The p53/p21 Complex Regulates Cancer Cell Invasion and Apoptosis by Targeting Bcl-2 Family Proteins
The p53/p21 Complex Regulates Cancer Cell Invasion and Apoptosis by Targeting Bcl-2 Family Proteins
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DOI：
10.1158/0008-5472.can-16-2098
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发表时间：
2017-06-01
期刊：
影响因子：
11.2
通讯作者：
Um, Hong-Duck
中科院分区：
文献类型：
--
作者：
Kim, Eun Mi;Jung, Chan-Hun;Um, Hong-Duck
肿瘤抑制因子p53结合促生存Bcl-2家族蛋白如Bcl-w和Bcl-X-L以释放Bax，Bax进而根据应激环境发挥促凋亡或抗侵袭功能。在我们先前发现p53与p21相互作用的基础上，我们研究了p21在这些功能中的可能参与。在这里，我们报告说，虽然p53可以结合Bcl-w单独，它需要p21释放Bax抑制细胞侵袭和促进细胞死亡。p21结合Bcl-w，形成p53/p21/Bcl-w复合物，以维持所有成对p53/p21、p21/Bcl-w和p53/Bcl-w相互作用的方式。这使得Bax从复合体中解放出来。因此，不能结合p21的p53衍生物不能介导放射治疗诱导的小鼠肿瘤细胞死亡。Bcl-X-L也是p53和p21协同作用的靶点。总的来说，我们的研究结果表明，p53/p21复合物，而不是p53本身通过靶向Bcl-2蛋白调节细胞侵袭和死亡。我们认为p53/p21复合物是一个作用于多种细胞成分的功能单元，为理解p53和p21的肿瘤抑制功能提供了新的基础。(C)2017年AACR。
The tumor suppressor p53 binds prosurvival Bcl-2 family proteins such as Bcl-w and Bcl-X-L 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-X-L 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. (C) 2017 AACR.