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Cotranslational Functions of MTOR

MTOR 的共翻译功能

基本信息

批准号：
9502664
负责人：
Estela Jacinto
金额：
$ 7.5万
依托单位：
RBHS-ROBERT WOOD JOHNSON MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-06-01 至 2018-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9502664
关键词：
Address Animal Model Biogenesis Breast Cancer cell line Cell Count Cell Death Cell Lineage Cell Proliferation Cell model Cell physiology Cellular Metabolic Process Clinical Co-Translational Protein Processing Complex Couples Coupling Cues Endoplasmic Reticulum Epidermal Growth Factor Receptor Eukaryota Event FRAP1 gene Fluorescence Resonance Energy Transfer Generations Genetic Translation Growth Growth Factor Growth Factor Inhibition In Vitro Insulin Insulin Receptor Label Link Lymphoma Lymphomagenesis Malignant Neoplasms Mass Spectrum Analysis Mediating Membrane Membrane Proteins Metabolic Mus Mutagenesis Normal Cell Nutrient PTEN gene Pathologic Pharmaceutical Preparations Pharmacology Phosphorylation Play Polyribosomes Process Protein Biosynthesis Protein Deregulation Protein Kinase Proteins Quality Control Receptor Activation Receptor Signaling Recruitment Activity Research Proposals Ribosomes Role Signal Transduction Sirolimus Stimulus T-Cell Lymphoma T-Lymphocyte Testing Translating Translation Initiation Translations Up-Regulation cancer clinical trial cancer therapy cell growth extracellular in vivo inhibitor/antagonist insight link protein mouse model novel polypeptide premature prevent protein degradation protein folding protein misfolding receptor receptor expression response targeted cancer therapy thymocyte tumor growth tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Coordinated control of mRNA translation and proper folding of nascent polypeptides is critical for normal cell function. Deregulation of protein synthesis and misfolding underlie a number of pathological conditions such as cancer. The mechanisms that couple translation to protein folding are poorly understood particularly in higher eukaryotes. Most studies have focused on either translation or protein folding processes but signaling mechanisms that link these two events, particularly in response to extracellular conditions, remain to be elucidated. The mammalian target of rapamycin (mTOR) plays a central role in cell growth by promoting protein synthesis in response to nutrients, growth factors and energy status. Aberrant mTOR signaling can trigger oncogenesis; hence, mTOR inhibitors are currently under clinical trials for cancer therapy. mTOR functions in protein synthesis by controlling translation initiation and ribosome biogenesis. These processes can be inhibited by the clinically important drug, rapamycin, and are mediated by mTOR, as part of mTOR complex 1 (mTORC1). mTOR also forms a second complex (mTORC2) consisting of mTOR, rictor, SIN1, and mLST8 that is not directly targeted by rapamycin. This complex plays a pivotal role in the phosphorylation and activation of Akt, a protein kinase that is often deregulated in cancer. Because inhibiting Akt promotes cell death, drugs that can specifically inhibit mTORC2 could be more effective in preventing cancer. However, the cellular functions of mTORC2 are less characterized. We recently discovered that mTORC2 associates with translating ribosomes and couples translation with the processing of nascent Akt. This novel function of mTORC2 is critical for proper folding and stability of Akt to prevent premature degradation during translation. Thus, inhibition of mTORC2 would not only prevent Akt activation but also diminish its expression. Our research proposal will elucidate how mTORC2 functions in cotranslational processing of nascent polypeptides using both cellular and animal models. Because of the central role of mTOR in cell growth and metabolism, our studies will have significant implications in the understanding of how growth stimuli can be integrated by mTOR to control the quality and quantity of newly synthesized proteins.

描述（由申请人提供）：mRNA翻译的协调控制和新生多肽的正确折叠对于正常细胞功能至关重要。蛋白质合成的失调和错误折叠是许多病理状况如癌症的基础。翻译与蛋白质折叠的耦合机制知之甚少，特别是在高等真核生物中。大多数研究都集中在翻译或蛋白质折叠过程，但连接这两个事件的信号转导机制，特别是在响应细胞外条件下，仍有待阐明。哺乳动物雷帕霉素靶蛋白（mTOR）通过响应营养物质、生长因子和能量状态促进蛋白质合成而在细胞生长中起核心作用。异常的mTOR信号传导可以触发肿瘤发生;因此，mTOR抑制剂目前正在进行癌症治疗的临床试验。mTOR通过控制翻译起始和核糖体生物发生在蛋白质合成中起作用。这些过程可以被临床上重要的药物雷帕霉素抑制，并由mTOR介导，作为mTOR复合物1（mTORC 1）的一部分。mTOR还形成由mTOR、rictor、SIN 1和mLST 8组成的第二复合物（mTORC 2），其不被雷帕霉素直接靶向。这种复合物在Akt的磷酸化和激活中起着关键作用，Akt是一种在癌症中经常失调的蛋白激酶。由于抑制Akt会促进细胞死亡，因此可以特异性抑制mTORC 2的药物可能在预防癌症方面更有效。然而，mTORC 2的细胞功能特征较少。我们最近发现mTORC 2与翻译核糖体相关，并将翻译与新生Akt的加工偶联。mTORC 2的这种新功能对于Akt的正确折叠和稳定性至关重要，以防止翻译过程中的过早降解。因此，mTORC 2的抑制不仅会阻止Akt活化，而且会减少其表达。我们的研究计划将阐明mTORC 2如何使用细胞和动物模型在新生多肽的共翻译加工中发挥作用。由于mTOR在细胞生长和代谢中的核心作用，我们的研究将对理解mTOR如何整合生长刺激以控制新合成蛋白质的质量和数量具有重要意义。