The Human Glucocorticoid Receptor β Isoform

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