A novel role for CRIM1 in the corneal response to UV and pterygium development
| Autor: | Jonathan E. Moore, Pieter Gouws, Laura Mairs, Alastair T. Pagnamenta, M. Andrew Nesbit, Davide Schiroli, Barry O'Hagan, Jenny C. Taylor, Dave Goldsmith, Sarah D. Atkinson, Daniel E. Illanes-Velarde, Jesus J.D. Vasquez, Tara Moore, David G. Courtney, Victoria McGilligan, Eleonora Maurizi |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
Adult
Male MAPK/ERK pathway Ultraviolet Rays Angiogenesis Proliferation Blotting Western Mutation Missense Apoptosis Pterygium Real-Time Polymerase Chain Reaction Pathogenesis CRIM1 Cellular and Molecular Neuroscience Cornea In Situ Nick-End Labeling Ultraviolet light medicine Humans Variant Phosphorylation RNA Small Interfering Extracellular Signal-Regulated MAP Kinases Cells Cultured Whole Genome Sequencing Pterygium (conjunctiva) Chemistry Cell growth ERK UV Epithelium Corneal Membrane Proteins Bone Morphogenetic Protein Receptors Middle Aged medicine.disease Immunohistochemistry Sensory Systems eye diseases Pedigree Ophthalmology medicine.anatomical_structure Gene Expression Regulation Proto-Oncogene Proteins c-bcl-2 Mutagenesis Site-Directed Cancer research Female sense organs |
| Zdroj: | Experimental Eye Research. 179 |
| ISSN: | 1096-0007 0014-4835 |
| Popis: | Pterygium is a pathological proliferative condition of the ocular surface, characterised by formation of a highly vascularised, fibrous tissue arising from the limbus that invades the central cornea leading to visual disturbance and, if untreated, blindness. Whilst chronic ultraviolet (UV) light exposure plays a major role in its pathogenesis, higher susceptibility to pterygium is observed in some families, suggesting a genetic component. In this study, a Northern Irish family affected by pterygium but reporting little direct exposure to UV was identified carrying a missense variant in CRIM1 NM_016441.2: c.1235 A > C (H412P) through whole-exome sequencing and subsequent analysis. CRIM1 is expressed in the developing eye, adult cornea and conjunctiva, having a role in cell differentiation and migration but also in angiogenesis, all processes involved in pterygium formation. We demonstrate elevated CRIM1 expression in pterygium tissue from additional individual Northern Irish patients compared to unaffected conjunctival controls. UV irradiation of HCE-S cells resulted in an increase in ERK phosphorylation and CRIM1 expression, the latter further elevated by the addition of the MEK1/2 inhibitor, U0126. Conversely, siRNA knockdown of CRIM1 led to decreased UV-induced ERK phosphorylation and increased BCL2 expression. Transient expression of the mutant H412P CRIM1 in corneal epithelial HCE-S cells showed that, unlike wild-type CRIM1, it was unable to reduce the cell proliferation, increased ERK phosphorylation and apoptosis induced through a decrease of BCL2 expression levels. We propose here a series of intracellular events where CRIM1 regulation of the ERK pathway prevents UV-induced cell proliferation and may play an important role in the in the pathogenesis of pterygium. |
| Databáze: | OpenAIRE |
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