SIGNALING PATHWAYS UTILIZED BY V-ABL AND BCR-ABL

Abelson酪氨酸激酶的突变形式，v-Abl和BCR-ABL， 包括人类在内的许多哺乳动物的恶性转化。 理解v-Abl和BCR-ABL使用的信令路径是关键 了解它们导致恶性肿瘤的机制。目标 该项目的主要目的是研究以下三个方面： v-Abl和BCR-ABL的信号传导。项目#1，由Stephen Goff博士领导， 将研究一种新发现的β-结合蛋白Abi-1的作用， 可能在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物 下游效应子尤其是Ras项目#2由保罗博士领导 罗斯曼，将确定最近发现的激活的作用， Janus激酶（Jaks）的v-Abl。Jaks代表一种替代 信号通路，由正常细胞因子利用，这可能是重要的， Abl变换。由Kathryn Calame博士领导的项目#3将研究 最近发现的细胞周期调节和V- Abl包括vAbl依赖性细胞周期蛋白D mRNA诱导，v-Abl依赖性 v-Abl的p27蛋白减少和p53依赖性抑制 转型在每一个项目中， 函数的重要性，对于不同的 将确定信号通路。 这些项目将得到三个科学核心和一个 行政核心。第一个核心将提供标准化的病毒 储备液、单克隆抗体和Abelson转化的细胞系， 项目第二个核心将提供照顾和饲养老鼠 参与研究的途径的基因的无效合子。第三 核心将提供来自慢性骨髓性白血病患者的原代细胞。 白血病个人项目，由核心支持，将被分享 在项目之间进行合作实验， 确定所研究的每种途径的信号传导是如何相关的 其他人。本计划项目所获得的知识将不会 提高了我们对Abelson依赖变换理解， 也有助于我们理解肿瘤发生和信号传导的一般机制， 转导

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.