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[摘要]:Protein phosphatase 2A (PP2A) is a family of heterotrimeric protein phosphatases that has a multitude of functions inside the cell, acting through various substrate targets in cell-signaling pathways. Recent evidence suggests that a subset of PP2A holoenzymes function as tumor suppressors and one particular family of B subunits, B56, are implicated in this function. However, the regulatory mechanisms that govern activation of B56-PP2A tumor-suppressive function have not been elucidated. In the present study, we demonstrate that ataxia-telangiectasia mutated (ATM) directly phosphorylates and specifically regulates B56 gamma 3, B56 gamma 2 and B56 delta, after DNA damage. We further show that phosphorylation of B56 gamma 3 at Ser510 leads to an increase in B56 gamma 3-PP2A complexes, and direction of PP2A phosphatase activity toward the substrate p53, activating its tumor-suppressive functions. In addition, we found that under cell growth conditions B56 gamma 3 is kept at low levels through the actions of the E3 ubiquitin ligase MDM2, and, importantly, phosphorylation of B56 gamma 3 by ATM leads to upregulation of the protein by blocking MDM2-mediated B56 gamma 3 ubiquitination. Finally, we show that Ser510 phosphorylation significantly enhances the ability of B56 gamma 3 to inhibit cell proliferation and anchorage-independent growth. These results provide mechanistic insight into the regulation of PP2A tumor-suppressive function, and suggest a model for parallel regulation of p53 and B56 gamma 3. Oncogene (2011) 30, 3755-3765; doi:10.1038/onc.2011.95; published online 4 April 2011 |
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