Abelson Leukemia Virus Transformation

描述（由申请人提供）：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NIH 3T3成纤维细胞。v-Abl蛋白酪氨酸激酶 介导这些反应并传递刺激生长的信号， 抑制细胞凋亡和分化。所有这些信号都必须 适当地整合以进行转化。基因的组合 将使用方法来确定v-AbI如何实现这一点。我们将重点 在三个方面。遗传学和生物化学方法的结合将是 用于研究v-Abl SH2结构域在介导v-AbI信号中的作用 下游调解人。将使用两种突变体，一种条件突变体， 在39摄氏度的转化妥协，和一个突变体，编码 不能转化细胞的嵌合v-Abl/v-Src蛋白。在第二个目标中， 我们将研究v-Abl的COOH末端影响 淋巴样细胞转化Ras通路在这种反应中的作用将 使用遗传互补策略和序列进行研究， 将使用一系列的方法鉴定蛋白质的极端COOH末端。 缺失和截短突变体。这些序列的机制 将通过识别影响转化过程的 受这些序列影响的细胞靶点。在最后一个目标中，我们将 使用一种独特的弱致癌性AbMLV突变体， 了解影响c-onc基因的选择压力 进化病毒种群的动态和复杂性， 将测试选择过程和靶细胞生长刺激的作用 来揭示控制这个过程的特征。这些事件很可能是模仿 那些发生在v-onc基因捕获过程中的基因， 了解含有v-onc基因的病毒产生的方式， 诱发肿瘤。

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.