The human glucocorticoid receptor beta isoform - Expression, biochemical properties, and putative function

Alternative splicing of the human glucocorticoid receptor (hGR) primary transcript produces two receptor isoforms, hGR alpha and hGR beta, which differ at their carboxyl termini. The hGR alpha isoform conveys endocrine information to target tissues by altering patterns of gene expression in a hormone-dependent fashion, In contrast to hGR alpha, very little is known about the hGR beta splice variant. Using hGR alpha- and hGR beta-specific riboprobes on human multiple tissue Northern blots, we show that the hGR beta message has a widespread tissue distribution. We also prove by reverse transcriptase-polymerase chain reaction that the alternative splicing event underlying the formation of the hGR beta message occurs in these tissues. Because the hGR beta protein differs from hGR alpha at the extreme COOH terminus, we investigated several of the biochemical properties of hGR beta expressed in transfected cells. hGR beta does not bind the glucocorticoid agonist dexamethasone nor the glucocorticoid antagonist RU38486 in vivo. Moreover, in contrast to hGR beta, hGR beta is located primarily in the nucleus of transfected cells independent of hormone administration, Finally, in the absence of hGR alpha, hGR beta is transcriptionally inactive on a glucocorticoid-responsive enhancer. However, when both isoforms are expressed in the same cell, hGR beta inhibits the hormone-induced, hGR alpha-mediated stimulation of gene expression. Thus, hGR beta potentially functions as a dominant negative inhibitor of hGR alpha activity.