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

基本信息

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
项目类别：
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

项目摘要

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 Recent published and unpublished data from our lab indicate that mTORC1, in addition to its established role in promoting protein synthesis, stimulates de novo synthesis of the two other major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）：细胞生长条件不仅通过可用碳源和氮源形式的代谢途径来感知，而且还通过信号网络来感知，该信号网络紧密协调这些代谢底物的消耗与其他细胞过程的控制。正是这种新陈代谢和细胞生理学其他方面（例如细胞器生物发生、细胞周期进入等）的一致调节，使得合成代谢细胞生长和增殖得以进行。然而，感知正常生长信号以协调调节生长过程（包括新陈代谢）的信号网络也是人类癌症中最常被破坏的信号网络，例如 PI3K 和 Ras 通路。雷帕霉素 (mTOR) 复合物 1 (mTORC1) 的机制靶点是细胞生长的主要调节因子，也是这些通路的共享下游效应器。 mTORC1 如何影响细胞生长的下游细胞过程尚不完全清楚。我们实验室最近发表和未发表的数据表明，mTORC1 除了在促进蛋白质合成方面的既定作用外，还刺激细胞的其他两个主要构建模块（脂质和核苷酸）的从头合成。因此，响应生长信号，mTORC1 至少部分地通过诱导关键的合成代谢过程来促进细胞生长。由于存在大量上游癌基因和肿瘤抑制基因，mTORC1 在几乎所有谱系的超过 50% 的人类癌症中都被组成型激活。虽然现在人们普遍认识到细胞代谢的改变是癌症的普遍特征，但致癌途径如何促进代谢变化，从而驱动细胞自主生长，在很大程度上尚不清楚。在这里，我们假设 mTORC1 通过其对蛋白质、脂质和核苷酸合成的下游控制，是常见致癌信号事件和癌细胞合成代谢重编程之间的关键管道。该提案扩展了我们之前的机制研究，即 mTORC1 通过 SREBP 转录因子家族诱导脂质合成（目标 1），以及通过 S6K1 介导的 CAD（该途径中的限速酶）磷酸化从头合成嘧啶（目标 2）。将确定致癌 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。在目标 3 下，我们将把特定的遗传和药理学扰动与公正的代谢组学相结合，以表征 PI3K 信号网络内新的 mTORC1 或 mTORC2 依赖的代谢调节点。在所有这些研究中，我们将采用基于细胞的系统和小鼠肿瘤模型，重点是定义癌细胞代谢控制的分子机制，并以选择性靶向关键代谢酶和脆弱性的形式识别治疗机会。杀死癌细胞。