Protein Phosphatase 2A (PP2A) is a heterotrimeric serine/threonine phosphatase that has critical roles in numerous cellular pathways. The role of PP2A as an essential tumor suppressor in numerous death signaling pathways is well documented. In this regard, recent work from our laboratory has highlighted a novel mechanism of apoptosis inhibition via post-translational redox-modification of PP2A. Increase in intracellular superoxide, either by pharmacological inhibition or siRNA-mediated silencing of superoxide dismutase 1 (SOD1), results in the dissociation of PP2A-AC catalytic core from its B regulatory subunit. Dissociation of the PP2A heterotrimer is a result of the selective nitration [by peroxynitrite derived from the reaction of superoxide with nitric oxide] of a conserved tyrosine residue on B56δ which we identified as Y289 (B56δY289). Importantly, we showed in lymphoma cells that PP2A-AC catalytic core is typically targeted to Bcl-2 by its B56δ regulatory subunit. When O2- is elevated, it signals for the sustained phosphorylation of Bcl-2 at S70 by inducing the release of PP2A-AC catalytic core from B56δ-bound Bcl-2. This results in the sustained phospho-activation of anti-apoptotic Bcl-2 and resistance to apoptotic stimuli. Notably, Bcl-2 is not the only substrate of PP2A, nor is B56δ the only PP2A regulatory subunit susceptible to redox modification. Thus, implications from redox-modification of PP2A may extend beyond the phospho-activation of Bcl-2. In the context of carcinogenesis, another notable substrate of PP2A is the tumor suppressor, p53. p53 stability is negatively influenced by its phosphorylation status at threonine-55 (T55). Phosphorylation of T55, on the other hand, is countered by PP2A harboring the B56γ3 subunit. Here we provide evidence that the B56γ3 sub-unit of PP2A complexes with p53 and this complex is sustained upon an increase in intracellular superoxide. Importantly, redox-mediated inhibition of B56γ3-containing PP2A (PP2AB56γ3) prevents the dephosphorylation of p53 at T55, thereby negatively impacting the stability of p53 in tumor cells with elevated superoxide level. This, we hypothesize, may be a novel death inhibitory mechanism that renders tumor cells resistant to conventional DNA-damaging therapeutic agents that rely heavily on the activation of p53 for death induction.
Citation Format: Stephen Chong, Shazib Pervaiz. Redox regulation of p53 stability is a function of inhibition of PP2A-mediated dephosphorylation at threonine 55. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3685.