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Abstract #46772 Published in IGR 13-3
Spliceosome protein (SRp) regulation of glucocorticoid receptor isoforms and the glucocorticoid response in human trabecular meshwork cells
Jain A; Wordinger RJ; Clark AFJournal of Steroid Biochemistry and Molecular Biology 2011; 126
Introduction: Glaucoma is a leading cause of visual impairment and blindness, with elevated intraocular pressure (IOP) as a major causative risk factor. Glucocorticoid (GC) therapy causes morphological and biochemical changes in the trabecular meshwork (TM), an ocular tissue involved in regulating IOP, which can lead to the development of glaucoma in susceptible individuals (steroid responders). Steroid responders comprise 40% of the general population and are at higher risk of developing glaucoma. In addition, almost all glaucoma patients are steroid responders. Differential distribution of various isoforms of GC receptor (GR) may be responsible for this heterogeneity in the steroid response. The alternatively spliced GR(beta) isoform acts as dominant negative regulator of classical GR(alpha) transcriptional activity. mRNA splicing is mediated by spliceosomes, which include SR proteins (SRps). The purpose of our study was to determine whether specific SRps regulate levels of these isoforms and therebyGC response in TM. Methods: Quantitative RT-PCR was used to determine the differential expression of SRp20, SRp30c and SRp40 in human normal and glaucomatous TM cell strains. A peptide modulator of splicing (bombesin) and SRp expression vectors were used to modulate SRps levels and determine their effects on GR(alpha)/GR(beta) ratios as well as dexamethasone (DEX) responsiveness via GRE-luciferase reporter activity, fibronectin and myocilin induction in TM cells. Results: SRp20, SRp30c and SRp40 regulate GR splicing and the GC response in TM cells. Modulation of SRps levels altered the GR(alpha)/(beta) ratio which correlated with DEX responsiveness. Bombesin increased SRp30c levels, decreased GR(alpha)/(beta) ratio, and suppressed DEX response in TM cells. Conclusion: Relative levels of SRp20, SRp30c, and SRp40 in TM cells control differential expression of the two alternatively spliced isoforms of the GR and thereby regulate GC responsiveness. Different levels and/or activities of these SRps may account for differential GC sensitivity among the normal and glaucoma populations.
A. Jain. UNT Health Science Center, Fort Worth, United States.
Classification:
2.5.1 Trabecular meshwork (Part of: 2 Anatomical structures in glaucoma > 2.5 Meshwork)
9.4.1 Steroid-induced glaucoma (Part of: 9 Clinical forms of glaucomas > 9.4 Glaucomas associated with other ocular and systemic disorders)