Function and mechanism of REDD1 signaling to TSC1/2 and mTORC1

REDD1 信号传导至 TSC1/2 和 mTORC1 的功能和机制

• 批准号: 8102702
• 负责人: LEIF W ELLISEN
• 金额: $ 31.42万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-24 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8102702
• 关键词: Alleles; Autoimmune Diseases; Binding; Biochemical; Biochemistry; Biological Assay; Cells; Complex; Data; Diabetes Mellitus; Diagnosis; Disease; Down-Regulation; Drosophila genus; Event; Exhibits; Feedback; Frequencies; Gene Proteins; Genes; Genetic; Genetic Crosses; Germ-Line Mutation; Human; Hypoxia; In Vitro; Inherited; Mammalian Cell; Mediating; Metabolism; Modeling; Molecular Profiling; Mus; Mutation; Neoplasms; PI3K/AKT; PTEN gene; Pathway interactions; Patients; Phosphorylation; Phosphorylation Site; Phosphotransferases; Physiological; Polyribosomes; Premalignant; Primary Neoplasm; Proteins; Proto-Oncogene Proteins c-akt; RNA; Regulation; Role; STK11 gene; Signal Pathway; Signal Transduction; Stress; TSC1 gene; TSC1/2 gene; TSC2 gene; Testing; Translational Regulation; Translations; Tuberous Sclerosis; Tumor Suppressor Proteins; Work; biological adaptation to stress; cancer type; cell growth; defined contribution; human FRAP1 protein; human TSC2 protein; human disease; hypoxia inducible factor 1; in vivo; in vivo Model; inhibitor/antagonist; insight; loss of function; mTOR inhibition; mTOR protein; malignant phenotype; mutant; novel; protein complex; response; tumor; tumorigenesis; upstream kinase

DESCRIPTION (provided by applicant): The long-term objectives of this project are to understand how stress signals are transduced to control cellular metabolism, and how dysregulation of specific stress response pathways contributes to human disease. The checkpoint kinase mTOR is an essential regulator of cellular metabolism in all human cells. Dysregulated activity of the mTOR protein complex I (mTORC1) has been associated with a wide variety of human diseases, including diabetes, autoimmune disease, and many types of cancer. One critical upstream regulator of mTORC1 activity is another protein complex composed of the human tuberous sclerosis tumor suppressors TSC1 and TSC2. The importance of TSC-dependent regulation of mTORC1 activity is evidenced by the high frequency of neoplasms observed in patients with inherited germline mutation of either TSC1 or TSC2. We have identified the stress response gene REDD1 as an essential regulator of mTORC1 activity in response to hypoxia and energy stress. Genetic studies in Drosophila and our own work in mammalian cells demonstrate that REDD1 functions as an inhibitor of TORC1 activity through the TSC1/2 complex. We provide evidence for a mechanism of REDD1 function that has broad implications for understanding upstream signal integration by the TSC1/2 complex. These findings imply a potentially important contribution of REDD1-mediated signaling to disease states characterized by mTORC1 dysregulation. In particular, our data suggest that the REDD1-TSC pathway may function as a tumor suppressor mechanism in human cells. This proposal aims to uncover the biochemistry of REDD1 regulation and signaling within the TSC-mTORC1 pathway. In addition, we will directly investigate the contribution of REDD1 to regulation of protein translation under hypoxic conditions and will identify specific genes and proteins exhibiting REDD1-dependent regulation. Finally, we will investigate the mechanisms by which loss of REDD1 may cooperate with other relevant genetic events during tumorigenesis. By characterizing this novel and essential pathway for TSC1/2 and mTORC1 regulation through the REDD1 protein, these studies have the potential to provide new targets for diagnosis and treatment of tuberous sclerosis and a wide variety of other human diseases.

描述（由申请人提供）：该项目的长期目标是了解应激信号如何转导以控制细胞代谢，以及特定应激反应途径的失调如何导致人类疾病。检查点激酶 mTOR 是所有人类细胞中细胞代谢的重要调节因子。 mTOR 蛋白复合物 I (mTORC1) 的活性失调与多种人类疾病有关，包括糖尿病、自身免疫性疾病和多种癌症。 mTORC1 活性的一个关键上游调节因子是另一种由人类结节性硬化症肿瘤抑制因子 TSC1 和 TSC2 组成的蛋白质复合物。在具有 TSC1 或 TSC2 遗传性种系突变的患者中观察到的高肿瘤发生率证明了 mTORC1 活性的 TSC 依赖性调节的重要性。我们已经确定应激反应基因 REDD1 是 mTORC1 响应缺氧和能量应激活性的重要调节因子。果蝇的遗传学研究和我们自己在哺乳动物细胞中的研究表明，REDD1 通过 TSC1/2 复合物发挥 TORC1 活性抑制剂的作用。我们为 REDD1 功能机制提供了证据，该机制对于理解 TSC1/2 复合物的上游信号整合具有广泛的影响。这些发现意味着 REDD1 介导的信号传导对以 mTORC1 失调为特征的疾病状态具有潜在的重要作用。特别是，我们的数据表明 REDD1-TSC 通路可能在人类细胞中发挥肿瘤抑制机制的作用。该提案旨在揭示 TSC-mTORC1 通路内 REDD1 调节和信号传导的生物化学。此外，我们将直接研究REDD1在缺氧条件下对蛋白质翻译调节的贡献，并将鉴定表现出REDD1依赖性调节的特定基因和蛋白质。最后，我们将研究肿瘤发生过程中 REDD1 缺失与其他相关遗传事件协同作用的机制。通过表征这种通过 REDD1 蛋白调节 TSC1/2 和 mTORC1 的新颖且重要的途径，这些研究有可能为结节性硬化症和多种其他人类疾病的诊断和治疗提供新的靶标。