Abstract 2307: The p53/p21 complex is a functional unit that regulates cancer cell invasion and apoptosis by targeting Bcl-2 family proteins

Abstract

Abstract Although well known as a transcription factor, the p53 tumor suppressor also exists in the cytoplasm (including the mitochondria) of normal and cancer cells. Moreover, nuclear p53 is translocated to the mitochondria upon apoptotic stimulation of cells. The cytoplasmic/mitochondrial p53 can bind pro-survival Bcl-2 family proteins (e.g., Bcl-2, Bcl-XL, and Bcl-w), liberating Bax therefrom. Bax then exerts its pro-apoptotic or anti-invasive function depending on experimental conditions. Given the ability of p53 to interact with p21, we investigated the possible involvement of p21 in these functions. Here, we show that whereas p53 can bind to Bcl-w alone, it requires p21 to liberate Bax from Bcl-w and suppress/promote cell invasion/death, respectively. p21 consistently binds Bcl-w, forming a p53/p21/Bcl-w complex. Only this trifold complex, but not any of the pairings, facilitates the release of Bax from Bcl-w. Accordingly, a p53 derivative incapable of binding p21 fails to mediate radiotherapy-induced tumor retardation and cell death in mice. We further show that Bcl-2 and Bcl-XL also serves as a target of p53/p21 cooperative action. Overall, our findings indicate that the p53/p21 complex rather than p53 itself regulates cell invasion and death by targeting Bcl-2 proteins. We propose that the p53/p21 complex is a functional unit that acts on multiple types of cellular components, providing a new foundation for understanding the tumor-suppressing functions of p53 and p21. Citation Format: Eun Mi Kim, Hong-Duck Um. The p53/p21 complex is a functional unit that regulates cancer cell invasion and apoptosis by targeting Bcl-2 family proteins [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2307. doi:10.1158/1538-7445.AM2017-2307