTF-1 and the glucocorticoid receptor represents a novel regulatory mechanism in the cross-coupling of signal transduction pathways of nuclear receptors and constitutive transcription factors.

scholarly journals Amiodarone and Bepridil Inhibit Anthrax Toxin Entry into Host Cells

2007 ◽  
Vol 51 (7) ◽  
pp. 2403-2411 ◽  
Author(s):  
Ana M. Sanchez ◽  
Diane Thomas ◽  
Eugene J. Gillespie ◽  
Robert Damoiseaux ◽  
Joseph Rogers ◽  
...  
Keyword(s):  
Small Molecules ◽  
Lethal Toxin ◽  
Host Cells ◽  
Anthrax Lethal Toxin ◽  
Raw 264.7 Macrophages ◽  
Endosomal Acidification ◽  
A Cell

ABSTRACT Anthrax lethal toxin is one of the fundamental components believed to be responsible for the virulence of Bacillus anthracis. In order to find novel compounds with anti-lethal toxin properties, we used a cell-based assay to screen a collection of approximately 500 small molecules. Nineteen compounds that blocked lethal toxin-mediated killing of RAW 264.7 macrophages were identified, and we report here on the characterization of the two most potent antitoxic compounds, amiodarone and bepridil. These drugs are used to treat cardiac arrhythmia or angina in humans at doses similar to those that provide protection against lethal toxin in vitro. Our results support a model whereby the antitoxic properties of both drugs result from their ability to block endosomal acidification, thereby blocking toxin entry. Amiodarone was tested in vivo and found to significantly increase survival of lethal toxin-challenged Fischer rats.

scholarly journals Glucocorticoid Receptor Homodimers and Glucocorticoid-Mineralocorticoid Receptor Heterodimers Form in the Cytoplasm through Alternative Dimerization Interfaces

2001 ◽  
Vol 21 (3) ◽  
pp. 781-793 ◽  
Author(s):  
Joanne G. A. Savory ◽  
Gratien G. Préfontaine ◽  
Claudia Lamprecht ◽  
Mingmin Liao ◽  
Rhian F. Walther ◽  
...  
Keyword(s):  
Dna Binding ◽  
Glucocorticoid Receptor ◽  
Ligand Binding ◽  
Gene Transcription ◽  
Mineralocorticoid Receptor ◽  
Binding Domain ◽  
Ligand Binding Domain ◽  
Steroid Hormone Receptors ◽  
Specific Gene

ABSTRACT Steroid hormone receptors act to regulate specific gene transcription primarily as steroid-specific dimers bound to palindromic DNA response elements. DNA-dependent dimerization contacts mediated between the receptor DNA binding domains stabilize DNA binding. Additionally, some steroid receptors dimerize prior to their arrival on DNA through interactions mediated through the receptor ligand binding domain. In this report, we describe the steroid-induced homomeric interaction of the rat glucocorticoid receptor (GR) in solution in vivo. Our results demonstrate that GR interacts in solution at least as a dimer, and we have delimited this interaction to a novel interface within the hinge region of GR that appears to be both necessary and sufficient for direct binding. Strikingly, we also demonstrate an interaction between GR and the mineralocorticoid receptor in solution in vivo that is dependent on the ligand binding domain of GR alone and is separable from homodimerization of the glucocorticoid receptor. These results indicate that functional interactions between the glucocorticoid and mineralocorticoid receptors in activating specific gene transcription are probably more complex than has been previously appreciated.

scholarly journals The DNA Binding-Independent Function of the Glucocorticoid Receptor Mediates Repression of Ap-1–Dependent Genes in Skin

1999 ◽  
Vol 147 (7) ◽  
pp. 1365-1370 ◽  
Author(s):  
Jan P. Tuckermann ◽  
Holger M. Reichardt ◽  
Rosa Arribas ◽  
K. Hartmut Richter ◽  
Günther Schütz ◽  
...  
Keyword(s):  
Dna Binding ◽  
Glucocorticoid Receptor ◽  
Target Genes ◽  
Animal Cell ◽  
Biological Effects ◽  
Mouse Skin ◽  
Independent Function ◽  
Culture Cells ◽  
Defective Mutant

The glucocorticoid receptor (GR) mediates the biological effects of glucocorticoids (GCs) through activation or repression of gene expression, either by DNA binding or via interaction with other transcription factors, such as AP-1. Work in tissue culture cells on the regulation of AP-1–dependent genes, such as collagenase (MMP-13) and stromelysin (MMP-3) has suggested that the antitumor and antiinflammatory activity of GCs is mediated, at least in part, by GR-mediated downmodulation of AP-1. Here, we have identified phorbol ester-induced expression of MMP-3 and MMP-13 in mouse skin as the first example of an in vivo system to measure negative interference between AP-1 and GR in the animal. Cell type-specific induction of these genes by tumor promoters is abolished by GCs. Importantly, this is also the case in GRdim mice expressing a DNA binding-defective mutant version of GR. In contrast, the newly identified target genes in skin, plasma glutathione peroxidase and HSP-27, were induced by GC in wild-type, but not in GRdim mice. Thus, these data suggest that the DNA binding-independent function of the GR is dispensable for repression of AP-1 activity in vivo and responsible for the antitumor promoting activity of GCs.

scholarly journals Functional interference between the ubiquitous and constitutive octamer transcription factor 1 (OTF-1) and the glucocorticoid receptor by direct protein-protein interaction involving the homeo subdomain of OTF-1.

1992 ◽  
Vol 12 (11) ◽  
pp. 4960-4969 ◽  
Author(s):  
E Kutoh ◽  
P E Strömstedt ◽  
L Poellinger
Keyword(s):  
Transcription Factor ◽  
Dna Binding ◽  
Glucocorticoid Receptor ◽  
Protein Interaction ◽  
Binding Activity ◽  
Dependent Manner ◽  
Protein Protein Interaction ◽  
Dna Binding Activity ◽  
Functional Interference

The ubiquitous and constitutive octamer transcription factor OTF-1 (Oct 1) is the target of positive regulation by the potent herpes simplex virus trans-activator VP16, which forms a complex with the homeodomain of OTF-1. Here we present evidence that the glucocorticoid receptor can negatively regulate OTF-1 function by a mechanism that is independent of DNA binding. In vivo-expressed glucocorticoid receptor inhibited in a hormone-dependent manner activation of a minimal promoter construct carrying a functional octamer site. Moreover, expression of the receptor in vivo resulted in hormone-dependent repression of OTF-1-dependent DNA-binding activity in nuclear extract. In vitro, the DNA-binding activity of partially purified OTF-1 was repressed following incubation with purified glucocorticoid receptor. Cross-linking and immunoprecipitation experiments indicated that the functional interference may be due to a strong association between these two proteins in solution. Finally, preliminary evidence indicates that the homeo subdomain of OTF-1 that directs formation of a complex with VP16 may also be critical for interaction with the glucocorticoid receptor. Thus, OTF-1 is a target for both positive and negative regulation by protein-protein interaction. Moreover, the functional interference between OTF-1 and the glucocorticoid receptor represents a novel regulatory mechanism in the cross-coupling of signal transduction pathways of nuclear receptors and constitutive transcription factors.

scholarly journals Endocrine Perturbation Increases Susceptibility of Mice to Anthrax Lethal Toxin

2005 ◽  
Vol 73 (7) ◽  
pp. 4238-4244 ◽  
Author(s):  
Mahtab Moayeri ◽  
Jeanette I. Webster ◽  
Jason F. Wiggins ◽  
Stephen H. Leppla ◽  
Esther M. Sternberg
Keyword(s):  
Glucocorticoid Receptor ◽  
Bacillus Anthracis ◽  
Steroid Therapy ◽  
Receptor Gene ◽  
Gene Activation ◽  
Lethal Toxin ◽  
Anthrax Lethal Toxin ◽  
Treatment Protocols ◽  
Glucocorticoid Receptor Gene ◽  
Increased Susceptibility

ABSTRACT Bacillus anthracis lethal toxin (LT) causes vascular collapse and high lethality in BALB/cJ mice, intermediate lethality in C57BL/6J mice, and no lethality in DBA/2J mice. We found that adrenalectomized (ADX) mice of all three strains had increased susceptibility to LT. The increased susceptibility of ADX-DBA/2J mice was not accompanied by changes in their macrophage sensitivity or cytokine response to LT. DBA/2J mice showed no change in serum corticosteroid levels in response to LT injection, while BALB/cJ mice showed a fivefold increase in serum corticosterone. However, LT inhibited dexamethasone (DEX)-induced glucocorticoid receptor gene activation to similar extents in all three strains. DEX treatment did not rescue ADX mice from LT-mediated mortality. Surprisingly, oral DEX treatment also sensitized adrenally intact DBA/2J mice to LT lethality at all doses tested and also exacerbated LT-mediated pathogenesis and mortality in BALB/cJ mice. Aldosterone did not protect ADX mice from toxin challenge. These results indicate that susceptibility to anthrax LT in mice depends on a fine but easily perturbed balance of endocrine functions. Thus, the potentially detrimental consequences of steroid therapy for anthrax must be considered in treatment protocols for this disease.

scholarly journals DNA binding triggers tetramerization of the glucocorticoid receptor in live cells

2016 ◽  
Vol 113 (29) ◽  
pp. 8236-8241 ◽  
Author(s):  
Diego M. Presman ◽  
Sourav Ganguly ◽  
R. Louis Schiltz ◽  
Thomas A. Johnson ◽  
Tatiana S. Karpova ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Dna Binding ◽  
Glucocorticoid Receptor ◽  
Rational Design ◽  
Quaternary Structure ◽  
Imaging Techniques ◽  
Steroid Receptor ◽  
Receptor Activation ◽  
Live Cells

Transcription factors dynamically bind to chromatin and are essential for the regulation of genes. Although a large percentage of these proteins appear to self-associate to form dimers or higher order oligomers, the stoichiometry of DNA-bound transcription factors has been poorly characterized in vivo. The glucocorticoid receptor (GR) is a ligand-regulated transcription factor widely believed to act as a dimer or a monomer. Using a unique set of imaging techniques coupled with a cell line containing an array of DNA binding elements, we show that GR is predominantly a tetramer when bound to its target DNA. We find that DNA binding triggers an interdomain allosteric regulation within the GR, leading to tetramerization. We therefore propose that dynamic changes in GR stoichiometry represent a previously unidentified level of regulation in steroid receptor activation. Quaternary structure analysis of other members of the steroid receptor family (estrogen, androgen, and progesterone receptors) reveals variation in oligomerization states among this family of transcription factors. Because GR’s oligomerization state has been implicated in therapy outcome, our findings open new doors to the rational design of novel GR ligands and redefine the quaternary structure of steroid receptors.

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