FOXO Regulon and Translation Control

FOXO 调节子和翻译控制

• 批准号: 9005639
• 负责人: MICHAEL Thomas MARR
• 金额: $ 31.82万
• 依托单位: BRANDEIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-06 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9005639
• 关键词: Affect; Agreement; Animals; Biological Assay; Boxing; Cell Proliferation; Cells; Cues; Diabetes Mellitus; Drosophila genus; Endocrine; Ensure; FRAP1 gene; Family; Gene Expression; Gene Targeting; Growth; Human Pathology; Immune Targeting; Internal Ribosome Entry Site; Investigation; Link; Malignant Neoplasms; Messenger RNA; MicroRNAs; Nutrient; Organism; Pathology; Pathway interactions; Play; Process; Protein Biosynthesis; Proteins; Proto-Oncogene Proteins c-akt; RNA chemical synthesis; Regulation; Regulon; Ribosomes; Role; Signal Transduction; Small Interfering RNA; Small RNA; Stress; Testing; Transcript; Transcriptional Regulation; Translating; Translation Initiation; Translational Regulation; Translations; Work; age effect; base; cell growth; human disease; inhibitor/antagonist; interest; mTOR Signaling Pathway; public health relevance; research study; response; sensor; transcription factor

 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.

 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多种人类疾病的病理学中发挥着核心作用。该通路是能量状态、营养可用性、压力和内分泌生长因子的传感器。 这些线索表明该途径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 合成。该途径确保只有在条件有利时才翻译新蛋白质，而 RNA 合成则通过 Forkhead-box 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，并找到了 FOXO 目标与翻译起始之间的联系。起始负调控因子在已识别的 FOXO 靶标组中出现过多，表明控制 RNA 合成的 AKT/mTOR 通路分支与控制蛋白质合成的分支之间存在联系。几个新发现的 FOXO 靶点不受 AKT/mTOR 通路施加的翻译调控的影响。我们相信这提供了一种将蛋白质合成的调节与作为该途径的靶标的基因的转录调节整合起来的机制。我们假设：AKT/mTOR 通路通过 FOXO 控制多种翻译抑制剂的表达来改变翻译谱。为了测试这个想法的普遍性，我们建议通过分析在激活的 FOXO 表达过程中主动翻译的 mRNA 来确定特定转录本的翻译效率。我们还将定义造成这种效应的直接 FOXO 目标，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的显着影响。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 FOXO 对小 RNA 的影响。该提案中的工作将阐明从 mRNA 合成到蛋白质合成的基因表达整合未被充分认识。