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The Origin and Functions of Multiple Human Glucocorticoid Receptor Isoforms
NICK Z. LU AND
JOHN A. CIDLOWSKI
The Laboratory of Signal Transduction, Molecular Endocrinology Group, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina 27709, USA
Address for correspondence: John A. Cidlowski, The Laboratory of Signal Transduction, Molecular Endocrinology Group, National Institute of Environmental Health Sciences, NIH, Department of Health and Human Services, 111 Alexander Drive, Research Triangle Park, NC 27709. Voice: 919-541-1564; fax: 919-541-1367. cidlowski{at}niehs.nih.gov
Ann. N.Y. Acad. Sci. 1024: 102-123 (2004).
Glucocorticoid hormones are necessary for life and are essential in all aspects of human health and disease. The actions of glucocorticoids are mediated by the glucocorticoid receptor (GR), which binds glucocorticoid hormones and regulates gene expression, cell signaling, and homeostasis. Decades of research have focused on the mechanisms of action of one isoform of GR, GRa. However, in recent years, increasing numbers of human GR (hGR) isoforms have been reported. Evidence obtained from this and other laboratories indicates that multiple hGR isoforms are generated from one single hGR gene via mutations and/or polymorphisms, transcript alternative splicing, and alternative translation initiation. Each hGR protein, in turn, is subject to a variety of posttranslational modifications, and the nature and degree of posttranslational modification affect receptor function. We summarize here the processes that generate and modify various hGR isoforms with a focus on those that impact the ability of hGR to regulate target genes. We speculate that unique receptor compositions and relative receptor proportions within a cell determine the specific response to glucocorticoids. Unchecked expression of some isoforms, for example hGRß, has been implicated in various diseases.
Key Words: glucocorticoid receptor isoforms • alternative splicing • phosphorylation • ubiquitination • receptor mobility
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