Non-transcriptional Mechanisms of p53-mediated Apoptosis

描述（由申请人提供）：p53对正常和病理生理学背景的许多方面的影响在体外和体内研究中都很明显。文献支持p53是包括大多数细胞和组织类型的细胞周期抑制、基因组稳定性和凋亡的关键调节因子。很明显，p53作为一个转录因子的功能，以调节上述效果和组合的结构/突变的研究表明，DNA结合和富含脯氨酸的结构域的p53是至关重要的许多脊椎动物的保护作用。然而，越来越多的证据表明，p53也控制细胞凋亡的转录非依赖性途径。 本研究的目的是探索p53可以通过转录非依赖性的方式诱导细胞凋亡的中枢机制，使用几种新的体外和体内模型。这项工作将在我们实验室开发的独特的无细胞系统中进行，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。努力将集中在促凋亡Bcl-2家族成员在线粒体外膜透化中的作用，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.