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Human glucocorticoid receptor isoform beta: recent understanding of its potential implications in physiology and pathophysiology.

ABSTRACT: The human glucocorticoid receptor (GR) gene expresses two splicing isoforms alpha and beta through alternative use of specific exons 9alpha and 9beta. In contrast to the classic receptor GRalpha, which mediates most of the known actions of glucocorticoids, the functions of GRbeta have been largely unexplored. Owing to newly developed methods, for example microarrays and the jellyfish fluorescence proteins, we and others have recently revealed novel functions of GRbeta. Indeed, this enigmatic GR isoform influences positively and negatively the transcriptional activity of large subsets of genes, most of which are not responsive to glucocorticoids, in addition to its well-known dominant negative effect against GRalpha-mediated transcriptional activity. A recent report suggested that the "ligand-binding domain" of GRbeta is active, forming a functional ligand-binding pocket associated with the synthetic compound RU 486. In this review, we discuss the functions of GRbeta, its mechanisms of action, and its pathologic implications.

SUBMITTER: Kino T

PROVIDER: S-EPMC2796272 | biostudies-literature | 2009 Nov

REPOSITORIES: biostudies-literature

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Human glucocorticoid receptor isoform beta: recent understanding of its potential implications in physiology and pathophysiology.

Kino Tomoshige T Su Yan A YA Chrousos George P GP

Cellular and molecular life sciences : CMLS 20090726 21

The human glucocorticoid receptor (GR) gene expresses two splicing isoforms alpha and beta through alternative use of specific exons 9alpha and 9beta. In contrast to the classic receptor GRalpha, which mediates most of the known actions of glucocorticoids, the functions of GRbeta have been largely unexplored. Owing to newly developed methods, for example microarrays and the jellyfish fluorescence proteins, we and others have recently revealed novel functions of GRbeta. Indeed, this enigmatic GR ...[more]

PMID: 19633971

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Project description:Alternative splicing of the human glucocorticoid receptor gene generates two isoforms, hGRα and hGRβ. hGRβ functions as a dominant-negative regulator of hGRα activity and but also has inherent transcriptional activity, collectively altering glucocorticoid sensitivity. Single-nucleotide polymorphisms in the 3' UTR of hGRβ have been associated with altered receptor protein expression, glucocorticoid sensitivity, and disease risk. Characterization of the hGRβ G3134T polymorphism has been limited to a relatively small, homogenous population. The objective of this study was to determine the prevalence of hGRβ G3134T in a diverse population and assess the association of hGRβ G3134T in this population with physiological outcomes. In a prospective cohort study, 3730 genetically diverse participants were genotyped for hGRβ G3134T and four common GR polymorphisms. A subset of these participants was evaluated for clinical and biochemical measurements. Immortalized human osteosarcoma cells (U-2 OS), stably transfected with wild-type or G3134T hGRβ, were evaluated for receptor expression, stability, and genome-wide gene expression. Glucocorticoid-mediated gene expression profiles were investigated in primary macrophages isolated from participants. In a racially diverse population, the minor allele frequency was 74% (50.7% heterozygous carriers and 23.3% homozygous minor allele), with a higher prevalence in Caucasian non-Hispanic participants. After adjusting for confounding variable, carriers of hGRβ G3134T were more likely to self-report allergies, have higher serum cortisol levels, and reduced cortisol suppression in response to low-dose dexamethasone. The presence of hGRβ G3134T in U-2 OS cells increased hGR mRNA stability and protein expression. Microarray analysis revealed that the presence of the hGRβ G3134T polymorphism uniquely altered gene expression profiles in U-2 OS cells and primary macrophages. hGRβ G3134T is significantly present in the study population and associated with race, self-reported disease, and serum levels of glucocorticoids. Underlying these health differences may be changes in gene expression driven by altered receptor stability.

Dataset Information

Human glucocorticoid receptor isoform beta: recent understanding of its potential implications in physiology and pathophysiology.

Publications

Human glucocorticoid receptor isoform beta: recent understanding of its potential implications in physiology and pathophysiology.

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