Activating mutants of mTOR

描述（由申请人提供）：TSC/Rheb/mTOR信号通路在蛋白质合成、生长和细胞周期进程中发挥重要作用，响应营养物质、能量和生长因子，如胰岛素和胰岛素样生长因子。在多种人类癌症中检测到这一信号通路的过度激活，而雷帕霉素（mTOR的抑制剂）正在临床试验中进行评估。我们最近的工作表明，一个单一的氨基酸变化可以赋予本构激活。最近，我们在人类癌症基因组数据库中发现了mTOR的激活突变体。在本应用中，我们将重点关注这些mTOR突变体，并首先询问这些突变体是否表现出转化活动。然后，我们将开展旨在深入了解突变激活mTOR的机制的实验。最后，我们将使用裂变酵母菌作为一个适合遗传分析的系统，以进一步了解TOR信号的激活机制。

DESCRIPTION (provided by applicant): The TSC/Rheb/mTOR signaling pathway plays important roles in protein synthesis, growth and cell cycle progression in response to nutrients, energy and growth factors such as insulin and insulin like growth factor. Overactivation of this signaling pathway is detected in a variety of human cancers and rapamycin, an inhibitor of mTOR, is being evaluated in clinical trials. Our recent work demonstrated that a single amino acid change can confer constitutive activation. More recently, we have made an important discovery that activating mutants of mTOR can be identified in human cancer genome database. In this application, we will focus on these mTOR mutants and ask first whether these mutants exhibit transforming activities. We will then carry out experiments aimed at gaining insight into the mechanism of activation of mTOR by the mutations. Finally, we will use fission yeast as a system amenable to genetic analysis to gain further insight into the mechanism of activation of the TOR signaling.