Trends in Cell Biology
Glucocorticoid receptor isoforms generate transcription specificity
Introduction
Tissue-specific regulation of glucocorticoid responses provides a challenge for researchers and physicians and the molecular mechanisms underlying the tissue-specific actions of glucocorticoids are not completely understood. Endogenous glucocorticoids are hormones secreted by the adrenal cortex that mediate various physiologic processes including metabolism, immune responses and electrolyte homeostasis. Reflecting this wide array of functions, synthetic glucocorticoids compose a large class of drugs indispensable in treating inflammation, autoimmune disorders, cancer, organ transplant rejection and brain edema [1]. Although glucocorticoids have extensive physiologic importance, the response to glucocorticoids is not uniform. Glucocorticoid sensitivity varies considerably among individuals; even within the same individual, responsiveness to glucocorticoids differs among tissues [1]. Studies using transgenic mouse models have shown that tissue-specific disruption of glucocorticoid signaling leads to loss of tissue-specific functions such as impaired growth (liver specific) and altered neuroendocrine functions (brain specific) [2]. Tissue-specific glucocorticoid resistance has been reported in several autoimmune and/or inflammatory diseases, such as rheumatoid arthritis, osteoarthritis, Crohn's disease, ulcerative colitis and asthma [3]. Interestingly, glucocorticoid sensitivity fluctuates not only in disease states, but also during normal physiological processes, including the cell cycle and during development [4]. These tissue type-specific, development stage-specific and pathology-specific glucocorticoid responses are a particular challenge for cell and molecular biologists attempting to elucidate the mechanisms of glucocorticoid action. Here, we outline the current knowledge regarding the tissue-specific actions of GR with particular emphasis on the recent discovery of multiple GR isoforms and their specific actions.
Section snippets
The glucocorticoid receptor transcriptome
Several molecular mechanisms underlying glucocorticoid actions have been elucidated, most of which involve transcriptional regulation of gene expression. GR that is not bound to ligand predominantly resides in the cytoplasm. Binding of glucocorticoids induces conformational changes in the receptor, dissociation from chaperone proteins, dimerization of the receptor, nuclear import and DNA binding [4]. Activated GR also selectively recruits cofactors in a coordinated fashion [5]. Many of the
Molecular basis for tissue-specific glucocorticoid responses
Three key elements can affect transcription regulation by glucocorticoids: ligand availability, the receptor itself, and recruitment of cofactors and other proteins. Two of these, ligand and protein recruitment, have been studied extensively. The bioavailability of glucocorticoids is tissue specific. In kidney, colon, pancreas and placenta, the expression of 11 β-hydroxysteroid dehydrogenase (11β-HSD2) is high [22] and this enzyme selectively converts active glucocorticoids such as cortisol to
GR splice variants
The GR gene contains nine exons: the first and last of which are subject to alternative splicing (Figure 2). Alternative splicing generates several GR splice variants [4], two of which (GRα and β) have been the focus of most studies because of their relative abundance. Amino acid sequence analysis revealed that GRα and GRβ isoforms are identical from the amino terminus to amino acid 727 but diverge beyond this position, with GRα having an additional 50 amino acids and GRβ having an additional,
GRα isoforms
Because GRα is generally expressed at much higher levels than GRβ in healthy individuals, who also have tissue-selective responses to glucocorticoids, additional mechanisms probably underlie the tissue-selective effects of glucocorticoids. In this regard, we have recently discovered additional GRα isoforms generated from translational mechanisms [7]. During translation of GRα transcripts, ribosome entry occurs at the 5′ end of the GRα message. Sequential addition of amino acids occurs after the
Post-translational modification of GR isoforms
GR isoform proteins are subject to covalent post-translational modifications, which further modulate the transcriptional activity of the receptor. Similar to most other nuclear receptors, GR proteins are phosphorylated at the N terminus of the receptor (Figure 2). At least five serine residues in human GR, S113, S141, S203, S211 and S226, are modified in this manner [32]. Phosphorylation of GR changes the transcriptional activity of the receptor on some genes but not on others [33]. For
Concluding remarks
A survey of eukaryotic mRNAs has revealed that alternative start codon usage can occur in as many as 5% of transcribed messages [43]. Protein isoforms generated via translational mechanisms have been identified for critical molecules such as transcription factors and growth factors [43]. The GRα isoforms described here demonstrate how the capability for a single gene can be maximized to control a wide range of cellular functions with fine-tuned precision. Interestingly, multiple AUG codons are
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