Metabolic control of cell growth by the mTOR signaling network

mTOR 信号网络对细胞生长的代谢控制

• 批准号: 8759755
• 负责人: BRENDAN D. MANNING
• 金额: $ 35.31万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8759755
• 关键词: Accounting; Affect; Biogenesis; Cancer Etiology; Carbon; Cell Culture Techniques; Cell Cycle; Cell Line; Cell Proliferation; Cell physiology; Cells; Complex; Consumption; DNA Damage; Data; Enzymes; Event; Family; Genetic; Grant; Growth; Guidelines; Human; Learning; Lipids; Malignant Neoplasms; Mediating; Metabolic; Metabolic Control; Metabolic Pathway; Metabolism; Modeling; Molecular; Mus; Nitrogen; Normal Cell; Normal tissue morphology; Nucleic Acids; Nucleotides; Oncogenes; Oncogenic; Organelles; PTEN gene; Pathway interactions; Phenotype; Phosphorylation; Phosphorylation Site; Physiological; Process; Property; Protein Biosynthesis; Proteins; Publishing; Pyrimidine; Regulation; Research; Resistance; Ribosomes; Role; Signal Pathway; Signal Transduction; Sirolimus; Source; System; Therapeutic; Tumor Suppressor Genes; Tumor Tissue; United States National Institutes of Health; Warburg Effect; base; cancer cell; cell growth; human FRAP1 protein; inhibitor/antagonist; killings; lipid biosynthesis; metabolomics; mutant; neoplastic cell; novel; novel therapeutics; nucleotide metabolism; public health relevance; response; transcription factor; tumor; tumor growth; tumorigenesis; tumorigenic; uncontrolled cell growth

DESCRIPTION (provided by applicant): Cellular growth conditions are sensed not only by metabolic pathways in the form of available carbon and nitrogen sources but also by signaling networks that tightly coordinate the consumption of these metabolic substrates with the control of other cellular processes. It is this coincident regulation of metabolism and other aspects of cell physiology (e.g., organelle biogenesis, cell-cycle entry, etc.) that allows anabolic cell growh and proliferation to proceed. However, the same signaling networks that perceive normal growth signals to coordinately regulate growth processes, including metabolism, are also those most commonly corrupted in human cancers, such as the PI3K and Ras pathways. The mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) is a master regulator of cell growth and a shared downstream effector of these pathways. How mTORC1 influences the downstream cellular processes underlying cell growth is not fully understood. Recent published and unpublished data from our lab indicate that mTORC1, in addition to its established role in promoting protein synthesis, stimulates de novo synthesis of the two other major building blocks of the cell, lipids and nucleotides. Therefore, in response to growth signals, mTORC1 promotes cell growth, at least in part, by inducing key anabolic processes. Due to a large number of upstream oncogenes and tumor suppressors, mTORC1 is constitutively activated in over 50% of human cancers, across nearly all lineages. While it is now well recognized that altered cellular metabolism is a ubiquitous feature of cancer, how oncogenic pathways promote the metabolic changes that drive cell autonomous growth is largely unknown. Here, we hypothesize that mTORC1, through its downstream control of protein, lipid, and nucleotide synthesis, is a key conduit between common oncogenic signaling events and the anabolic reprogramming of cancer cells. This proposal extends our previous mechanistic studies on mTORC1 inducing lipid synthesis through the SREBP family of transcription factors (Aim 1) and de novo pyrimidine synthesis through the S6K1-mediated phosphorylation of CAD, the rate-limiting enzyme in this pathway (Aim 2). The effects of oncogenic PI3K and Ras signaling on lipid and nucleotide synthesis downstream of mTORC1 will be determined. We will also establish the role of these mTORC1-stimulated changes in cellular metabolism in promoting cell growth and tumorigenesis. Under Aim 3, we will combine specific genetic and pharmacological perturbations with unbiased metabolomics to characterize novel mTORC1- or mTORC2-dependent points of metabolic regulation within the PI3K signaling network. In all of these studies, we will employ both cell-based systems and mouse tumor models, with an emphasis on defining molecular mechanisms of metabolic control in cancer cells and the identification of therapeutic opportunities in the form of targeting key metabolic enzymes and vulnerabilities to selectively kill cancer cells.

描述（由申请人提供）：细胞生长条件不仅是通过可用的碳和氮源形式的代谢途径来感知的，而且还通过信号网络的信号网络与其他细胞过程的控制紧密地协调这些代谢底物的消耗。正是这种新陈代谢和细胞生理学的其他方面（例如细胞器生物发生，细胞周期进入等）的同时调节，使合成代谢细胞成长和增殖进行。但是，感知正常生长信号以协调调节生长过程（包括代谢）的相同信号网络也是人类癌症中最常见的人，例如PI3K和RAS途径。雷帕霉素（MTOR）复合物1（MTORC1）的机械靶标是细胞生长的主要调节剂和这些途径的共享下游效应子。 MTORC1如何影响细胞生长的下游细胞过程尚不完全了解。最新发表和未发表的数据来自我们实验室的数据表明，除了其在促进蛋白质合成中的确定作用外，还刺激了细胞其他两个主要构件的从头合成，脂质和核苷酸。因此，根据生长信号，MTORC1至少部分通过诱导关键合成代谢过程促进细胞生长。由于大量上游的癌基因和肿瘤抑制剂，MTORC1在几乎所有谱系中都在超过50％的人类癌症中组成式激活。虽然现在众所周知，细胞代谢改变是癌症的无处不在特征，但致癌途径如何促进驱动细胞自主生长的代谢变化在很大程度上是未知的。在这里，我们假设MTORC1通过其蛋白质，脂质和核苷酸合成的下游控制是常见的致癌信号事件与癌细胞的合成代谢重编程之间的关键渠道。该提案通过SREBP转录因子家族（AIM 1）和DE NOVO嘧啶合成，通过S6K1介导的CAD的CAD（该途径中的速率限制酶）（AIM 2）扩展了我们先前对MTORC1诱导脂质合成（AIM 1）和DE NOVO嘧啶合成的机理研究。致癌PI3K和RAS信号传导对MTORC1下游脂质和核苷酸合成的影响。我们还将确定这些MTORC1刺激的细胞代谢变化在促进细胞生长和肿瘤发生中的作用。在AIM 3下，我们将将特定的遗传和药理扰动与无偏的代谢组学结合，以表征PI3K信号网络中代谢调节的新型MTORC1-或MTORC2依赖性点。在所有这些研究中，我们将同时采用基于细胞的系统和小鼠肿瘤模型，重点是定义癌细胞中代谢控制的分子机制，并以靶向关键代谢酶和脆弱性的形式鉴定治疗机会，以选择性地杀死癌细胞。