Paradoxical Effects of Bax and Bcl-2 on Oncogenesis

描述(由申请人提供)：这项工作的主要目标是了解Bcl-2家族成员调控肿瘤发生的机制。Bcl2家族蛋白可分为两大类：a)促进细胞死亡的蛋白(Bax、Bak等)和阻止细胞死亡的蛋白(Bcl2、Bclxl等)。癌细胞的一个使其得以存活的特征是，它们能够通过上调抗凋亡蛋白(如Bcl-2)来避开细胞死亡途径。我们实验室以前使用转基因小鼠模型在T细胞中表达促凋亡Bax的研究表明，无论P53状态如何，胸腺淋巴瘤都会加速发展。有趣的是，其他研究人员发现，Bcl-2的表达可以防止肿瘤的形成。综上所述，这些自相矛盾的发现表明，Bax和Bcl-2在调节肿瘤发生方面具有新的功能。肿瘤发生的一个特征是基因组不稳定，几乎在所有人类恶性肿瘤中都观察到了这种不稳定，并加速了肿瘤的形成。目前的提议将检验Bax和Bcl-2的表达调节基因组不稳定性的假设。我们将通过1)在表达Bax和Bcl-2的转基因小鼠中确定非克隆性染色体不稳定性的比率，以及2)在Bax和Bcl-2基因组不稳定性的体外模型中测定等位基因修饰(HPRT，CAD)的比率来验证我们的假设。这些研究的结果将有助于更多地了解Bcl-2家族如何调节转化细胞的基因组不稳定性和凋亡，并将为肿瘤发生的生物学提供重要的见解。

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.