SIGNALING PATHWAYS UTILIZED BY V-ABL AND BCR-ABL

V-ABL 和 BCR-ABL 使用的信号通路

• 批准号: 6137618
• 负责人: KATHRYN L. CALAME
• 金额: $ 71.3万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-01-20 至 2003-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6137618
• 关键词: Abelson leukemia virus; biological signal transduction; oncoproteins; protein tyrosine kinase; viral leukemogenesis

Mutant forms of the Abelson tyrosine kinase, v-Abl and BCR-ABL, cause malignant transformation in many mammalian species including humans. Understanding the signaling paths utilized by v-Abl and BCR-ABL is key to understanding the mechanisms by which they cause malignancy. The goal of this Program Project is to study three particular aspects of signaling by v-Abl and BCR-ABL. Project #1, led by Dr. Stephen Goff, will study the role of a newly discovered Abl-binding protein, Abi-l is probably important in early signaling events which link Abl tyrosine kinase activity to downstream effectors which link Abl tyrosine activity to downstream effectors, particularly Ras. Project #2 led by Dr. Paul Rothman, will determine the role of the recently discovered activation of Janus kinases (Jaks) by v-Abl. Jaks represent an alternative signaling path, utilized by normal cytokines, which may be important for Abl transformation. Project #3, led by Dr. Kathryn Calame will study recently discovered connections between regulation of cell cycle and V- Abl including vAbl dependent induction of cyclin D mRNA, v-Abl-dependent decrease in p27 protein and p53-dependent inhibition of v-Abl transformation. In each of these projects the molecular mechanisms and functional importance for Abl-dependent transformation of different signaling pathways will be determined. The projects will be supported by three scientific cores and one administrative core. The first Core will provide standardized virus stocks, monoclonal antibodies and Abelson transformed cell lines to all projects. The second Core will provide care and breeding of mice nullizygous for genes involved in the pathways under study. The third Core will supply primary cells from patients with Chronic Myelogenous Leukemia to individual projects, supported by the Cores, will be shared among the projects so that collaborative experiments can be performed to determine how signaling by each of the pathways under study is related to the others. The knowledge gained by this Program Project will not improve our understanding of Abelson-dependent transformation but will also help us understand general mechanisms of oncogenesis and signal transduction.

Abelson 酪氨酸激酶 v-Abl 和 BCR-ABL 的突变形式导致 包括人类在内的许多哺乳动物物种的恶性转化。 了解 v-Abl 和 BCR-ABL 使用的信号路径是关键 了解它们引起恶性肿瘤的机制。目标 该计划项目的目的是研究以下三个特定方面 v-Abl 和 BCR-ABL 信号传导。项目#1，由 Stephen Goff 博士领导， 将研究新发现的 Abl 结合蛋白 Abi-l 的作用 可能在连接 Abl 酪氨酸的早期信号事件中很重要 激酶活性与连接 Abl 酪氨酸活性的下游效应器 下游效应器，特别是 Ras。项目 #2 由 Paul 博士领导 罗斯曼将确定最近发现的激活的作用 通过 v-Abl 检测 Janus 激酶 (Jaks)。 Jaks代表了另一种选择 正常细胞因子利用的信号通路，这对于 Abl 变换。由 Kathryn Calame 博士领导的项目 #3 将进行研究 最近发现细胞周期调节与 V- 之间的联系 Abl 包括 vAbl 依赖性细胞周期蛋白 D mRNA 诱导，v-Abl 依赖性 p27 蛋白减少和 v-Abl 的 p53 依赖性抑制 转变。在每个项目中，分子机制和 不同 Abl 依赖性转化的功能重要性 信号通路将被确定。 这些项目将得到三个科学核心和一个 行政核心。第一个Core将提供标准化病毒 库存、单克隆抗体和 Abelson 转化细胞系适用于所有 项目。第二个核心将提供小鼠的护理和繁殖 参与所研究途径的基因无效。第三个 Core 将提供来自慢性粒细胞性骨髓瘤患者的原代细胞 白血病到各个项目，由核心支持，将被共享 项目之间可以进行协作实验 确定所研究的每个通路的信号传导是如何相关的 给其他人。通过本计划项目获得的知识不会 提高我们对阿贝尔森相关变换的理解，但会 还帮助我们了解肿瘤发生和信号的一般机制 转导。