Separating transrepression and transactivation: a distressing divorce for the glucocorticoid receptor?

Newton, Robert and Holden, Neil S. (2007) Separating transrepression and transactivation: a distressing divorce for the glucocorticoid receptor? Molecular pharmacology, 72 (4). pp. 799-809. ISSN 0026-895X

Full content URL: http://molpharm.aspetjournals.org/content/72/4/799

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Separating transrepression and transactivation: a distressing divorce for the glucocorticoid receptor?

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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-kappaB, 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.

Keywords:glucocorticoids, endothelium cell, gene expression, Transactivation, gene transcription, anti-inflammatories
Subjects:B Subjects allied to Medicine > B210 Pharmacology
Divisions:College of Science > School of Life Sciences
ID Code:15127
Deposited On:21 Nov 2014 11:23

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