Brm inhibits the proliferative response of keratinocytes and corneal epithelial cells to ultraviolet radiation-induced damage

Ultraviolet radiation (UV) from sunlight is the primary cause of skin and ocular neoplasia. Brahma (BRM) is part of the SWI/SNF chromatin remodeling complex. It provides energy for rearrangement of chromatin structure. Previously we have found that human skin tumours have a hotspot mutation in BRM a...

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Bibliographic Details
Published in:PloS one 2014-09, Vol.9 (9), p.e107931
Main Authors: Hassan, Nur Mohammad Monsur, Painter, Nicole, Howlett, C Rolfe, Farrell, Andrew W, Di Girolamo, Nick, Lyons, J Guy, Halliday, Gary M
Format: Article
Language:English
Subjects:
Alleles
Animal experimentation
Animal tissues
Animals
Atrophy
Cell division
Cell Division - radiation effects
Cell growth
Cell Proliferation - radiation effects
Chromatin remodeling
Cornea
Epidermis
Epithelial cells
Epithelium
Epithelium, Corneal - cytology
Epithelium, Corneal - metabolism
Epithelium, Corneal - radiation effects
Humans
Hyperplasia
Keratinocytes
Keratinocytes - cytology
Keratinocytes - metabolism
Keratinocytes - radiation effects
Ki-67 Antigen - metabolism
Medicine and Health Sciences
Mice
Mice, Inbred C57BL
Mutation
Mutation hot spots
Physical Sciences
Radiation damage
Radiation effects
Regeneration
Skin
Skin cancer
Stroma
Transcription Factors - deficiency
Transcription Factors - metabolism
Tumor Suppressor Protein p53 - genetics
Tumors
U.V. radiation
Ultraviolet radiation
Ultraviolet Rays - adverse effects
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Summary:Ultraviolet radiation (UV) from sunlight is the primary cause of skin and ocular neoplasia. Brahma (BRM) is part of the SWI/SNF chromatin remodeling complex. It provides energy for rearrangement of chromatin structure. Previously we have found that human skin tumours have a hotspot mutation in BRM and that protein levels are substantially reduced. Brm-/- mice have enhanced susceptibility to photocarcinogenesis. In these experiments, Brm-/- mice, with both or a single Trp53 allele were exposed to UV for 2 or 25 weeks. In wild type mice the central cornea and stroma became atrophic with increasing time of exposure while the peripheral regions became hyperplastic, presumably as a reparative process. Brm-/-, Trp53+/-, and particularly the Brm-/- Trp53+/- mice had an exaggerated hyperplastic regeneration response in the corneal epithelium and stroma so that the central epithelial atrophy or stromal loss was reduced. UV induced hyperplasia of the epidermis and corneal epithelium, with an increase in the number of dividing cells as determined by Ki-67 expression. This response was considerably greater in both the Brm-/- Trp53+/+ and Brm-/- Trp53+/- mice indicating that Brm protects from UV-induced enhancement of cell division, even with loss of one Trp53 allele. Cell division was disorganized in Brm-/- mice. Rather than being restricted to the basement membrane region, dividing cells were also present in the suprabasal regions of both tissues. Brm appears to be a tumour suppressor gene that protects from skin and ocular photocarcinogenesis. These studies indicate that Brm protects from UV-induced hyperplastic growth in both cutaneous and corneal keratinocytes, which may contribute to the ability of Brm to protect from photocarcinogenesis.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0107931