Serine 15 Phosphorylation of p53 Directs Its Interaction with B56γ and the Tumor Suppressor Activity of B56γ-Specific Protein Phosphatase 2A

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Abstract
Earlier studies have demonstrated a functional link between B56γ-specific protein phosphatase 2A (B56γ-PP2A) and p53 tumor suppressor activity. Upon DNA damage, a complex including B56γ-PP2A and p53 is formed which leads to Thr55 dephosphorylation of p53, induction of the p53 transcriptional target p21, and the inhibition of cell proliferation. Although an enhanced interaction between p53 and B56γ is observed after DNA damage, the underlying mechanism and its significance in PP2A tumor-suppressive function remain unclear. In this study, we show that the increased interaction between B56γ and p53 after DNA damage requires ATM-dependent phosphorylation of p53 at Ser15. In addition, we demonstrate that the B56γ3-induced inhibition of cell proliferation, induction of cell cycle arrest in G1, and blockage of anchorage-independent growth are also dependent on Ser15 phosphorylation of p53 and p53-B56γ interaction. Taken together, our results provide a mechanistic link between Ser15 phosphorylation-mediated p53-B56γ interaction and the modulation of p53 tumor suppressor activity by PP2A. We also show an important link between ATM activity and the tumor-suppressive function of B56γ-PP2A.