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D.W. Li, J.–P. Liu, P.C. Schmid, R. Schlosser, H. Feng, W.–B. Liu, Q. Yan, L. Gong, S. Sun, M. Deng, Y. Liu; Protein Phosphatase–1 Dephosphorylates P53 At Ser–15 And Ser–37 To Modulate Its Transcriptional And Apoptotic Activities . Invest. Ophthalmol. Vis. Sci. 2006;47(13):2550.
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We have previously demonstrated that the serine/threonine protein phosphatase–1 (PP–1) plays an important role in promoting survival of lens epithelial cells. However, how PP–1 promotes survival remain largely unknown. In the present study, we provide strong evidence to show that PP–1 can directly dephosphorylate a master regulator of apoptosis, p53, to negatively modulate its transcriptional and apoptotic activities, and thus to promote cell survival.
Dephosphorylation of p53 at Ser–15 and Ser–37 by protein phosphatase–1 was explored with in vitro dephosphorylation assay, co–immunoprecipitation, and in vivo dephosphorylation assays. The function of both wild type and mutant (imitating constant phosphorylation or dephosphorylation at Ser–15 and Ser–37) p53 in regulating gene expression and mediating apoptosis was analyzed with reporter activity assay, RNAi and apoptosis assays. The phosphorylation status of p53 was analyzed with Western blot analysis.
PP–1 and P53 can form in vivo complex. PP–1 directly dephosphorylates p53 at Ser–15 and Ser–37 both in vitro and in vivo. Overexpression or silence of the gene encoding the catalytic subunit for PP–1 causes corresponding hypo– or hyperphosphorylation of p53 at Ser–15 and Ser–37. Mutations imitating constant phosphorylation of p53 at the above sites enhance p53 transactivity and apoptotic activity. In contrast, mutations imitating constant dephosphorylation substantial attenuate p53 functions in the above aspects.
Dephosphorylation of p53 by PP–1 has as important impact on its functions as phosphorylation does. One of the molecular mechanisms by which PP–1 promotes cell survival is derived from its ability to dephosphorylate p53, and thus negatively regulate p53–dependent apoptosis. Supported by EY 15765, the Hormel Foundation, and the Lotus Scholar Professorship funds from Hunan Province Government and Hunan Normal University.
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