title: Brm inhibits the proliferative response of keratinocytes and corneal epithelial cells to ultraviolet radiation-induced damage.
abstract: 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.
authors.affiliation: Discipline of Dermatology, Bosch Institute, Sydney Medical School, Royal Prince Alfred Hospital and University of Sydney, Sydney, Australia.
authors.forename: Nur Mohammad Monsur
authors.initials: NM
authors.lastname: Hassan
authors.affiliation: Discipline of Dermatology, Bosch Institute, Sydney Medical School, Royal Prince Alfred Hospital and University of Sydney, Sydney, Australia.
authors.forename: Nicole
authors.initials: N
authors.lastname: Painter
authors.affiliation: Department of Pathology and Graduate School of Biomedical Engineering, University of New South Wales, Sydney, Australia.
authors.forename: C Rolfe
authors.initials: CR
authors.lastname: Howlett
authors.affiliation: Discipline of Dermatology, Bosch Institute, Sydney Medical School, Royal Prince Alfred Hospital and University of Sydney, Sydney, Australia.
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Farrell
authors.affiliation: School of Medical Sciences, University of New South Wales, Sydney, Australia.
authors.forename: Nick
authors.initials: N
authors.lastname: Di Girolamo
authors.affiliation: Discipline of Dermatology, Bosch Institute, Sydney Medical School, Royal Prince Alfred Hospital and University of Sydney, Sydney, Australia; Sydney Head and Neck Cancer Institute, Cancer Services, Royal Prince Alfred Hospital, Sydney, Australia.
authors.forename: J Guy
authors.initials: JG
authors.lastname: Lyons
authors.affiliation: Discipline of Dermatology, Bosch Institute, Sydney Medical School, Royal Prince Alfred Hospital and University of Sydney, Sydney, Australia.
authors.forename: Gary M
authors.initials: GM
authors.lastname: Halliday
mesh_terms: D000483:Alleles; D000818:Animals; D002455:Cell Division / Q000528:radiation effects; D049109:Cell Proliferation / Q000528:radiation effects; D019573:Epithelium, Corneal / Q000166:cytology* / Q000378:metabolism / Q000528:radiation effects*; D006801:Humans; D015603:Keratinocytes / Q000166:cytology* / Q000378:metabolism / Q000528:radiation effects*; D019394:Ki-67 Antigen / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D014157:Transcription Factors / Q000172:deficiency / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D014466:Ultraviolet Rays / Q000009:adverse effects*
chemical_list: D019394:Ki-67 Antigen; C499503:Smarca2 protein, mouse; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53