Cotranslational Functions of MTOR

MTOR 的共翻译功能

• 批准号: 8700943
• 负责人: Estela Jacinto
• 金额: $ 30.86万
• 依托单位: RBHS-ROBERT WOOD JOHNSON MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8700943
• 关键词: Address; Animal Model; Biogenesis; Breast Cancer Cell; Cancer cell line; Cell Count; Cell Death; Cell Lineage; Cell Proliferation; Cell model; Cell physiology; Clinical Trials; Co-Translational Protein Processing; Complex; Couples; Coupling; Cues; Endoplasmic Reticulum; Epidermal Growth Factor Receptor; Eukaryota; Event; Fluorescence Resonance Energy Transfer; Generations; Genetic Translation; Growth; Growth Factor; Growth Factor Receptors; In Vitro; Insulin; Insulin Receptor; Label; Link; Lymphoma; Lymphomagenesis; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; Membrane; Membrane Proteins; Metabolic; Metabolism; Mus; Mutagenesis; Normal Cell; Nutrient; PTEN gene; Pharmaceutical Preparations; Phosphorylation; Play; Polyribosomes; Process; Protein Biosynthesis; Protein Kinase; Proteins; Quality Control; Receptor Activation; Recruitment Activity; Research Proposals; Ribosomes; Role; Signal Transduction; Sirolimus; Stimulus; T-Cell Lymphoma; T-Lymphocyte; Testing; Translating; Translation Initiation; Translation Process; Translation Process Protein; Translations; Up-Regulation; cancer therapy; cell growth; computerized data processing; extracellular; in vivo; inhibitor/antagonist; insight; link protein; mTOR protein; mouse model; novel; polypeptide; premature; prevent; protein degradation; protein folding; protein misfolding; receptor; receptor expression; response; thymocyte; tumor growth; tumorigenesis

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。蛋白质合成失调和错误折叠是许多病理状况（例如癌症）的基础。人们对翻译与蛋白质折叠耦合的机制知之甚少，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上，但连接这两个事件的信号机制，特别是响应细胞外条件的信号机制仍有待阐明。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，在细胞生长中发挥核心作用。异常的 mTOR 信号传导可触发肿瘤发生；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发挥作用。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 (mTORC1) 的一部分。 mTOR 还形成第二个复合物 (mTORC2)，由 mTOR、rictor、SIN1 和 mLST8 组成，雷帕霉素不直接靶向该复合物。该复合物在 Akt 的磷酸化和激活中发挥着关键作用，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，因此能够特异性抑制 mTORC2 的药物可能更有效地预防癌症。然而，mTORC2 的细胞功能尚不清楚。我们最近发现 mTORC2 与核糖体翻译相关，并将翻译与新生 Akt 的加工耦合起来。 mTORC2 的这一新功能对于 Akt 的正确折叠和稳定性至关重要，以防止翻译过程中过早降解。因此，抑制 mTORC2 不仅会阻止 Akt 激活，还会减少其表达。我们的研究计划将利用细胞和动物模型阐明 mTORC2 在新生多肽的共翻译加工中如何发挥作用。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 如何整合生长刺激来控制新合成蛋白质的质量和数量具有重要意义。