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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

基本信息

批准号：
7236187
负责人：
Charles Michael Knudson
金额：
$ 22.94万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-08-01 至 2009-05-31
项目状态：
已结题

项目摘要

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）：Bcl-2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。Bcl-2家族包含抗凋亡（Bcl-2样）和促凋亡（Bax样）成员。尽管Bcl-2具有抗凋亡功能，但许多研究和我们的初步数据发现，Bcl-2对肿瘤的发展具有矛盾的作用。此外，我们的初步研究表明，Bax对肿瘤形成也有意想不到的作用（Bax高表达促进胸腺淋巴瘤的发展）。基因组不稳定性是肿瘤发生的标志。在人类恶性肿瘤中经常观察到染色体不稳定性，并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Bax的表达与高频率的非整倍体细胞和T细胞和胸腺细胞中的非整倍体增加有关。Bcl-2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因子，这些研究探索了线粒体和/或活性氧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的：1）在肿瘤形成之前确定Lck-Bax、Lck-Bcl-2和对照转基因小鼠中染色体不稳定性的比率。2)确定Caspase 9显性负性表达对溶酶体的抑制是否加速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性中的作用。4)开发和利用染色体不稳定性的体外模型，以确定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，我们的初步数据连接Bax表达染色体不稳定性是新的和潜在的非常重要的了解肿瘤发生。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对癌症的矛盾作用和基因组不稳定性的改变适用于几乎所有类型的肿瘤。了解控制基因组不稳定性的途径可能会导致新的治疗策略，用于预防或治疗淋巴瘤和其他不同的人类恶性肿瘤。