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，原因 包括人类在内的许多哺乳动物物种的恶变。 了解v-abl和bcr-abl使用的信令路径是关键 以了解它们导致恶性肿瘤的机制。目标是 这个项目的目的是研究以下三个方面的具体内容 V-abl和bcr-abl信令。第一个项目，由斯蒂芬·戈夫博士领导， 将研究一种新发现的Abl结合蛋白的作用，Abi-L是 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。保罗博士领导的第二个项目 Rothman将确定最近发现的激活的作用 的Janus Kinase(JAKS)。杰克代表了另一种选择 信号通路，由正常的细胞因子利用，这可能对 ABL变换。项目3，由凯瑟琳·卡拉姆博士领导，将研究 新近发现细胞周期调节与V- ABL包括vAb1依赖的细胞周期蛋白D mRNA的诱导，v-Abl依赖的诱导 P27蛋白降低与p53依赖的v-Abl抑制作用 转型。在每个项目中，分子机制和 不同的依赖于Abl的变换的函数重要性 信号通路将被确定。 这些项目将得到三个科学核心和一个科学核心的支持 行政核心。第一个核心将提供标准化的病毒 原种、单抗和Abelson转化细胞系至ALL 项目。第二个核心将提供老鼠的护理和饲养 参与研究的通路中的基因无效。第三 CORE将提供慢性粒细胞白血病患者的原代细胞 由核心支持的单个项目的白血病将被共享 在这些项目中，以便能够执行协作实验 确定被研究的每条通路的信号是如何相关的 敬其他人。通过本计划项目获得的知识将不会 提高我们对Abelson依赖的转换的理解，但将 也有助于我们理解肿瘤发生和信号的一般机制 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.