Abstract SY07-03: Gain-of-function activities of mutant p53

Abstract

Abstract Mutations in p53 in tumors vary from deletions and nonsense mutations that lead to the absence of p53 protein to missense mutations that disrupt the DNA binding function of p53 and that exhibit gain-of-function phenotypes. The p53R172H protein manifests one of its gain-of-function activities as a metastatic phenotype in vivo. To understand the contribution of mutant p53 to metastasis, expression arrays were used to compare primary osteosarcomas from p53R172H/+ mice with metastasis to osteosarcomas from p53+/- mice lacking metastasis. Of 213 gene differences, Pla2g16 was overexpressed in metastatic osteosarcomas and was of particular interest as it encodes a phospholipase that catalyzes phosphatidic acid into lysophosphatidic acid and free fatty acid (both implicated in metastasis). Functional analyses showed that Pla2g16 knockdown decreased migration and invasion in mutant p53 expressing cells, and vice versa, overexpression of Pla2g16 increased the invasion of p53-null cells. Mechanistically, various mutant p53 proteins bind the Pla2g16 promoter at ETS binding motifs and knockdown of ETS2 in particular suppressed mutant p53 induction of Pla2g16. Thus, our study identifies a phospholipase as a transcriptional target of mutant p53 that contributes to metastasis. Citation Format: Guillermina Lozano. Gain-of-function activities of mutant p53. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr SY07-03. doi:10.1158/1538-7445.AM2014-SY07-03