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Wenfeng Hu, Xiao-Hui Hu, Weike Ji, Mi Deng, Zachary Woodward, David Li; The Function of the E3 Ligase, MDM2 Is Subjected to Dephosphorylation Regulation by Protein Serine/Threonine Phosphatase-1 and -2A. Invest. Ophthalmol. Vis. Sci. 2013;54(15):477. doi: https://doi.org/.
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Stress-induced apoptosis of lens epithelial cells plays an important role during stress-induced cataractogenesis. As the major serine/threonine phosphatases, our previous studies have shown that PP-1 and PP-2A are implicated in regulation of p53 functions and thus participate in the control of p53-mediated apoptosis. On the other hand, the stability of p53 is regulated by the E3 ligase, MDM2. Whether PP-1 or PP-2A directly regulates the function of MDM2 through dephosphorylation to control p53 functions remains largely unknown. The present study investigates the dephosphorylation regulation of MDM2 functions by PP-1 and PP-2A.
Human lens epithelial cells, alphaTN4-1 mouse lens epithelial cells, wild type and p53 knockout mice were used as testing systems. Lens epithelial cells or organ cultures were subjected to different oxidative stress conditions. Co-immunoprecipitation assays were used to investigate the interaction between MDM2 and PP-1/-2A. Immunofluroescence was used to detect the expression patterns of MDM2 in embryonic lens from wild type and p53 knockout mice. QRT-PCR and Western-blot analysis were used to study the activation of MDM2 signaling pathway under various conditions of PP-1/-2A expression (overexpression and knockdown).
In the p53 knockout mice, expression of MDM2 was significantly decreased during embryonic development of mouse lens. Both PP-1 and PP-2A can dephosphorylate MDM2 as demonstrated from Co-IP between MDM2 and PP-1/-2A, and overexpression and knockdown of PP-1 and -2A.
PP-1 and -2A directly dephosphorylate MDM2 to modulate its interaction with p53 and thus regulate oxidative stress-induced apoptosis of lens epithelial cells. (Supported by EY018380, CSC and HNU)
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