Function and mechanism of REDD1/mTOR signaling in metabolism and tumorigenesis

REDD1/mTOR信号在代谢和肿瘤发生中的功能和机制

• 批准号: 8641665
• 负责人: LEIF W ELLISEN
• 金额: $ 31.11万
• 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 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8641665
• 关键词: Ablation; Acute; Address; Affect; Autoimmune Diseases; Autophagocytosis; BRAF gene; Biochemical; Biological Assay; Biological Models; Breast; Catabolism; Cell Proliferation; Cell Respiration; Cells; Complex; DNA Damage; Data; Diabetes Mellitus; Diagnosis; Disabled Persons; Disease; Drosophila genus; Energy Metabolism; Epidermal Growth Factor Receptor; Epithelial Cells; Event; Exhibits; Feedback; Funding; Future; Genes; Genetic; Genetic Crosses; Genotype; Grant; Homeostasis; Human; Hypoxia; Hypoxia Inducible Factor; Incidence; Individual; KRAS2 gene; Knowledge; Lead; Link; Maintenance; Malignant Neoplasms; Mediating; Metabolic; Metabolic Activation; Metabolism; Mitochondria; Mitochondrial Proteins; Modeling; Molecular; Mus; Mutation; Oncogenic; Output; Oxidants; Oxidative Phosphorylation; Pancreas; Pathway interactions; Phosphotransferases; Physiological; Positioning Attribute; Process; Proteins; Publishing; Reactive Oxygen Species; Regulation; Role; Sampling; Signal Pathway; Signal Transduction; Staging; Stress; TSC1/2 gene; Testing; Tissues; Translations; Tuberous Sclerosis; Tumor Suppression; Tumor Suppressor Proteins; Work; biological adaptation to stress; cancer type; cell growth; defined contribution; human FRAP1 protein; human disease; in vivo; insight; knowledge base; loss of function; mTOR Inhibitor; mTOR protein; malignant phenotype; mitochondrial autophagy; mitochondrial dysfunction; mutant; novel; programs; protein complex; public health relevance; reconstitution; repository; response; restoration; tumor; tumor metabolism; tumor progression; tumorigenesis; tumorigenic

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. Activation of mTORC1 orchestrates cell growth and cellular proliferation in large part by promoting protein translation and by inhibiting a process of self-catabolism known as macro-autophagy. The complex interplay of signaling pathways to mTORC1 and the resulting physiologic outputs remain poorly understood. Studies in the previous funding cycle identified the stress response gene REDD1 as an essential inhibitor of mTORC1 activity in response to hypoxia and energy stress. We elucidated the mechanism whereby hypoxia inhibits mTORC1 activity, in which REDD1 functions to activate the tuberous sclerosis (TSC1/2) tumor suppressor complex. We demonstrated how mTORC1 via REDD1 regulates translation of key proteins including p53 to control the DNA damage response in vivo. In the absence of p53, genetic loss of REDD1 is potent driver of tumorigenesis, in keeping with the silencing or loss of REDD1 observed in several human tumors. REDD1-dependent tumorigenesis is associated with glycolytic reprogramming and suppression of oxidative metabolism in cells and tissues of REDD1-deficient mice. Preliminary data suggest these effects are attributable to a critical role for REDD1 in promoting both autophagy and mitochondrial activity, functioning through distinct mechanisms upstream and downstream of mTORC1. These findings position REDD1 as a critical control point for metabolic homeostasis and tumor suppression. Here we propose a systematic approach to pursuing the biochemical and physiological role of REDD1 in controlling mTORC1, autophagy, and mitochondrial function in human cancer. We will first determine the molecular mechanism of REDD1-mediated regulation of autophagy and oxidative metabolism independent of mTORC1. Second, we have established a novel primary cell/in vivo orthotopic model, which we will use to functionally dissect the contribution of these individual REDD1-controlled pathways to cellular signaling, metabolism, and tumorigenesis in vivo. Finally, we will uncover specific tumor genetic contexts in which REDD1 silencing activates autophagy and the glycolytic switch to drive tumorigenesis, through genetic crosses and through analysis of our established repository of thousands of genotyped human tumors. These studies will provide new insights into tumor metabolism and its relationship to specific oncogenic driver events. Our findings will thus contribute directly to the knowledge base required to therapeutically target de-regulated metabolism and cellular signaling in human cancer.

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的激活在很大程度上通过促进蛋白质翻译和抑制称为宏自噬的自我催化过程来协调细胞生长和细胞增殖。mTORC 1信号通路的复杂相互作用和由此产生的生理输出仍然知之甚少。 上一个资助周期的研究确定了应激反应基因REDD 1作为mTORC 1活性的重要抑制剂，以应对缺氧和能量应激。我们阐明了缺氧抑制mTORC 1活性的机制，其中REDD 1的功能是激活结节性硬化症（TSC 1/2）肿瘤抑制复合物。我们证明了mTORC 1如何通过REDD 1调节包括p53在内的关键蛋白的翻译，以控制体内的DNA损伤反应。在缺乏p53的情况下，REDD 1的遗传缺失是肿瘤发生的有力驱动因素，与在几种人类肿瘤中观察到的REDD 1沉默或缺失一致。REDD 1依赖性肿瘤发生与REDD 1缺陷小鼠细胞和组织中的糖酵解重编程和氧化代谢抑制有关。初步数据表明，这些影响可归因于REDD 1在促进自噬和线粒体活性方面的关键作用，通过mTORC 1上游和下游的不同机制发挥作用。这些发现将REDD 1定位为代谢稳态和肿瘤抑制的关键控制点。 在这里，我们提出了一个系统的方法来追求的生化和生理作用的REDD 1在控制mTORC 1，自噬和线粒体功能在人类癌症。我们将首先确定REDD 1介导的自噬和氧化代谢调节的分子机制，独立于mTORC 1。其次，我们已经建立了一种新的原代细胞/体内原位模型，我们将使用它来功能解剖这些个体REDD 1控制的通路对细胞信号传导、代谢和体内肿瘤发生的贡献。最后，我们将通过遗传杂交和分析我们建立的数千种基因型人类肿瘤的储存库，揭示特定的肿瘤遗传背景，其中REDD 1沉默激活自噬和糖酵解开关以驱动肿瘤发生。这些研究将为肿瘤代谢及其与特定致癌驱动事件的关系提供新的见解。因此，我们的研究结果将直接有助于治疗靶向人类癌症中失调的代谢和细胞信号传导所需的知识基础。