Discovery of glucocorticoid receptor-beta in mice with a role in metabolism.
MOLECULAR ENDOCRINOLOGY(2013)
摘要
Glucocorticoid hormones control diverse physiological processes, including metabolism and immunity, by activating the major glucocorticoid receptor (GR) isoform, GR alpha. However, humans express an alternative isoform, human (h)GR beta, that acts as an inhibitor of hGR alpha to produce a state of glucocorticoid resistance. Indeed, evidence exists that hGR beta contributes to many diseases and resistance to glucocorticoid hormone therapy. However, rigorous testing of the GR beta contribution has not been possible, because rodents, especially mice, are not thought to express the beta-isoform. Here, we report expression of GR beta mRNA and protein in the mouse. The mGR beta isoform arises from a distinct alternative splicing mechanism utilizing intron 8, rather than exon 9 as in humans. The splicing event produces a form of beta that is similar in structure and functionality to hGR beta. Mouse (m)GR beta has a degenerate C-terminal region that is the same size as hGR beta. Using a variety of newly developed tools, such as a mGR beta-specific antibody and constructs for overexpression and short hairpin RNA knockdown, we demonstrate that mGR beta cannot bind dexamethasone agonist, is inhibitory of mGR alpha, and is up-regulated by inflammatory signals. These properties are the same as reported for hGR beta. Additionally, novel data is presented that mGR beta is involved in metabolism. When murine tissue culture cells are treated with insulin, no effect on mGR alpha expression was observed, but GR beta was elevated. In mice subjected to fasting-refeeding, a large increase of GR beta was seen in the liver, whereas mGR alpha was unchanged. This work uncovers the much-needed rodent model of GR beta for investigations of physiology and disease. (Molecular Endocrinology 24: 1715-1727, 2010)
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关键词
gene expression profiling,amino acid sequence,introns,gene expression regulation,glucocorticoid receptor,cos cells,gene silencing
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