PP2A regulates ionizing radiation-induced apoptosis through Ser46 phosphorylation of p53

In response to ionizing radiation, p53 plays a critical role in regulating DNA repair and apoptosis. Among multiple phosphorylation sites, evidence suggests that Ser46 promotes apoptotic cell death through mitochondrial outer membrane permeabilization (MOMP) and subsequent activation of the caspase 7-PARP pathway. Therefore, we investigated which phosphatase regulates Ser46 after ionizing radiation, reasoning that the responsible phosphatase should be a target for radiosensitization. We determined that both inhibition of PP2A by the cell-permeable inhibitor calyculin A and knockdown of PP2A by RNAi (a) enhanced Ser46 phosphorylation in p53 and (b) induced coincident caspase 7 and PARP cleavage in response to ionizing radiation. Furthermore, mutation of p53 Ser46 to Ala attenuated ionizing radiation-induced apoptotic signaling. Consequently, we concluded that PP2A regulates ionizing radiation-induced apoptotic signaling through dephosphorylation of p53 Ser46. [Mol Cancer Their 2009;8(1):135-40]