Department of Molecular, Cellular and Developmental Biology, Howard Hughes Medical Institute, The University of Colorado, Boulder, CO 80309-0347, USA.
EMBO J. 2012 Mar 7;31(5):1266-78. doi: 10.1038/emboj.2011.498. Epub 2012 Jan 13.
The cellular response to p53 activation varies greatly in a stimulus- and cell type-specific manner. Dissecting the molecular mechanisms defining these cell fate choices will assist the development of effective p53-based cancer therapies and also illuminate fundamental processes by which gene networks control cellular behaviour. Using an experimental system wherein stimulus-specific p53 responses are elicited by non-genotoxic versus genotoxic agents, we discovered a novel mechanism that determines whether cells undergo proliferation arrest or cell death. Strikingly, we observe that key mediators of cell-cycle arrest (p21, 14-3-3σ) and apoptosis (PUMA, BAX) are equally activated regardless of outcome. In fact, arresting cells display strong translocation of PUMA and BAX to the mitochondria, yet fail to release cytochrome C or activate caspases. Surprisingly, the key differential events in apoptotic cells are p53-dependent activation of the DR4 death receptor pathway, caspase 8-mediated cleavage of BID, and BID-dependent activation of poised BAX at the mitochondria. These results reveal a previously unappreciated role for DR4 and the extrinsic apoptotic pathway in cell fate choice following p53 activation.
细胞对 p53 激活的反应在刺激和细胞类型特异性方面差异很大。解析定义这些细胞命运选择的分子机制将有助于开发有效的基于 p53 的癌症治疗方法，并阐明基因网络控制细胞行为的基本过程。使用一种实验系统，其中通过非遗传毒性与遗传毒性试剂来引发刺激特异性的 p53 反应，我们发现了一种决定细胞是经历增殖停滞还是细胞死亡的新机制。引人注目的是，我们观察到细胞周期停滞（p21、14-3-3σ）和凋亡（PUMA、BAX）的关键介质无论结果如何都同样被激活。事实上，停滞的细胞显示出强烈的 PUMA 和 BAX 向线粒体的易位，但未能释放细胞色素 C 或激活半胱天冬酶。令人惊讶的是，凋亡细胞中的关键差异事件是 p53 依赖性激活 DR4 死亡受体途径、caspase 8 介导的 BID 切割以及 BID 依赖性激活位于线粒体的潜在 BAX。这些结果揭示了 DR4 和外在凋亡途径在 p53 激活后细胞命运选择中的先前未被认识的作用。
