FOXO Regulon and Translation Control

 描述（由申请人提供）：AKT/mTOR信号通路在包括癌症和糖尿病在内的几种人类疾病的病理学中起核心作用。该途径是能量状态、营养物质可用性、压力和内分泌生长因子的传感器。响应于 这些信号通路调节细胞生长和增殖。这种控制的一部分是通过调节蛋白质和RNA的合成。该途径确保只有在条件有利时才能翻译新的蛋白质，而RNA合成则由Forkhead-box家族O（FOXO）转录因子的激活或失活来调节。我们已经确定了FOXO的直接目标，并找到FOXO目标和翻译启动之间的联系。起始的负调节因子在所鉴定的FOXO靶标组中过度表达，表明控制RNA合成的AKT/mTOR途径的分支与控制蛋白质合成的分支之间存在联系。几个新鉴定的FOXO靶点对AKT/mTOR途径施加的翻译调节免疫。我们相信这提供了一种机制，整合蛋白质合成的调控与转录调控的基因，这是这一途径的目标。我们假设：AKT/mTOR途径通过控制多种翻译抑制剂的表达，通过FOXO改变翻译谱。为了测试这一想法的普遍性，我们建议通过分析激活的FOXO表达过程中被积极翻译的mRNA来确定特定转录本的翻译效率。我们还将定义负责这种效应的直接FOXO靶点，并从功能上描述其效应。此外，我们发现小RNA途径受到激活的FOXO的显著影响。小RNA的变化也有可能广泛改变细胞的翻译谱，因此我们将定义小RNA的翻译谱。 FOXO对小RNA的影响。这项提案中的工作将阐明从mRNA合成到蛋白质合成的基因表达的未被重视的整合。

 DESCRIPTION (provided by applicant: The AKT/mTOR signaling pathway plays central roles in the pathology of several human diseases including cancer and diabetes. This pathway is a sensor of energy status, nutrient availability, stress and endocrine growth factors. In response to these cues the pathway modulates cell growth and proliferation. Part of this control is through regulating both protein and RNA synthesis. The pathway ensures that new proteins are translated only when conditions are favorable, while RNA synthesis is regulated by activation or inactivation of the Forkhead-box family O (FOXO) transcription factors. We have identified the direct targets of FOXO and find a connection between FOXO targets and translation initiation. Negative regulators of initiation are overrepresented in the identified set of FOXO targets suggesting a connection between the branch of the AKT/mTOR pathway that controls RNA synthesis and the branch that controls protein synthesis. Several of the newly identified FOXO targets are immune to the translational regulation imposed by the AKT/mTOR pathway. We believe this provides a mechanism for integrating the regulation of protein synthesis with transcriptional regulation of genes that are targets of this pathway. We hypothesize that: the AKT/mTOR pathway changes translational profiles through FOXO by controlling the expression of multiple translational inhibitors. To test the generality of this idea, we propose to determine the efficiency of translation of specific transcripts by profiling mRNAs being actively translated during expression of an activated FOXO. We will also define the direct FOXO targets that are responsible for this effect and functionally characterize their effects. In addition, we find that he small RNA pathway is dramatically affected by activated FOXO. Changes in small RNAs also have the potential to extensively change the translation profile of the cell, so we will define the effect of FOXO on small RNAs. The work in this proposal will illuminate an underappreciated integration of gene expression from mRNA synthesis through protein synthesis.