Paradoxical Effects of Bax and Bcl-2 on Oncogenesis

Bax 和 Bcl-2 对肿瘤发生的矛盾作用

• 批准号: 6747038
• 负责人: CHRIS I VAN DE WETERING
• 金额: $ 2.62万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-26 至 2006-09-25
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6747038
• 关键词: BCL2 gene /protein; Bax gene /protein; carcinogenesis; genetic regulation; genetically modified animals; laboratory mouse; neoplasm /cancer genetics; predoctoral investigator

DESCRIPTION (provided by applicant): The major goal of this work is to understand the mechanism by which members of the Bcl-2 family regulate oncogenesis. The Bcl-2 family of proteins can be divided into two main classes: A) those that promote cell death (Bax, Bak, etc), and those that prevent it (Bcl-2, Bcl-xL, etc). An enabling characteristic of cancer cells that allows them to survive is their ability to evade cell death pathways by the upregulation of anti-apoptotic proteins like Bcl-2. Previous studies in our laboratory employing transgenic mouse models expressing pro-apoptotic Bax in T cells demonstrated an accelerated development of thymic lymphomas regardless of p53 status. Interestingly, other investigators have found Bcl-2 expression can prevent tumor formation. Taken together, these paradoxical findings suggest that Bax and Bcl-2 have novel functions in regulating oncogenesis. A hallmark of oncogenesis is genomic instability which has been observed in nearly all human malignancies and accelerates tumor formation. The current proposal will test the hypothesis that expression of Bax and Bcl-2 regulates genomic instability. We will test our hypothesis by 1) determining the rate on non-clonal chromosomal instability in transgenic mice expressing Bax and Bcl-2, and 2) the rate of allele modification (HPRT, CAD) in in vitro models of Bax and Bcl-2 genomic instability. The results of these studies will contribute greater knowledge of how the Bcl-2 family can regulate genomic instability and apoptosis in transformed cells and will shed important insight into the biology of oncogenesis.

描述（由申请人提供）：这项工作的主要目标是了解Bcl-2家族成员调节肿瘤发生的机制。Bcl-2蛋白家族可分为两大类：A）促进细胞死亡的蛋白（Bax、巴克等）和阻止细胞死亡的蛋白（Bcl-2、Bcl-xL等）。允许癌细胞存活的一个使能特征是它们通过上调抗凋亡蛋白如Bcl-2来逃避细胞死亡途径的能力。在我们实验室以前的研究采用转基因小鼠模型表达促凋亡Bax的T细胞表现出加速发展的胸腺淋巴瘤，无论p53的状态。有趣的是，其他研究人员发现Bcl-2表达可以防止肿瘤形成。总之，这些矛盾的发现表明Bax和Bcl-2在调节肿瘤发生中具有新的功能。肿瘤发生的一个标志是基因组不稳定性，这在几乎所有的人类恶性肿瘤中都观察到，并加速了肿瘤的形成。目前的建议将测试Bax和Bcl-2的表达调节基因组不稳定性的假设。我们将通过以下方式检验我们的假设：1）确定表达Bax和Bcl-2的转基因小鼠中非克隆染色体不稳定性的比率，和2）Bax和Bcl-2基因组不稳定性的体外模型中等位基因修饰（HPRT，CAD）的比率。这些研究的结果将有助于更多的了解Bcl-2家族如何调节基因组的不稳定性和细胞凋亡的转化细胞，并将揭示重要的洞察肿瘤发生的生物学。