Non-transcriptional Mechanisms of p53-mediated Apoptosis

描述（由申请人提供）：在体外和体内研究中，p53对正常和病理生理环境的许多方面的影响是显而易见的。文献支持p53是包括大多数细胞和组织类型在内的细胞周期抑制、基因组稳定性和细胞凋亡的关键调节因子。很明显，p53作为一种转录因子调节上述作用，结合结构/突变研究表明，p53的DNA结合和富含脯氨酸的结构域对其在脊椎动物中的许多保护作用至关重要。然而，越来越多的证据表明p53也通过转录不依赖的途径控制细胞凋亡。本研究计划的目的是利用几种新的体外和体内模型，探索p53以转录不依赖的方式诱导细胞凋亡的核心机制。这项工作将在我们实验室开发的一种独特的无细胞系统、几种不同来源的细胞系以及最近产生的敲入小鼠的原代细胞中进行。我们将重点研究促凋亡的Bcl-2家族成员在线粒体外膜通透性中的作用以及p53如何调节这一过程。

DESCRIPTION (provided by applicant): The impact of p53 on numerous aspects of normal and pathophysiological contexts is apparent from both in vitro and in vivo studies. Literature supports p53 is a critical regulator of cell cycle inhibition, genomic stability and apoptosis inclusive of most cell and tissue types. It is clear that p53 functions as a transcription factor to regulate the above effects and combined structure/mutation studies demonstrate the DNA binding and proline-rich domains of p53 are crucial to many of its protective effects in vertebrates. However, increasing evidence suggests p53 also controls apoptosis in a transcription-independent route. The goal of this research proposal is to explore the central mechanisms by which p53 can induce apoptosis in a transcription-independent manner using several novel in vitro and in vivo models. This work will be done in a unique cell-free system developed by our laboratory, several cell lines of diverse origin, and in primary cells from a recently generated knock-in mouse. Efforts will focus on the role of pro-apoptotic Bcl-2 family members in the permeabilization of the mitochondrial outer membrane and how p53 regulates this process.