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

Abstract

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 effect has been predominantly attributed to the repression of key inflammatory transcription factors, including AP-1 and NF-B, and is termed transrepression. The ability to functionally separate these transcriptional functions of GR has prompted a search for dissociated GR ligands that can differentially induce transrepression but not transactivation. In this review, we present evidence that post-transcriptional mechanisms of action are highly important to the anti-inflammatory actions of glucocorticoids. Furthermore, we present the case that mechanistically distinct forms of glucocorticoid-inducible gene expression are critical to the development of anti-inflammatory effects by repressing inflammatory signaling pathways and inflammatory gene expression at multiple levels. Considerable care is therefore required to avoid loss of anti-inflammatory effectiveness in the development of novel transactivation-defective ligands of GR.

Repression of DNA-binding dependent glucocorticoid receptor-mediated gene expression

“…Because of the central role of GR in multiple inflammatory response pathways and its role as a drug target, mechanistic studies of GR-modulated gene expression are a growing field of study. However, the multiple mechanisms by which GR mediates gene expression makes identification of GR target genes a challenge (6,15,31). The complex transcriptional activity of the GR involves DNA-binding dependent as well as DNA-binding independent mechanisms that result in both gene activation and gene repression.…”

“…Like other steroid hormone receptors, GR is known to modulate gene transcription via the binding of receptor dimers to specific palindromic sequences called glucocorticoid response elements (GREs), usually located in the cis-regulatory region of target genes-a mode of action termed transactivation. Additionally, the GR has been shown to exert its actions through an indirect non-DNA-binding mechanism, termed transrepression, in which transcriptional modulation is achieved through cross-talk between GR and other transcription factors such as NF-B (3), activator protein-1 (AP-1) (4, 5), Sma and Mad-related protein, and members of the STAT family (6). This protein-protein cross-talk does not require the DNA-binding activity of the GR, because GR mutants that are deficient in dimerization function have been shown to lose DNA-binding ability as well as simple GRE-mediated transcription function but retain their transrepression activity (4,7).…”

Δ-9,11 Modification of Glucocorticoids Dissociates Nuclear Factor-κB Inhibitory Efficacy from Glucocorticoid Response Element-Associated Side Effects

“…Transrepression involves ligand/receptor interactions with other cellular signaling proteins, such as the inhibition of nuclear factor-B (NF-B) complexes (Rhen and Cidlowski, 2005;Newton and Holden, 2007). Transrepression has been associated with anti-inflammatory activity and clinical efficacy.…”

“…Transactivation (also termed cis-regulation) is mediated by ligand/glucocorticoid receptor (GR) translocation from the cytoplasm to the nucleus, with ligand/receptor dimers binding directly to glucocorticoid response elements (GREs) in the promoters of target genes (Dostert and Heinzel, 2004). Transactivation has been associated with deleterious side effects (Newton and Holden, 2007).…”

“…However, the side-effect profiles of pharmacological glucocorticoids are significant, including muscle atrophy, adrenal deficiency, osteoporosis, spleen atrophy, short stature, and mood and sleep disturbances, among others (Chrousos et al, 1993;DeBosscher, 2010). This has led to a search for dissociative steroids-drugs able to retain activities responsible for molecular and clinical efficacy with the loss of subactivities responsible for side effects (Newton and Holden, 2007).…”