Cell Growth Signaling in Cancer Development

癌症发展中的细胞生长信号传导

• 批准号: 7464742
• 负责人: David M. Sabatini
• 金额: $ 39.99万
• 依托单位: WHITEHEAD INSTITUTE FOR BIOMEDICAL RES
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-08 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7464742
• 关键词: Address; Affect; Alleles; Animal Model; Animal Structures; Binding; Biochemistry; Biological Assay; Biological Process; Biology; Cancer Etiology; Catalytic Domain; Cells; Class; Collaborations; Community Clinical Oncology Program; Complex; Crystallography; Data; Development; Disease; Dose; Electron Microscopy; Future; GTP-Binding Proteins; GTPase-Activating Proteins; Genes; Genetic; Goals; Growth; Growth Factor; Human; Image; Individual; Insulin; Knockout Mice; Lead; Lesion; Lymphangioleiomyomatosis; Malignant Neoplasms; Mammals; Medical; Methods; Modeling; Molecular; Molecular Biology; Molecular Structure; Mus; Mutation; Normal Cell; Nutrient; Organism; PTEN gene; Pathway interactions; Patients; Phosphorylation; Phosphorylation Site; Phosphotransferases; Play; Process; Prostate; Prostate Adenocarcinoma; Protein Kinase; Protein p53; Proteins; Public Health; Raptors; Research; Resolution; Role; STK11 gene; Signal Pathway; Signal Transduction; Sirolimus; Stress; Structural Models; Structure; Syndrome; TSC1 gene; TSC2 gene; Testing; Therapeutic; Tuberous sclerosis protein complex; Tumor Suppressor Proteins; Work; cancer therapy; cell growth; drug development; high throughput screening; human FRAP1 protein; human disease; inhibitor/antagonist; insight; mTOR Inhibitor; mouse model; novel; response; size; small molecule; structural biology; therapy development; tool; tumor; tumorigenesis

DESCRIPTION (provided by applicant): Growth is the process through which cells accumulate mass and increase in size. mTORC1 is a protein kinase composed of the mTOR catalytic subunit and the associated proteins raptor and mLST8 and the central component of a signaling network that regulates growth in response to growth factors, nutrients, and stress. It is increasingly apparent that many cancer-promoting lesions activate the mTORC1 pathway. Most notably, the TSC1-TSC2 tumor suppressor complex--whose inactivation causes the tumor- prone syndrome Tuberous Sclerosis Complex (TSC) and the related disease Lymphangioleiomyomatosis (LAM)--is a major negative regulator of mTORC1. The TSC1-TSC2 heterodimer is a GTPase activating protein (GAP) that inhibits rheb, a GTP-binding protein that activates mTORC1 through a poorly understood mechanism. TSC1-TSC2 and rheb are also important for the activation of mTORC1 that occurs in cells that have lost the PTEN, NF1, LKB1, or p53 tumor suppressors. We propose to address key gaps in our understanding of mTORC1 biology. First, we will determine the molecular mechanisms that activate mTORC1 in response to growth factors or inactivation of TSC1- TSC2 or PTEN. Second, using mouse models we are developing, we will rigorously test the role of mTORC1 in tumorigenesis caused by inactivation of PTEN. Third, we will obtain structural information about intact mTORC1 and the mTOR kinase domain. We will accomplish our goals with a collaborative multi-disciplinary approach that exploits the tools of biochemistry, molecular biology, mouse models of cancer, and structural biology. We believe that our results are likely to have significant medical implications for the treatment of Tuberous Sclerosis Complex. An understanding of how the inactivation of TSC1-TSC2 activates mTORC1 is necessary for the rational development of therapies for TSC. With our animal models we will obtain a definitive genetic answer to the potential value of inhibiting mTORC1 in patients with tumors missing PTEN. Lastly, modified versions of our novel mTORC1 kinase assay may be useful for the high- throughput screening of small molecules that inhibit mTORC1 and our structural work will inform the development of inhibitors of the mTOR kinase. PUBLIC HEALTH RELEVANCE: Growth is the process through which cells and organisms accumulate mass and increase in size. It is increasingly apparent that this basic biological process is deregulated in common human diseases, most notably in cancer. In this application we propose to study one of the major growth regulators in mammals, a complex of several proteins called mTORC1. We propose to elucidate the molecular mechanisms that activate mTORC1 in cancer and normal cells, to determine if inhibiting mTORC1 is likely to be a good treatment for tumors that have a common cancer-causing genetic alteration, and, lastly, to determine the molecular structure of mTORC1. The overall goal of our proposed work is to increase the capacity of the oncology community to rationally exploit mTORC1 in the treatment of cancer. We anticipate that our work will help understand which tumor classes should be treated with mTORC1 inhibitors, aid in the development of more specific mTORC1 inhibitors, and lead to the discovery of mechanisms that may be targets for future drug development.

描述（由申请人提供）：生长是细胞积累质量并增大尺寸的过程。 mTORC1 是一种蛋白激酶，由 mTOR 催化亚基以及相关蛋白 raptor 和 mLST8 组成，是响应生长因子、营养物质和应激而调节生长的信号网络的核心组件。越来越明显的是，许多促癌病变会激活 mTORC1 通路。最值得注意的是，TSC1-TSC2 肿瘤抑制复合物（其失活会导致肿瘤倾向综合征结节性硬化症复合物 (TSC) 和相关疾病淋巴管平滑肌瘤病 (LAM)）是 mTORC1 的主要负调节因子。 TSC1-TSC2 异二聚体是一种 GTP 酶激活蛋白 (GAP)，可抑制 rheb，而 rheb 是一种 GTP 结合蛋白，可通过一种鲜为人知的机制激活 mTORC1。 TSC1-TSC2 和 rheb 对于 mTORC1 的激活也很重要，mTORC1 发生在失去 PTEN、NF1、LKB1 或 p53 肿瘤抑制因子的细胞中。我们建议解决我们对 mTORC1 生物学理解中的关键差距。首先，我们将确定响应生长因子或 TSC1-TSC2 或 PTEN 失活而激活 mTORC1 的分子机制。其次，使用我们正在开发的小鼠模型，我们将严格测试mTORC1在PTEN失活引起的肿瘤发生中的作用。第三，我们将获得有关完整 mTORC1 和 mTOR 激酶结构域的结构信息。我们将通过利用生物化学、分子生物学、小鼠癌症模型和结构生物学工具的多学科协作方法来实现我们的目标。我们相信，我们的结果可能对结节性硬化症的治疗具有重大的医学意义。了解 TSC1-TSC2 失活如何激活 mTORC1 对于合理开发 TSC 疗法是必要的。通过我们的动物模型，我们将获得关于抑制 mTORC1 对于缺少 PTEN 的肿瘤患者的潜在价值的明确遗传答案。最后，我们的新型 mTORC1 激酶测定的修改版本可能有助于高通量筛选抑制 mTORC1 的小分子，并且我们的结构工作将为 mTOR 激酶抑制剂的开发提供信息。 公共卫生相关性：生长是细胞和生物体积累质量并增大体积的过程。越来越明显的是，这种基本的生物过程在常见的人类疾病中不受管制，尤其是在癌症中。在此应用中，我们打算研究哺乳动物的主要生长调节剂之一，即 mTORC1 几种蛋白质的复合物。我们建议阐明在癌症和正常细胞中激活 mTORC1 的分子机制，以确定抑制 mTORC1 是否可能是具有常见致癌基因改变的肿瘤的良好治疗方法，最后确定 mTORC1 的分子结构。我们提出的工作的总体目标是提高肿瘤学界在癌症治疗中合理利用 mTORC1 的能力。我们预计我们的工作将有助于了解哪些肿瘤类别应该用 mTORC1 抑制剂治疗，帮助开发更特异性的 mTORC1 抑制剂，并导致发现可能成为未来药物开发目标的机制。