Separating Transrepression and Transactivation: A Distressing Divorce for the Glucocorticoid Receptor?

  title={Separating Transrepression and Transactivation: A Distressing Divorce for the Glucocorticoid Receptor?},
  author={Robert Newton and Neil S Holden},
  journal={Molecular Pharmacology},
  pages={799 - 809}
Glucocorticoids (corticosteroids) are highly effective in combating inflammation in the context of a variety of diseases. However, clinical utility can be compromised by the development of side effects, many of which are attributed to the ability of the glucocorticoid receptor (GR) to induce the transcription of, or transactivate, certain genes. By contrast, the anti-inflammatory effects of glucocorticoids are due largely to their ability to reduce the expression of pro-inflammatory genes. This… 

Figures and Tables from this paper

Maps and legends: the quest for dissociated ligands of the glucocorticoid receptor.

Transrepression and transactivation potencies of inhaled glucocorticoids.

It is concluded that, within the studied cell system, inhaled corticosteroids did not exhibit preferential transrepression, but had higher potencies for transactivation than for trans repression via NF-kappaB and had differential potenciesfor the two transrepressive pathways.

The Glucocorticoid Receptor

The molecular and cellular mechanisms of GR signaling, and the potential role for GR isoforms in regulating the specificity and sensitivity of glucocorticoid responsiveness in healthy and diseased tissues are discussed.

Role of Dual Specificity Phosphatases in Biological Responses to Glucocorticoids*

The discovery of a negative regulatory function of GR shifted the focus away from GC-induced genes as anti-inflammatory mediators and attention has begun to move back toward the idea that the anti- inflammatory response to GCs is partially dependent on the positive regulation of gene expression by GR.

Glucocorticoid Repression of Inflammatory Gene Expression Shows Differential Responsiveness by Transactivation- and Transrepression-Dependent Mechanisms

Roles for both transrepression and transactivation in the glucocorticoid-dependent repression of inflammatory gene expression are indicated, suggesting that the repression ofinflammatory mRNAs by GR transactivation-dependent mechanisms accounts for the greatest levels of repression and the most potent repression by dexamethasone.

Mineralocorticoid Receptor (MR) trans-Activation of Inflammatory AP-1 Signaling

Interestingly, aldosterone interactions with both GR and MR demonstrated a potential to activate AP-1, and MR modulation of NFκB and AP- 1 signaling was consistent with a trans-mechanism, andAP-1 effects were confirmed for specific gene targets in primary human cells.

Crosstalk in inflammation: the interplay of glucocorticoid receptor-based mechanisms and kinases and phosphatases.

The integrated interplay between GR signaling and its correlating kinases and phosphatases are illuminated in the context of the clinically important combat of inflammation, giving attention to implications on GC-mediated side effects and therapy resistance.

How glucocorticoid receptors modulate the activity of other transcription factors: A scope beyond tethering




The glucocorticoid RU24858 does not distinguish between transrepression and transactivation in primary human eosinophils

In human eosinophils RU24858 acts as transactivator and transrepressor like classical glucocorticoids, and seems not to be a "dissociated steroid" in primary human eOS in contrast to that reported in animal cells.

Dissociation of transactivation from transrepression by a selective glucocorticoid receptor agonist leads to separation of therapeutic effects from side effects

The selective GR agonists represent a promising previously undescribed class of drug candidates with an improved therapeutic index compared to classical GCs and are useful tool compounds for further investigating the mechanisms of GR-mediated effects.

Analysis of the Dissociated Steroid RU24858 Does Not Exclude a Role for Inducible Genes in the Anti-Inflammatory Actions of Glucocorticoids

It is concluded that glucocorticoid-dependent gene expression is necessary for repression by both dexamethasone and RU24858, and classic transactivation- and transrepressionbased screens for anti-inflammatory “dissociated” GR ligands may be flawed because they may not reflect the effects on real glucose-inducible genes.

Synthetic glucocorticoids that dissociate transactivation and AP-1 transrepression exhibit antiinflammatory activity in vivo.

Screening of a library of compounds using transactivation and AP-1 transrepression models in transiently transfected cells identified dissociated glucocorticoids, which exerted an antiinflammatory and immunosuppressive activity as potent as that of the classic glucoc Corticoid prednisolone.

A fully dissociated compound of plant origin for inflammatory gene repression.

Compound A (CpdA), a plant-derived phenyl aziridine precursor, although not belonging to the steroidal class of GR-binding ligands, does mediate gene-inhibitory effects by activating GR and may be a lead compound of a class of antiinflammatory agents with fully dissociated properties and might hold great potential for therapeutic use.

Therapeutic Benefit of a Dissociated Glucocorticoid and the Relevance of In Vitro Separation of Transrepression from Transactivation Activity

The results suggest that in vitro separation of transrepression from transactivation activity does not translate to an increased therapeutic ratio for GCs in vivo or that adverse effects are a consequence of trans repression.

Glucocorticoid repression of AP-1 is not mediated by competition for nuclear coactivators.

It is concluded that glucocorticoid repression occurs by a promoter-independent mechanism involving a nuclear interplay between activated GR and AP-1, independently of CBP levels in the cell.

Dissociated glucocorticoids with anti-inflammatory potential repress interleukin-6 gene expression by a nuclear factor-kappaB-dependent mechanism.

It is concluded that, in addition to dissociating transactivation from activator protein 1 transrepression, dissociated GCs mediate inhibition of NF-kappaB signaling by a mechanism that is independent of inhibitor kappaB induction.

Negative cross-talk between RelA and the glucocorticoid receptor: a possible mechanism for the antiinflammatory action of glucocorticoids.

Evidence is presented that the ligand-activated glucocorticoid receptor (GR) is able to repress RelA-mediated activation of the ICAM-1 NF-kappa B site, which highlights a possible molecular mechanism that can explain the antiinflammatory effects of glucoc Corticoid treatment during inflammation.

Glucocorticoids: effects on gene transcription.

Oxidative stress due to cigarette smoke may be an important factor in inducing glucocorticoid resistance in chronic obstructive pulmonary disease and may involve changes in histone acetylation/deacetylation balance.