Regulation ofp53 by TAF1, PP2A and PTEN

The tumor suppressor protein p53 functions as a transcriptional factor and plays a pivotal role in the cellular response to genotoxic damage. p53 activity is regulated through post-translational modifications and its binding proteins. In this study, we specifically characterize the regulation of p53 activity by TAF1, PP2A and PTEN.; We report that Thr55 phosphorylation regulates p53 cellular localization. TAF1 phosphorylates p53 at Thr55 in the nucleus under normal growth conditions, which induces the interaction of p53 with its nuclear exporter, CRM1. As a consequence, p53 is exported to the cytoplasm where p53 is degraded. Upon DNA damage, B56gamma specific PP2A dephosphorylates p53 at Thr55, which dissociates p53 from CRM1 and activates p53 to turn on its downstream genes. Together, our data demonstrate that Thr55 phosphorylation links two signaling pathways, TAF1 and PP2A, in regulation of p53 activity.; We also show that apigenin, TAF1 kinase inhibitor, specifically inhibits p53 nuclear export, restores p53 nuclear localization and sensitizes tumor cells with cytoplasm localized wild type p53 to DNA damage. These results suggest an avenue for targeted therapy for cancers caused by abnormal cytoplasm localization of wild-type p53.; Finally, we show that PTEN interacts with p300 in the nucleus. This interaction increases p53 acetylation by p300 and induces p53-dependent cell G1 arrest. Further, we show that PTEN physically interacts with PML in vivo, providing a possible link between PTEN and PML in the regulation of p53 acetylation and activity.; In summary, our studies establish the regulation of p53 activity by Thr55 phosphorylation via TAF1 and PP2A and provide a novel mechanism for regulation of p53 cellular localization. We also demonstrate regulation of p53 acetylation by nuclear PTEN and provide a new molecular mechanism for the regulation of cell growth by nuclear PTEN.