Generalised Glucocorticoid Resistance

Generalised Glucocorticoid Resistance

Charmandari Evangelia, Chrousos George P, Kino Tomoshige
US Endocrinology - Volume 4 - Issue II European Endocrinology - Volume 4 - Issue II
Published: February 2009
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Glucocorticoids are steroid hormones synthesised and secreted by the adrenal cortices under the regulation of the hypothalamic–pituitary– adrenal (HPA) axis. Glucocorticoids regulate a broad spectrum of physiological functions essential for life and play an important role in the maintenance of basal and stress-related homeostasis.1–4 At the cellular level, the actions of glucocorticoids are mediated by the human glucocorticoid receptor (hGR), which belongs to the steroid/thyroid/ retinoic acid nuclear receptor superfamily of transcription factor proteins and is expressed in virtually all cells.5,6

The gene encoding hGRα(hGR gene) is one locus on the long arm of chromosome 5 (q31.3), and consists of nine exons spanning over 150kb. Expressed hGRαis a panel of eight amino terminal translational isoforms of varying lengths, each of which consists of three subdomains: the N-terminal (NTD), the DNA-binding (DBD) and the ligand-binding (LBD) domains. In our expression and functional studies referred to here we have employed as representative the longest GRαisoform, comprising 777 amino acids. The hGR gene also produces an equal number of hGRβisoforms by the use of an alternative 3’ exon 9β, which cannot bind glucocorticoids and exert a dominant negative effect upon the transcriptional activity of hGRα.1,5,6

In the absence of ligand, hGRαresides mostly in the cytoplasm of cells as part of a hetero-oligomeric complex, which contains chaperon heat shock proteins (HSPs) 90, 70, 23 and FKBP51, as well as other proteins.7 Upon ligand-induced activation, the receptor dissociates from this multiprotein complex and translocates into the nucleus through the nuclear pore with the energy-dependent mechanism that includes importin αand β. Inside the nucleus, hGRαbinds as a homodimer to glucocorticoid response elements (GREs) in the promoter regions of target genes and regulates their expression positively or negatively, depending on GRE sequence and promoter context.7–10 The ligand-activated hGRαcan also modulate gene expression independently of DNA binding by interacting, possibly as a monomer, with other transcription factors such as nuclear factor-κB (NF-κB), activator protein1 (AP-1), p53 and signal transducers and activators of transcription (STATs)11–14 (see Figure 1a).

To initiate the transcription, hGRαuses its transcriptional activation domains, activation function (AF)-1 and AF-2, located in NTD and LBD, respectively, as surfaces to interact with co-activators or co-repressors.15–19 The p160 co-activators such as the glucocorticoid receptor-interacting protein 1 (GRIP1) play an important role in the hGRα-mediated transactivation of glucocorticoid-responsive genes given that they interact directly with both the AF-1 of hGRαthrough their carboxyl-terminal domain and the AF-2 through multiple amphipathic LXXLL signature motifs located in their nuclear receptor-binding (NRB) domain.20 They also have histone acetyltransferase (HAT) activity, which promotes chromatin decondensation and facilitates initiation of transcription15–18 (see Figure 1b).
Alterations in the molecular mechanisms of hGRαaction may lead to alterations in tissue sensitivity to glucocorticoids, which may take the form of resistance or hypersensitivity and may be associated with significant morbidity.21–24 In this article we summarise the molecular mechanisms underlying primary generalised glucocorticoid resistance and secondary, inflammation-induced, generalised glucocorticoid resistance.

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