Bcl-2 family and redox control of genomic instability

描述（由申请人提供）：Bcl-2是一种控制细胞死亡的致癌基因，在某些类型的B细胞淋巴瘤中高度表达。Bcl-2家族包含抗凋亡成员（Bcl-2样）和促凋亡成员（Bax样）。尽管具有抗凋亡功能，但大量研究和我们的初步数据发现，Bcl-2在肿瘤发展中具有矛盾的作用。此外，我们的初步研究表明，Bax对肿瘤的形成也有意想不到的影响（高Bax表达促进胸腺淋巴瘤的发展）。基因组不稳定是肿瘤发生的一个标志。染色体不稳定性在人类恶性肿瘤中经常观察到，并被认为通过增加基因突变率促进肿瘤形成。在我们的初步数据中，我们发现在T细胞和胸腺细胞中，Bax的表达与非整倍体细胞的高频率和非整倍体的增加有关。Bcl-2可拮抗Bax诱导的肿瘤形成和非整倍体。基于此，我们假设Bcl-2和Bax对肿瘤发生和肿瘤进展的矛盾作用是由这些蛋白质增加或减少染色体不稳定性的能力决定的。鉴于Bcl-2家族成员是线粒体的关键调节者，这些研究探讨了线粒体和/或活性氧在这些作用中的作用。基于这一假设，我们提出以下具体目标：1)确定肿瘤形成前Lck-Bax、Lck-Bcl-2和对照转基因小鼠的染色体不稳定性率。2)确定Caspase 9显性负表达抑制凋亡细胞是否加速Bax依赖性肿瘤的发展。3)确定氧化剂在Bcl-2家族成员诱导的肿瘤发生和染色体不稳定中的作用。4)建立和利用染色体不稳定性体外模型，确定Bax和Bcl-2表达对基因组不稳定性的影响。从癌症生物学的角度来看，我们将Bax表达与染色体不稳定性联系起来的初步数据既新颖又可能对理解肿瘤发生非常重要。将Bcl-2家族与染色体不稳定性联系起来，为Bcl-2家族如何控制肿瘤发生提供了新的见解。也许更重要的是，Bcl-2对癌症和基因组不稳定性改变的矛盾作用几乎适用于所有类型的肿瘤。了解控制基因组不稳定性的途径可能会导致预防或治疗淋巴瘤和其他各种人类恶性肿瘤的新治疗策略。

DESCRIPTION (provided by applicant): Bcl-2 is an oncogene that controls cell death and is highly expressed in some types of B cell lymphomas. The Bcl-2 family contains both anti-apoptotic (Bcl-2 like) and pro-apoptotic members (Bax like). Despite its anti-apoptotic function, numerous studies and our preliminary data have found that Bcl-2 has paradoxical effects on tumor development. In addition, our preliminary studies demonstrate that that Bax also has unexpected effects on tumor formation (High Bax expression promotes thymic lymphoma development). Genomic instability is a hallmark of oncogenesis. Either chromosomal instability is frequently observed in human malignancies and thought to facilitate tumor formation through increased rates of genetic mutation. In our preliminary data, we find that Bax expression is associated with a high frequency of aneuploid cells and increased aneuploidy in both T cells and thymocytes. Bcl-2 antagonizes Bax induced tumor formation and aneuploidy. Based on this, we hypothesize that the paradoxical effect of Bcl-2 and Bax on oncogenesis and tumor progression is determined by the ability of these proteins to increase or decrease chromosomal instability. Given that Bcl-2 family members are critical regulators of mitochondria, these studies explore the role of mitochondria and/or reactive oxygen species in these effects. Based on this hypothesis we propose the following Specific Aims 1) Determine the rate of chromosome instability in Lck-Bax, Lck-Bcl-2 and control transgenic mice prior to tumor formation. 2) Determine if inhibition of the apoptosome by Caspase 9 dominant negative expression accelerates Bax dependent tumor development. 3) Determine the role of oxidants in Bcl-2 family member induced oncogenesis and chromosome instability. 4) Develop and utilize in vitro models of chromosome instability to determine the effect of Bax and Bcl-2 expression on genomic instability. From the perspective of cancer biology, our preliminary data linking Bax expression to chromosomal instability is both novel and potentially very important in understanding oncogenesis. Linking the Bcl-2 family to chromosomal instability provides novel insight into how the Bcl-2 family controls oncogenesis. Perhaps more importantly, the paradoxical effects of Bcl-2 on cancer and alterations in genomic instability apply to nearly all types of tumors. Understanding the pathways that control genomic instability may result in novel therapeutic strategies for the prevention or treatment of lymphoma and other diverse human malignancies.