FOXO Regulon and Translation Control

 描述(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中发挥核心作用。这一途径是能量状态、营养可获得性、压力和内分泌生长因子的传感器。作为对.的回应 这些信号表明，该途径调节细胞的生长和增殖。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的情况下才能翻译新的蛋白质，而RNA的合成则通过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的直接靶标，并发现FOXO靶标与翻译启动之间的联系。在识别的一组FOXO靶标中，启动的负调控因子被过度表达，这表明控制RNA合成的AKT/mTOR通路的分支和控制蛋白质合成的分支之间存在联系。新发现的几个FOXO靶点对AKT/mTOR途径实施的翻译调控具有免疫力。我们认为，这提供了一种机制，将蛋白质合成的调控与作为这一途径靶标的基因的转录调控结合起来。我们假设：AKT/mTOR通路通过FOXO控制多个翻译抑制物的表达而改变翻译谱。为了测试这一想法的普遍性，我们建议通过分析在激活的FOXO表达过程中主动翻译的mRNAs来确定特定转录本的翻译效率。我们还将定义对这种效应负责的直接FOXO目标，并从功能上描述它们的影响。此外，我们还发现，激活的FOXO显著影响了小RNA途径。小RNA中的变化也有可能广泛地改变细胞的翻译配置文件，因此我们将定义 FOXO对小RNA的影响这项提案中的工作将阐明基因表达从mRNA合成到蛋白质合成的整合没有得到充分的重视。

 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.