Lindemeyer R G, Robertson N M, Litwack G
Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, Pennsylvania 19140.
Cancer Res. 1990 Dec 15;50(24):7985-91.
The mechanism of action of the synthetic glucocorticoid antagonist, RU 38486, has yet to be completely elucidated. Although RU 38486 is a potent antiglucocorticoid in vivo, several studies have indicated that it has some agonist activities in vitro, such as high-affinity steroid binding to the receptor, activation, and DNA binding. Nevertheless, these in vitro postbinding events do not lead to any known gene expression. To understand the action of the glucocorticoid antagonist RU 38486, we studied glucocorticoid receptor localization on a mouse melanoma cell line (B16C3) by indirect immunofluorescent staining techniques, using monoclonal antibodies to the glucocorticoid receptor. Our data in intact cells suggest that, unlike glucocorticoid agonists such as triamcinolone acetonide, and similar to the glucocorticoid antagonist cortexolone, RU 38486-bound receptors do not translocate to the nucleus and hence do not allow for transcription of glucocorticoid-regulated genes to occur. Passage through the nuclear membrane may be a rate-limiting step in the action of glucocorticoid antagonists, and translocation may in itself be an important regulatory mechanism of steroid hormone action.
合成糖皮质激素拮抗剂RU 38486的作用机制尚未完全阐明。尽管RU 38486在体内是一种强效抗糖皮质激素，但多项研究表明它在体外具有一些激动剂活性，如与受体的高亲和力类固醇结合、激活和DNA结合。然而，这些体外结合后事件不会导致任何已知的基因表达。为了了解糖皮质激素拮抗剂RU 38486的作用，我们使用抗糖皮质激素受体单克隆抗体，通过间接免疫荧光染色技术研究了糖皮质激素受体在小鼠黑色素瘤细胞系（B16C3）上的定位。我们在完整细胞中的数据表明，与糖皮质激素激动剂如曲安奈德不同，与糖皮质激素拮抗剂皮质酮类似，与RU 38486结合的受体不会转运到细胞核，因此不会使糖皮质激素调节的基因发生转录。穿过核膜可能是糖皮质激素拮抗剂作用中的一个限速步骤，而转运本身可能是类固醇激素作用的一种重要调节机制。
