Apoptotic Response to DNA Damage Initiated by PUMA

描述（由申请人提供）：细胞凋亡或程序性细胞死亡是保护细胞免受DNA损伤的基本生物学过程。参与调节细胞凋亡的基因的缺陷经常在肿瘤中发现。在哺乳动物细胞中，由DNA损伤诱导的细胞凋亡通过线粒体由Bcl-2蛋白家族调节。然而，DNA损伤引发细胞凋亡的机制仍有待充分表征。我们最近的研究发现了一种新的Bcl-2家族蛋白，称为BclA，它似乎在细胞死亡中起着重要作用。在人类癌细胞中，诱导CD 45 A引发了快速而深刻的凋亡反应。BclA通过其他Bcl-2家族蛋白（包括Bax、Bcl-2和Bcl-XL）发挥功能。p53在DNA损伤反应中起核心作用，p53是p53的直接靶点。化疗药物，如DNA损伤剂阿霉素，也可以以p53依赖性的方式诱导CD 3A。此外，通过同源重组在结肠癌细胞中缺失p53和阿霉素导致凋亡反应显着降低。基于这些观察结果，我们提出检验以下假设：在人癌细胞中，CD 4A介导DNA损伤诱导的凋亡的起始：明确PUMA介导的人癌细胞凋亡启动机制;目的2。以确定是否 通过p53调节的DNA损伤反应途径激活p53;目的3。研究PUMA缺陷细胞对DNA损伤的凋亡反应是否消失。

DESCRIPTION (provided by applicant): Apoptosis, or programmed cell death, is a fundamental biological process to protect cells from DNA damage. Defects in the genes involved in regulating apoptosis are frequently found in tumors. In mammalian cells, apoptosis induced by DNA damage is regulated through mitochondria by the Bcl-2 family of proteins. However, the mechanism by which DNA damage initiates apoptosis remains to be fully characterized. Our recent studies identified a novel Bcl-2 family protein called PUMA, which appears to play an important role in cell death. Induction of PUMA triggered a rapid and profound apoptotic response in human cancer cells. PUMA functions through other Bcl-2 family proteins including Bax, Bcl-2 and Bcl-XL. PUMA is a direct target of p53, which plays a central role in DNA damage response. PUMA can also be induced by chemotherapeutic drugs, such as the DNA damaging agent adriamycin, in a p53-dependent manner. Furthermore, deletion of PUMA in colon cancer cells by homologous recombination led to a markedly decreased apoptotic response to p53 and adriamycin. Based on these observations, we propose to test the hypothesis that PUMA mediates initiation of DNA damage-induced apoptosis in human cancer cells: Aim l. To define the mechanism of PUMA-mediated apoptosis initiation in human cancer cells; Aim 2. To determine if PUMA is activated through the p53-regulated DNA damage response pathway; Aim 3. To investigate if the apoptotic response to DNA damage is abrogated in PUMA-deficient cells.