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

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因子。mTOR蛋白复合物I （mTORC1）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因子是另一个由人类结节硬化肿瘤抑制因子TSC1和TSC2组成的蛋白复合物。在TSC1或TSC2遗传种系突变患者中观察到的高肿瘤频率证明了tsc依赖性mTORC1活性调节的重要性。我们已经确定应激反应基因REDD1是mTORC1活性在缺氧和能量应激反应中的重要调节因子。在果蝇和哺乳动物细胞中的遗传学研究表明，REDD1通过TSC1/2复合物作为TORC1活性的抑制剂起作用。我们为REDD1功能的机制提供了证据，该机制对理解TSC1/2复合体的上游信号整合具有广泛的意义。这些发现表明，redd1介导的信号传导对以mTORC1失调为特征的疾病状态有潜在的重要贡献。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。本研究旨在揭示TSC-mTORC1通路中REDD1调控和信号转导的生化机制。此外，我们将直接研究red1在缺氧条件下对蛋白质翻译调控的贡献，并将确定表现出red1依赖性调控的特定基因和蛋白质。最后，我们将探讨在肿瘤发生过程中，REDD1的缺失与其他相关遗传事件的合作机制。通过表征这种通过REDD1蛋白调控TSC1/2和mTORC1的新颖和必要途径，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。

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.