Abelson Leukemia Virus Transformation

阿贝尔森白血病病毒转化

• 批准号: 6512544
• 负责人: NAOMI ROSENBERG
• 金额: $ 29.8万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 1978
• 资助国家: 美国
• 起止时间: 1978-09-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6512544
• 关键词: Abelson leukemia virus; cell cycle proteins; enzyme activity; enzyme inhibitors; guanine nucleotide binding protein; laboratory mouse; neoplasm /cancer genetics; p53 gene /protein; protein tyrosine kinase; protooncogene; viral leukemogenesis; virus genetics

DESCRIPTION (provided by applicant): Abelson murine leukemia virus is a rapidly transforming retrovirus that induces pre-B cell lymphoma and transforms pre-B lymphocytes and NIH 3T3 fibroblasts in vitro. The v-Abl protein tyrosine kinase mediates these responses and transmits signals that stimulate growth and suppress apoptosis and differentiation. All of these signals must be appropriately integrated for transformation to occur. A combination of genetic approaches will be used to determine how v-AbI accomplishes this. We will focus on three areas. A combination of genetic and biochemical approaches will be used to study the role of the v-Abl SH2 domain in mediating signals from v-AbI to downstream mediators. Two mutants will be used, a conditional mutant that is compromised for transformation at 39 degrees celcius, and a mutant that encodes a chimeric v-Abl/v-Src protein that fails to transform cells. In a second aim, we will examine the mechanism by which the COOH terminus of v-Abl affects lymphoid cell transformation. The role of the Ras pathway in this response will be investigated using a genetic complementation strategy and sequences at the extreme COOH terminal end of the protein will be identified using a series of deletion and truncation mutants. The mechanism by which these sequences influence the transformation process will be studied by identifying the cellular targets that are affected by these sequences. In the last aim, we will use a unique weakly oncogenic AbMLV mutant that generates highly oncogenic variants in vivo to understand the selective pressures that affect c-onc gene evolution. The dynamics and complexity of the viral population during the selection process and the role of target cell growth stimulation will be tested to uncover features that control this process. These events are likely to mimic those that occur during the v-onc gene capture and should advance our understanding of the way in which v-onc gene containing viruses arise and induce tumors.

描述(申请人提供)：Abelson鼠白血病病毒是一种快速 诱导前B细胞淋巴瘤并转化前B细胞的转化逆转录病毒 淋巴细胞和NIH3T3成纤维细胞的体外培养。V-Abl蛋白酪氨酸激酶 调节这些反应并传递刺激生长和 抑制细胞凋亡和分化。所有这些信号都必须是 适当地集成，以便发生转换。一种基因的组合 将使用各种方法来确定v-abi如何实现这一目标。我们将专注于 在三个方面。基因和生化方法的结合将是 用于研究v-Abl SH2结构域在v-ABI信号传递中的作用 到下游的调解人。将使用两个突变体，一个条件突变体是 在39摄氏度的温度下进行转化的妥协，以及一个编码的突变体 一种嵌合的v-Abl/v-Src蛋白，无法转化细胞。在第二个目标中， 我们将研究v-Abl的COOH末端影响的机制 淋巴样细胞转化。RAS途径在这一反应中的作用将 使用遗传互补策略和序列在 蛋白质的极端COOH末端将使用一系列 缺失和截断突变体。这些序列的机制 对转型过程的影响将通过确定 受这些序列影响的细胞靶标。在最后一个目标中，我们将 使用独特的弱致癌性AbMLV突变体，可产生高致癌性 体内变异以了解影响c-onc基因的选择压力 进化论。病毒种群的动态和复杂性 将测试目标细胞生长刺激的选择过程和作用 以发现控制这一过程的特征。这些事件很可能会模仿 在v-onc基因捕获过程中发生的那些应该会推进我们的 了解含v-onc基因的病毒产生和传播的途径 诱发肿瘤。