Bcl-2 family and redox control of genomic instability

Bcl-2 家族和基因组不稳定性的氧化还原控制

• 批准号: 6931114
• 负责人: Charles Michael Knudson
• 金额: $ 24.19万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6931114
• 关键词: B cell lymphoma; BCL2 gene /protein; Bax gene /protein; apoptosis; carcinogenesis; chemical stability; chromosome aberrations; cysteine endopeptidases; free radicals; gene expression; genetic models; genetic regulation; genetically modified animals; genome; laboratory mouse; mitochondria; neoplasm /cancer genetics; neoplastic process; oxidation reduction reaction; oxidizing agents; protein structure function

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.

描述(申请人提供)：bcl2是一种控制细胞死亡的癌基因，在某些类型的B细胞淋巴瘤中高度表达。Bcl2家族既有抗细胞凋亡的成员(如Bcl2)，也有促细胞凋亡的成员(如Bax)。尽管它具有抗细胞凋亡的功能，但许多研究和我们的初步数据发现，Bcl-2在肿瘤的发展中具有自相矛盾的作用。此外，我们的初步研究表明，Bax在肿瘤形成中也有意想不到的作用(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。染色体不稳定在人类恶性肿瘤中经常被观察到，并被认为通过增加基因突变率来促进肿瘤的形成。在我们的初步数据中，我们发现Bax的表达与T细胞和胸腺细胞中高比例的非整倍体细胞和增加的非整倍体细胞有关。BCL-2拮抗Bax诱导的肿瘤形成和非整倍体。在此基础上，我们假设Bcl2和Bax在肿瘤发生和肿瘤进展中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Bc l-2家族成员是线粒体的关键调节者，这些研究探索了线粒体和/或活性氧物种在这些效应中的作用。基于这一假设，我们提出了以下具体目标：1)确定Lck-Bax、Lck-Bcl2和对照转基因小鼠在肿瘤形成之前的染色体不稳定性。2)确定Caspase 9显性负表达抑制凋亡体是否会加速Bax依赖性肿瘤的发生。3)确定氧化剂在Bcl2家族成员诱导的肿瘤发生和染色体不稳定性中的作用。4)建立和利用染色体不稳定性的体外模型，以确定Bax和Bcl2表达对基因组不稳定性的影响。从癌症生物学的角度来看，我们的初步数据将Bax的表达与染色体不稳定性联系起来，这既是新颖的，也可能对理解肿瘤发生非常重要。将Bcl2家族与染色体不稳定联系起来，为了解Bcl2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在癌症中的矛盾作用和基因组不稳定性的变化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的治疗策略。