Abstract 2608: Defining the function of tumor suppressor p53 arginine 181 residue in tumorigenesis

Abstract The gene Tp53 encodes for the protein p53 which has many tumor suppressive functions. Li-Fraumeni syndrome is characterized by germline Tp53 mutations that significantly increase the risk of cancer. The p53 amino acid residue arginine 181 is one such mutation site that promotes tumorigenesis by impacting a phenomenon known as p53 cooperativity. This is the ability of one p53 molecule to interact with another in order to efficiently bind specific sites on DNA to enact specific p53 functional pathways. Two p53 molecules interact with each other through the formation of a salt bridge between H1 helices found in respective DNA binding domains. The two key amino acid residues in this salt bridge are positively charged arginine (R) 181 and negatively charged glutamic acid (E) 180 which form electrostatic interactions with the residues on the opposite p53 H1 helix. Cooperativity mutants such as R181H and R181C show a hypomorphic behavior wherein much of p53’s canonical functions remain intact. Colony suppression data show that H1299 cells with p53 R181H and R181C yield a similar number of colonies as p53 wild type, which is significantly fewer than the yield of p53 hotspot mutation R175H and the absence of p53. Despite retaining some wild-type behavior, R181 mutants are found in LFS patients with cancer. Discovering the importance of the R181 residue for p53’s role in defending against tumorigenesis can lead to unique treatment opportunities for LFS patients with cooperativity mutants. Citation Format: Renyta Moses, Gregory Kelly, Alexandra Indeglia, Sven Miller, John Karanicolas, Maureen Murphy, Kara Maxwell. Defining the function of tumor suppressor p53 arginine 181 residue in tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2608.