Abstract
The tumor suppressor p53 binds prosurvival Bcl-2 family proteins such as Bcl-w and Bcl-XL to liberate Bax, which in turn exerts proapoptotic or anti-invasive functions depending on stress context. On the basis of our previous finding that p53 interacts with p21, we investigated the possible involvement of p21 in these functions. Here, we report that although p53 can bind Bcl-w alone, it requires p21 to liberate Bax to suppress cell invasion and promote cell death. p21 bound Bcl-w, forming a p53/p21/Bcl-w complex in a manner that maintained all pairwise p53/p21, p21/Bcl-w, and p53/Bcl-w interactions. This allowed Bax liberation from the complex. Accordingly, a p53 derivative incapable of binding p21 failed to mediate radiotherapy-induced tumor cell death in mice. Bcl-XL also served as a target of the cooperative action of p53 and p21. 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 cell components, providing a new foundation for understanding the tumor-suppressing functions of p53 and p21. Cancer Res; 77(11); 3092-100. ©2017 AACR.
Highlights
The p53 tumor suppressor/transcription factor regulates various cell functions, including the promotion of apoptosis and senescence, and the suppression of cell growth, migration, and invasion [1]
Cytoplasmic p53 and p21 cooperate to inhibit cell invasion To investigate whether p21 is required for cell invasion suppression mediated by cytoplasmic p53 targeting of Bcl-2 proteins, we introduced p53K305N, which localizes in the cytoplasm and mitochondria of healthy cells [7], into H1299 lung cancer cells (p53null). p53K305N expression reduced cellular reactive oxygen species (ROS) levels and invasiveness [7]
Bcl-w is a target of the p53/p21 complex To investigate whether p21 interacts with the prosurvival Bcl-2 proteins as p53 and p53K305N do [4, 7], we performed Bcl-w coimmunoprecipitation assays with in vitro translated proteins or in cell lysates
Summary
The p53 tumor suppressor/transcription factor regulates various cell functions, including the promotion of apoptosis and senescence, and the suppression of cell growth, migration, and invasion [1]. Most studies of the mechanisms of p53 action have focused on the transcriptional targets of p53, which mediate p53 functions. We have recently shown that p21 does not serve as a downstream mediator of p53 but cooperates with p53 to suppress cell invasion [3]. The cooperative function of p53 and p21 might affect other cellular targets. This hypothesis has not yet been explored, despite the new insights into the mechanisms underlying p53 tumor suppression that it can provide
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