A specific PP2A regulatory subunit, B56γ, mediates DNA damage-induced dephosphorylation of p53 at Thr55

Abstract

Protein phosphatase 2A (PP2A) has been implicated to exert its tumor suppressive function via a small subset of regulatory subunits. In this study, we reported that the specific B regulatory subunits of PP2A B56c1 and B56c3 mediate dephosphorylation of p53 at Thr55. Ablation of the B56c protein by RNAi, which abolishes the Thr55 dephosphorylation in response to DNA damage, reduces p53 stabilization, Bax expression and cell apoptosis. To investigate the molecular mechanisms, we have shown that the endogenous B56c protein level and association with p53 increase after DNA damage. Finally, we demonstrate that Thr55 dephosphorylation is required for B56c3-mediated inhibition of cell proliferation and cell transformation. These results suggest a molecular mechanism for B56c-mediated tumor suppression and provide a potential route for regulation of B56c-specific PP2A complex function.

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

“…B56␦-specific PP2A was shown to function in a mitotic checkpoint in Xenopus laevis (15) and B56␥3-specific PP2A in blocking the proliferation of lung cancer cell lines (3). Importantly, evidence from our laboratory indicates that B56␥-PP2A participates in the activation of the tumor suppressor protein p53 after DNA damage (13).…”

“…After genotoxic stress, B56␥ and p53 protein levels are induced and B56␥-PP2A associates with p53, promoting p53 activation through dephosphorylation of Thr55 (13). To better understand the mechanism of the enhanced interaction between B56␥-PP2A and p53 after DNA damage and its functional significance in tumor suppression, we recently generated polyclonal antibody against full-length B56␥ protein (see Fig.…”

“…Once activated, it acts as a transcription factor, eliciting the transcription of genes that induce cell cycle arrest or programmed cell death (23, 28). Our studies have shown that, under cell growth conditions, p53 is phosphorylated at Thr55 by TAF1, which helps to keep the protein inactive, and upon genotoxic stress, B56␥-PP2A complexes dephosphorylate p53 at this residue, leading to p53 activation, p21 expression, and G 1 cell cycle arrest (12,13). Interestingly, in the course of our studies, we observed an enhanced interaction between B56␥ and p53 upon DNA damage; however, its significance in p53 activation and in PP2A tumor suppressor function remains unknown.…”

LB100, a small molecule inhibitor of PP2A with potent chemo- and radio-sensitizing potential

“…17,18 PP2A also directly dephosphorylates sites on p53, promoting p53 stability, cell cycle arrest, expression of Bax, and apoptosis in the context of irreparable DNA damage. 19,20 Mitotic Cell Cycle Progression PP2A activity plays a key role in the regulation of normal mitotic progression. In particular, PP2A is regulated by Greatwall kinase (called microtubule-associated serine/threonine kinase-like [Mastl] in mammals), which when depleted is associated with severe mitotic defects.…”

PP2A impaired activity is a common event in acute myeloid leukemia and its activation by forskolin has a potent anti-leukemic effect

“…9 In this regard, several members of the B56 family of regulatory PP2A subunits seems to have a main role in directing PP2A potential tumor-suppressive activity. [24][25][26][27][28][29][30] With regard to the endogenous PP2A inhibitors, upregulation of SET by the BCR/ABL oncogene leads to the suppression of PP2A, and contributes to leukemogenesis in chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia. 31,32 In addition, Junttila et al 33 provide strong evidence that cancerous inhibitor of PP2A (CIP2A) selectively targets PP2A associated with c-Myc to inhibit its phosphatase activity and protect Ser62 from dephosphorylation.…”