Bamberger C M, Bamberger A M, de Castro M, Chrousos G P
National Institutes of Health, National Institute of Child Health and Human Development, Developmental Endocrinology Branch, Bethesda, Maryland 20892, USA.
J Clin Invest. 1995 Jun;95(6):2435-41. doi: 10.1172/JCI117943.
Alternative splicing of the human glucocorticoid receptor (hGR) pre-mRNA generates two highly homologous isoforms, termed hGR alpha and hGR beta. hGR alpha is a ligand-activated transcription factor which, in the hormone-bound state, modulates the expression of glucocorticoid-responsive genes by binding to specific glucocorticoid response element (GRE) DNA sequences. In contrast, hGR beta does not bind glucocorticoids and is transcriptionally inactive. We demonstrate here that hGR beta is able to inhibit the effects of hormone-activated hGR alpha on a glucocorticoid-responsive reporter gene in a concentration-dependent manner. [3H]-Dexamethasone binding studies indicate that hGR beta does not alter the affinity of hGR alpha for its hormonal ligand. The presence of hGR beta in nuclear extracts and its ability to bind to a radiolabeled GRE oligonucleotide suggest that its inhibitory effect may be due to competition for GRE target sites. Reverse transcription-PCR analysis shows expression of hGR beta mRNA in multiple human tissues. These results indicate that hGR beta may be a physiologically and pathophysiologically relevant endogenous inhibitor of glucocorticoid action, which may participate in defining the sensitivity of target tissues to glucocorticoids. They also underline the importance of distinguishing between the two receptor isoforms in all future studies of hGR function and the need to revisit old data.
人类糖皮质激素受体（hGR）前体mRNA的可变剪接产生了两种高度同源的异构体，即hGRα和hGRβ。hGRα是一种配体激活的转录因子，在激素结合状态下，通过与特定的糖皮质激素反应元件（GRE）DNA序列结合来调节糖皮质激素反应性基因的表达。相比之下，hGRβ不结合糖皮质激素且转录无活性。我们在此证明，hGRβ能够以浓度依赖的方式抑制激素激活的hGRα对糖皮质激素反应性报告基因的作用。[3H] - 地塞米松结合研究表明，hGRβ不会改变hGRα对其激素配体的亲和力。核提取物中存在hGRβ及其与放射性标记的GRE寡核苷酸结合的能力表明，其抑制作用可能是由于对GRE靶位点的竞争。逆转录 - PCR分析显示hGRβ mRNA在多种人类组织中表达。这些结果表明，hGRβ可能是糖皮质激素作用的一种生理和病理生理相关的内源性抑制剂，可能参与确定靶组织对糖皮质激素的敏感性。它们还强调了在未来所有hGR功能研究中区分两种受体异构体的重要性以及重新审视旧数据的必要性。
