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Content Provider | World Health Organization (WHO)-Global Index Medicus |
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Author | Wordinger, Robert J. Clark, Abbot F. Jain, Ankur Yorio, Thomas |
Description | Country affiliation: United States Author Affiliation: Jain A ( Department of Cell Biology and Anatomy, University of North Texas Health Science Center at Fort Worth, Fort Worth, Texas 76107, USA. anjain@live.unthsc.edu) |
Abstract | PURPOSE: 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 morphologic 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, a majority of 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 GRß isoform acts as dominant negative regulator of classical GR transcriptional activity. mRNA splicing is mediated by spliceosomes, which include serine-arginine rich proteins (SRps). The purpose of this study was to determine whether specific SRps regulate levels of these isoforms and thereby GC response in TM cells. METHODS: Quantitative RT-PCR, Western blot analysis, and immunocytochemistry were used to determine the differential expression of different SRps (SRp20, 30c, and 40) in human normal and glaucomatous TM cell strains. Bioinformatics was used to find putative binding sites for SRp20 and SRp40 on exon 9 of the GR gene. A peptide modulator of splicing (bombesin) and SRp expression vectors were used to modulate SRp levels and determine their effects on GR /GRß 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 SRp levels altered the GRß/ ratio that correlated with DEX responsiveness. Bombesin decreased SRp20; increased SRp30c, SRp40 levels, and GRß/ ratio, and suppressed DEX response in TM cells. CONCLUSIONS: 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. |
ISSN | 01460404 |
e-ISSN | 15525783 |
DOI | 10.1167/iovs.11-8497 |
Journal | Investigative Opthalmology & Visual Science |
Issue Number | 2 |
Volume Number | 53 |
Language | English |
Publisher | Association for Research in Vision and Ophthalmology |
Publisher Date | 2012-02-01 |
Publisher Place | United States |
Access Restriction | Open |
Subject Keyword | Gene Expression Regulation Glucocorticoids Pharmacology Rna, Messenger Genetics Receptors, Glucocorticoid Spliceosomes Trabecular Meshwork Metabolism Blotting, Western Cells, Cultured Electrophoresis, Agar Gel Enzyme-linked Immunosorbent Assay Gene Frequency Glaucoma Pathology Immunohistochemistry Nuclear Proteins Biosynthesis Rna-binding Proteins Real-time Polymerase Chain Reaction Serine-arginine Splicing Factors Cytology Drug Effects Comparative Study Research Support, N.i.h., Extramural Research Support, Non-u.s. Gov't Discipline Ophthalmology |
Content Type | Text |
Resource Type | Article |
Subject | Cellular and Molecular Neuroscience Ophthalmology Sensory Systems |
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