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Xiangcheng Tang, Fangyuan Liu, Zhongwen Luo, Weike Ji, Wenfeng Hu, Xiaohui Hu, Yizhi Liu, David W Li; Protein Serine/Threonine Phosphatases Dephosphorylate p53 at Multiple Sites and Negatively Regulates Its Ability on Lens Differentiation. Invest. Ophthalmol. Vis. Sci. 2014;55(13):742.
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© ARVO (1962-2015); The Authors (2016-present)
p53 is a transcription factor and play essential role in the ocular lens. Previous studies have shown that inactivation of p53 by viral gene expression or knockout leads to cataractogenesis. Our recent results provide first evidence that p53 regulates lens differentiation through control of both transcription factors, C-Maf and Prox-1, and also lens crystallin genes encoding alpha- and beta-crystallins. In the present study, we present evidence to show that PP-1 and PP-2A can dephosphorylate p53 at multiple sites (Ser-6, Ser-9 and Ser-20) to control its ability in regulating C-Maf, Prox-1, alphaA- and betaA3/A1-crystallin genes.
Human lens epithelial cells and alphaTN4-1 mouse lens epithelial cells were used as testing systems. Co-immunoprecipitation assays, in vitro dephosphorylation assay, inhibition of phosphatase activity, overexpression and knockdown of various subunits from PP-1 and PP-2A were used to determine the specific dephosphorylation of p53 by PP-1 and PP-2A. Reverse transcription polymerase chain reaction, Western-blot analysis and reporter gene activity assays were used to study gene expression involved in lens differentiation.
p53 was differentially phosphorylated at different sites during mouse lens development. PP-1 and PP-2A can dephosphorylate p53 at Ser-6, Ser-9 and Ser-20. Changes in the phosphorylation status of p53 at these sites alters its transcriptional activity and negatively regulates the expression of C-Maf, Prox-1, alphaA- and betaA3/A1-crystallin genes.
PP-1 and -2A directly dephosphorylate p53 to regulate lens differentiation via control of expression of the downstream genes.
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