title: Role of spliceosome proteins in the regulation of glucocorticoid receptor isoforms by cortisol and dehydroepiandrosterone.
abstract: 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.
authors.affiliation: Dipartimento di Scienze del Farmaco - Università degli Studi di Pavia, Viale Taramelli 12/14, 27100 Pavia, Italy.
authors.forename: Erica
authors.initials: E
authors.lastname: Buoso
authors.affiliation: Dipartimento di Scienze del Farmaco - Università degli Studi di Pavia, Viale Taramelli 12/14, 27100 Pavia, Italy.
authors.forename: Marilisa
authors.initials: M
authors.lastname: Galasso
authors.affiliation: Dipartimento di Scienze del Farmaco - Università degli Studi di Pavia, Viale Taramelli 12/14, 27100 Pavia, Italy.
authors.forename: Melania
authors.initials: M
authors.lastname: Ronfani
authors.affiliation: 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.
authors.forename: Melania Maria
authors.initials: MM
authors.lastname: Serafini
authors.affiliation: Dipartimento di Scienze del Farmaco - Università degli Studi di Pavia, Viale Taramelli 12/14, 27100 Pavia, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Lanni
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari - Università degli Studi di Milano, Via Balzaretti 9, 20133 Milano, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Corsini
authors.affiliation: Dipartimento di Scienze del Farmaco - Università degli Studi di Pavia, Viale Taramelli 12/14, 27100 Pavia, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Racchi
mesh_terms: D017398:Alternative Splicing; D002460:Cell Line; D003687:Dehydroepiandrosterone / Q000378:metabolism*; D005786:Gene Expression Regulation; D020868:Gene Silencing; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism*; D020033:Protein Isoforms / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D011965:Receptors, Glucocorticoid / Q000235:genetics*; D000068103:Serine-Arginine Splicing Factors / Q000235:genetics* / Q000378:metabolism; D017381:Spliceosomes / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D020033:Protein Isoforms; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; C491388:SRSF3 protein, human; C000595778:SRSF9 protein, human; C411470:glucocorticoid receptor alpha; C121943:glucocorticoid receptor beta; D000068103:Serine-Arginine Splicing Factors; D003687:Dehydroepiandrosterone; D006854:Hydrocortisone
keywords: Cortisol; Dehydroepiandrosterone (DHEA); Glucocorticoid receptor (GR); RACK1; Serine/arginine-Rich Splicing Factor 3(SRSF3); Serine/arginine-Rich Splicing Factor 9 (SRSF9)