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: 7499103
• 负责人: LEIF W ELLISEN
• 金额: $ 32.97万
• 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/7499103
• 关键词: Alleles; Autoimmune Diseases; Binding; Biochemical; Biochemistry; Biological Assay; Cells; Classification; Complex; Condition; 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; 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被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剂。mTOR蛋白复合物I（mTORC 1）的活性失调与多种人类疾病相关，包括糖尿病、自身免疫性疾病和许多类型的癌症。mTORC 1活性的一个关键上游调节因子是由人结节性硬化症肿瘤抑制因子TSC 1和TSC 2组成的另一种蛋白质复合物。在具有TSC 1或TSC 2遗传性生殖系突变的患者中观察到的肿瘤的高频率证明了mTORC 1活性的TSC依赖性调节的重要性。我们已经确定了应激反应基因REDD 1作为mTORC 1活性的重要调节因子，以应对缺氧和能量应激。果蝇的遗传研究和我们自己在哺乳动物细胞中的工作表明，REDD 1通过TSC 1/2复合物作为TORC 1活性的抑制剂发挥作用。我们提供了REDD 1功能机制的证据，该机制对理解TSC 1/2复合体的上游信号整合具有广泛的意义。这些发现意味着REDD 1介导的信号传导对以mTORC 1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，REDD 1-TSC途径可能在人类细胞中起肿瘤抑制机制的作用。该提案旨在揭示TSC-mTORC 1通路中REDD 1调节和信号传导的生物化学。此外，我们将直接研究REDD 1在缺氧条件下对蛋白质翻译调节的贡献，并将鉴定出表现出REDD 1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REDD 1的丢失可能与其他相关遗传事件合作的机制。通过表征这种通过REDD 1蛋白调节TSC 1/2和mTORC 1的新的和必要的途径，这些研究有可能为结节性硬化症和各种其他人类疾病的诊断和治疗提供新的靶点。