Mechanisms of P53 Mediated Apoptosis and Carcinogenesis

描述(由申请人提供)：作为了解 P53介导的细胞凋亡和肿瘤发生的机制，我们设计 研究决定细胞是否进入生长的分子事件 在P53诱导后停止或经历细胞凋亡。我们建议移位 Bax蛋白从胞浆到线粒体是一种重要的调节 在p53介导的细胞凋亡中起重要作用，这一过程受一类 被称为细胞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说。前两个具体的 AIMS的重点是研究Peg3/Pw1在调节 细胞死亡检查点，即Bax和Bcl2。在第一个具体目标中，我们将 建立体外和体内两种检测方法，以探讨其分子机制 Peg3/Pw1诱导Bax从胞浆移位到线粒体。在第二个 具体而言，我们将研究Peg3/Pw1诱导的Bcl-2的分子基础 泛素化和降解。第三个具体目标集中在 新型调控子的鉴定和初步表征 利用逆转录病毒基因捕获系统在小鼠细胞中进行细胞凋亡。遗传 P53基因改变常与人类癌症及P53介导的肿瘤相关 细胞凋亡在预防肿瘤发生和恶性肿瘤中起着至关重要的作用。 因此，了解P53诱导细胞凋亡的机制具有重要意义。 重要的研究途径，可能为更好的治疗提供科学依据 人类癌症。

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.