权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

基本信息

批准号：
7372035
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
项目类别：
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/7372035
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

项目摘要

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(申请人提供)：这个项目的长期目标是了解压力信号是如何被转导来控制细胞新陈代谢的，以及特定的压力反应通路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新陈代谢的重要调节因子。MTOR蛋白复合体I(MTORC1)活性异常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由人类结节性硬化症肿瘤抑制基因TSC1和TSC2组成的另一种蛋白质复合体。在TSC1或TSC2遗传性种系突变患者中观察到的肿瘤的高频率证明了依赖于TSC调节mTORC1活性的重要性。我们已经确定应激反应基因Redd1是mTORC1活性的重要调节因子，对低氧和能量应激做出反应。对果蝇的遗传学研究和我们在哺乳动物细胞中的工作表明，Redd1通过TSC1/2复合体发挥TORC1活性的抑制作用。我们为Redd1功能的机制提供了证据，该机制对于理解TSC1/2复合体的上游信号整合具有广泛的意义。这些发现暗示了Redd1介导的信号在以mTORC1失调为特征的疾病状态中的潜在重要贡献。特别是，我们的数据表明，Redd1-TSC途径可能在人类细胞中作为一种肿瘤抑制机制发挥作用。这项建议旨在揭示TSC-mTORC1途径中Redd1调控和信号的生物化学。此外，我们还将直接研究Redd1在低氧条件下对蛋白质翻译的调控作用，并将发现具有Redd1依赖调控作用的特定基因和蛋白质。最后，我们将研究在肿瘤发生过程中，Redd1的缺失可能与其他相关遗传事件协同作用的机制。通过表征这一通过Redd1蛋白调控TSC1/2和mTORC1的新的和必要的途径，这些研究有可能为结节性硬化症和其他多种人类疾病的诊断和治疗提供新的靶点。