Abstract 2468: Phosphorylation of Thr55 mediates the tumor suppression activities of p53

Abstract

Abstract P53 is a transcription factor that plays a central role in the regulation of cell cycle, apoptosis and senescence. In unstressed cells, p53 is kept at low level under the strict control of its negative regulators. Upon DNA damage or oncogenic stress, p53 is activated via post-translational modifications. The phosphorylation of serine and threonine, such as Ser15 and Ser46, play important roles in p53 regulation. However, data for Thr55 (T55) phosphorylation is limited and functions of T55 phosphorylation remain elusive. We have previously defined an intramolecular interaction in p53 which modulates DNA binding. The observation of altered intramolecular interactions in T55A and T55D mutants leads to the hypothesis that T55 phosphorylation might affect p53 functions. We generate a T55 phospho-specific antibody to investigate the regulation through this site. The results show T55 phosphorylation is induced by DNA damage compounds. We induce the expression of wild type and T55A mutant p53 in p53 null H1299 cells via the transduction of doxycycline-inducible lentiviral gene expression plasmids. T55A mutant p53 exhibits significantly weaker inhibition of cell viability compared with wild type p53 containing cell in the existence of DNA damaging compounds. Consistently, T55A mutant p53 induces lower mRNA expression level of several important apoptosis related genes and higher MDM2 level in comparison with wild type p53. Overall, our results reveal that phosphorylation of Thr55 is induced by several DNA damaging compounds and alters the expression of p53 target genes, leading to an enhanced tumor suppression. Citation Format: Fan He, Lihong Chen, Jiandong Chen. Phosphorylation of Thr55 mediates the tumor suppression activities of p53 [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2468.