The p53/p21 complex regulates cancer cell invasion and apoptosis by targeting Bcl-2 family proteins

The tumor suppressor p53 binds pro-survival Bcl-2 family proteins such as Bcl-w and Bcl-XL to liberate Bax, which in turn exerts pro-apoptotic or anti-invasive functions depending on stress context. Based on 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.

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