Mechanisms of P53 Mediated Apoptosis and Carcinogenesis

描述（由申请人提供）：作为了解 p53介导的细胞凋亡和癌变的机制，我们设计， 研究决定细胞是否进入生长的分子事件 在p53诱导下，细胞凋亡或停止。我们认为易位 Bax蛋白从细胞质到线粒体的迁移是一个重要的调节机制， p53介导的细胞凋亡中的一个步骤，这一过程是由一类 称为凋亡调节剂或共激活剂的蛋白质。研究计划 这一提议的核心是检验这一假设。前两个具体 目的是集中调查Peg 3/Pw 1的调节作用， 细胞死亡检查点，即Bax和Bcl-2。在第一个具体目标中，我们将 建立了体外和体内试验，以探索分子机制， Peg 3/Pw 1诱导Bax从细胞质易位到线粒体。在第二 具体而言，我们将研究Peg 3/Pw 1诱导Bcl-2的分子基础 泛素化和降解。第三个具体目标集中在 新的调节剂的鉴定和初步表征 使用逆转录病毒基因捕获系统在鼠细胞中进行细胞凋亡。遗传 p53的改变经常与人类癌症相关， 细胞凋亡在预防癌发生和恶性肿瘤中起关键作用。 因此，了解p53诱导细胞凋亡的机制， 这是一个重要的研究途径，可能为更好地治疗提供科学依据 人类的癌症。

DESCRIPTION (provided by applicant): As a step towards understanding the mechanisms of p53 mediated apoptosis and carcinogenesis, we design to investigate the molecular events determining whether the cell enters growth arrest or undergoes apoptosis upon p53 induction. We propose that translocation of Bax protein from cytosol to mitochondria represents an important regulatory step in p53-mediated apoptosis and this process is regulated by a class of proteins named as modulators or co-activators of apoptosis. The research plan of this proposal is centered on testing this hypothesis. The first two specific aims are focused on investigating the role of Peg3/Pw1 on the regulation of cell death checkpoint, namely Bax and Bcl-2. In the first specific aim, we will set up both in vitro and in vivo assays to explore the molecular mechanisms for Peg3/Pw1 -induced Bax translocation from cytosol to mitochondria. In the second specific aim, we will investigate the molecular basis of Peg3/Pw1-induced Bcl-2 ubiquitination and degradation. The third specific aim concentrates on the identification and preliminary characterization of novel modulators of apoptosis in murine cells using a retroviral gene trapping system. Genetic alteration of p53 is frequently associated with human cancers and p53-mediated apoptosis plays a critical role in preventing carcinogenesis and malignancies. Thus, understanding the mechanisms of p53-induced apoptosis represents an important research avenue and may provide scientific basis for better treatment of human cancers.