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Jeremy C. O'Connor, Deborah M. Wallace, Colm J. O'Brien, Thomas G. Cotter; A Novel Antioxidant Function for the Tumor-Suppressor Gene p53 in the Retinal Ganglion Cell. Invest. Ophthalmol. Vis. Sci. 2008;49(10):4237-4244. doi: 10.1167/iovs.08-1963.
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purpose. Recent evidence has suggested that the tumor-suppressor gene p53 has a role in regulating antioxidant response in cancer cells. This study was conducted to determine whether p53 regulates redox enzymes in a neuronal context in RGCs and whether this regulation contributes to an increased survival signal.
methods. The expression of p53, and its putative responsive antioxidant enzymes sestrin 2, catalase, Cu/ZnSOD, and MnSOD were evaluated in the developing rat retina by immunohistochemistry and Western blot. Small interfering (si)RNA to p53 was used in an RGC cell line, RGC-5, and downstream effects on antioxidants observed by Western blot. Transcription factor–analysis software was used to identify p53 binding sites on the catalase promoter, and chromatin immunoprecipitation (ChIP) assays on whole retina to demonstrate in vivo binding. The effect of p53 deficiency on basal reactive oxygen species levels (ROS) within the RGC and on susceptibility to oxidative-signaling–induced apoptosis was measured by flow cytometry.
results. Developmental expression patterns of p53 and catalase mirrored each other. p53 knockdown resulted in a significant decrease in catalase. p53-binding sites were identified on the rat catalase promoter and confirmed in vivo. p53 knockdown resulted in a corresponding increase in basal cellular ROS levels and increased susceptibility to oxidative-signaling–induced cell death.
conclusions. The results suggest a novel regulating influence of p53 on catalase in the retina—more specifically in the RGC—and an influence of p53 on the susceptibility of the cell to oxidative-signaling–induced apoptosis, which could implicate p53 as a potential neuroprotectant for the RGC.
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