Buoso Erica, Galasso Marilisa, Ronfani Melania, Serafini Melania Maria, Lanni Cristina, Corsini Emanuela, Racchi Marco
Dipartimento di Scienze del Farmaco - Università degli Studi di Pavia, Viale Taramelli 12/14, 27100 Pavia, Italy.
Dipartimento di Scienze del Farmaco - Università degli Studi di Pavia, Viale Taramelli 12/14, 27100 Pavia, Italy; Scuola Universitaria Superiore IUSS Pavia, Piazza della Vittoria n.15, 27100 Pavia, Italy.
Pharmacol Res. 2017 Jun;120:180-187. doi: 10.1016/j.phrs.2017.03.019. Epub 2017 Mar 31.
Dehydroepiandrosterone (DHEA) can counteract the activity of cortisol by modulating the glucocorticoid receptor β (GRβ) expression and antagonizing the binding of GRα to the glucocorticoid responsive element (GRE) in RACK1 (Receptor for Activated C Kinase 1) promoter. These observations are important in the context of immunosenescence and can be extended to recognize a complex hormonal balance in the control of GR isoform expression and consequently in the expression of GR responsive genes. To elucidate the mechanism of DHEA on GR alternative splicing, we investigated its possible involvement in the expression of proteins such as the Serine/arginine (SR)-Rich Splicing Factors (SRSF) regulating GR splicing, specifically SRSF9 and SRSF3 also known as SRp30c and SRp20 respectively. We demonstrated that DHEA can induce the up-regulation of GR mRNA which is preferentially directed toward the β isoform. The effect is due to an increase in expression of the splicing factor SRSF9. On the other hand cortisol up-regulated SRSF3, the splicing factor promoting GRα isoform. We demonstrated that DHEA and cortisol modulate SRSF9 and SRSF3 in a different way and our data suggest that the anti-glucocorticoid effect of DHEA, among other mechanisms, is also exerted by modulating the expression of proteins involved in the splicing of the GR pre-mRNA.
脱氢表雄酮（DHEA）可通过调节糖皮质激素受体β（GRβ）的表达以及拮抗GRα与活化C激酶1受体（RACK1）启动子中的糖皮质激素反应元件（GRE）的结合来抵消皮质醇的活性。这些观察结果在免疫衰老的背景下很重要，并且可以扩展到认识到在GR异构体表达的控制以及GR反应性基因的表达中存在复杂的激素平衡。为了阐明DHEA对GR可变剪接的作用机制，我们研究了其可能参与调节GR剪接的蛋白质的表达，例如富含丝氨酸/精氨酸（SR）的剪接因子（SRSF），特别是分别也被称为SRp30c和SRp20的SRSF9和SRSF3。我们证明DHEA可以诱导GR mRNA的上调，且这种上调优先导向β异构体。这种效应是由于剪接因子SRSF9的表达增加所致。另一方面，皮质醇上调了促进GRα异构体的剪接因子SRSF3。我们证明DHEA和皮质醇以不同的方式调节SRSF9和SRSF3，并且我们的数据表明，DHEA的抗糖皮质激素作用，除其他机制外，还通过调节参与GR前体mRNA剪接的蛋白质的表达来发挥。
