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: 7673530
• 负责人: LEIF W ELLISEN
• 金额: $ 32.68万
• 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 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7673530
• 关键词: Alleles; Autoimmune Diseases; Binding; Biochemical; Biochemistry; Biological Assay; Cells; Classification; 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; 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力信号如何转导至控制细胞代谢，以及特定压力反应途径失调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剂。 MTOR蛋白质复合物I（MTORC1）的活性失调与多种人类疾病有关，包括糖尿病，自身免疫性疾病和许多类型的癌症。 MTORC1活性的一个关键上游调节剂是另一种由人结核性硬化肿瘤抑制剂TSC1和TSC2组成的蛋白质复合物。 TSC依赖性调节MTORC1活性的重要性是由在TSC1或TSC2的遗传种系突变患者中观察到的肿瘤的高频率。我们已经确定了应力反应基因REDD1是响应缺氧和能量应激的MTORC1活性的重要调节剂。果蝇和我们在哺乳动物细胞中的工作中的遗传研究表明，REDD1通过TSC1/2复合物作为TORC1活性的抑制剂。我们为REDD1功能机制提供了证据，该机制对理解TSC1/2复合物的上游信号积分具有广泛的影响。这些发现意味着REDD1介导的信号传导对MTORC1失调为特征的疾病状态的潜在重要贡献。特别是，我们的数据表明，REDD1-TSC途径可能是人类细胞中肿瘤抑制机制。该建议旨在揭示TSC-MTORC1途径中REDD1调控和信号传导的生物化学。此外，我们将直接研究REDD1对低氧条件下蛋白质翻译的调节的贡献，并将确定表现出REDD1依赖性调节的特定基因和蛋白质。最后，我们将研究REDD1损失可能与肿瘤发生过程中其他相关遗传事件合作的机制。通过表征TSC1/2和MTORC1通过REDD1蛋白调节的新型和必不可少的途径，这些研究有可能为诊断和治疗结核性硬化和多种其他人类疾病提供新的靶标。