LARG, A Novel Leukemia Associated Guanine Exhange Factor

产品说明： （由申请人提供）小GTP酶的RAS超家族 由大约50个蛋白质成员组成，分为几个亚家族。 尽管Ras亚家族因其作用而被广泛研究， 在恶性转化中，人们越来越感兴趣的是表征 Rho GTP酶由于这些蛋白质在控制 细胞内稳态 Rho GTP酶是生物分子“开关”， 控制多种细胞过程，如生长，分化， 通过在非活性（GDP结合的）和活性（GTP结合的）之间循环来转化。 绑定）状态。 Rho鸟嘌呤核苷酸交换因子（GEFs）调节细胞内的 Rho GTP酶。 然而，Rho GTdR级联还远未完全 以及特定Rho GEF或Rho GTP酶对人类免疫应答的贡献。 疾病尚未确定。 我们最近发现了一个新的基因， 序列预测它是Rho GEF。 这种基因叫做白血病相关基因 RhoGEF或LARG在急性淋巴细胞白血病中与转录因子融合。 白血病 我们假设LARG具有致癌活性， 其假定的Rho GEF活性，以及其激活Rho的能力， GT3途径。 我们建议通过描述 LARG的功能，并评估其与白血病发生的相关性。 我们有 确定了实现这些目标的三个具体目标。 在第一个目标中， 将在体外表征LARG作为Rho GTP酶的GEF。 在第二 我们将确定LARG在Rho GTdR级联中的作用 在体内通过产生转基因果蝇系，我们将表征 LARG小鼠同源物（Larg）在小鼠生长过程中的表达模式 通过原位杂交进行胚胎发生。 在第三个具体目标中，我们将 评估LARG与急性白血病发病机制的相关性， 分析LARG融合基因和其他LARG基因的致白血病潜力 通过逆转录病毒转染鼠干细胞在体外和体内进行突变。 最终，我们相信K08提案将提供重要的见解 通过这种新的Rho GEF调节细胞功能，并将提供 为未来的独立调查基础科学工作奠定坚实的基础， 首席研究员（PI）。

DESCRIPTION: (provided by Applicant) The RAS superfamily of small GTPases consists of approximately 50 protein members divided into several subfamilies. Although the Ras subfamily has been the most extensively studied for its role in malignant transformation, there is an increasing interest in characterizing the Rho GTPases due to the role that these proteins play in the control of cell homeostasis. The Rho GTPases are biological molecular "switches" that control multiple cellular processes such as growth, differentiation, and transformation by cycling between an inactive (GDP-bound) and an active (GTP- bound) state. The Rho guanine nucleotide exchange factors (GEFs) regulate the Rho GTPases. The Rho GTPase cascade, however, is far from being completely resolved and the contributions of particular Rho GEFs or Rho GTPases to human diseases remain undetermined. We have recently identified a novel gene whose sequence predicts it to be a Rho GEF. This gene called Leukemia Associated Rho GEF, or LARG was found fused with a transcription factor in acute leukemia. We hypothesize that LARG has oncogenic activity that is mediated by its putative Rho GEF activity and, in turn, by its ability to activate Rho GTPase pathways. We propose to test this hypothesis by characterizing the functions of LARG and assessing its relevance to leukemogenesis. We have identified three specific aims to achieve these goals. In the first aim we will characterize in vitro LARG as a GEF for Rho GTPases. In the second specific aim we will determine the role of LARG within the Rho GTPase cascade in vivo by generating transgenic Drosophila lines, and we will characterize e x p ression patterns of the LARG murine homolog (Larg) during mouse embryogenesis by in situ hybridization. In the third specific aim, we will assess the relevance of LARG to the pathogenesis of acute leukemia by analyzing the leukemogenic potential of the LARG fusion gene and other LARG mutants in vitro and in vivo by retroviral transfection of murine stem cells. Ultimately, we believe that this K08 proposal will provide important insights into the regulation of cell functions by this novel Rho GEF, and will provide a firm foundation for future independent investigative basic science work by the principal investigator (P.I.).