Glucocorticoid receptor isoforms generate transcription specificity

doi:10.1016/j.tcb.2006.04.005

Trends in Cell Biology

Volume 16, Issue 6, June 2006, Pages 301-307

https://doi.org/10.1016/j.tcb.2006.04.005 Get rights and content

Glucocorticoids are necessary for life and are essential in all aspects of health and disease as they regulate processes from mitosis to apoptosis, from metabolism to growth and development. However, responses to glucocorticoids vary among individuals, cells and tissues. Recent evidence indicates that multiple glucocorticoid receptor (GR) isoforms are generated from one single GR gene by alternative splicing and alternative translation initiation. These isoforms all have unique tissue distribution patterns and transcriptional regulatory profiles. Furthermore, each is subject to various post-translational modifications that affect receptor function. Thus, increasing evidence suggests that unique GR isoform compositions within cells could determine the cell-specific response to glucocorticoids. Here, we discuss a new molecular model potentially underlying tissue-specific glucocorticoid resistance and selectivity.

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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Trends in Cell Biology

Glucocorticoid receptor isoforms generate transcription specificity

Introduction

Section snippets

The glucocorticoid receptor transcriptome

Molecular basis for tissue-specific glucocorticoid responses

GR splice variants

GRα isoforms

Post-translational modification of GR isoforms

Concluding remarks

J. Steroid Biochem. Mol. Biol.

J. Steroid Biochem. Mol. Biol.

Trends Biochem. Sci.

Mol. Cell

J. Steroid Biochem. Mol. Biol.

Genomics

J. Biol. Chem.

J. Steroid Biochem. Mol. Biol.

Vitam. Horm.

J. Biol. Chem.

Gastroenterology

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Gene

Antiinflammatory action of glucocorticoids – new mechanisms for old drugs

N. Engl. J. Med.

The origin and functions of multiple human glucocorticoid receptor isoforms

Ann. N. Y. Acad. Sci.

Gene profiling reveals unknown enhancing and suppressive actions of glucocorticoids on immune cells

FASEB J.

Differential gene expression profile of glucocorticoids, testosterone, and dehydroepiandrosterone in human cells

Horm. Metab. Res.

Expression profiling of glucocorticoid-treated T-ALL cell lines: rapid repression of multiple genes involved in RNA-, protein- and nucleotide synthesis

Oncogene

Gene expression profiles of proliferating vs. G1/G0 arrested human leukemia cells suggest a mechanism for glucocorticoid-induced apoptosis

FASEB J.