Regulation of Cell Survival by the Rapamycin-Insensitive mTOR Complex

雷帕霉素不敏感的 mTOR 复合物对细胞存活的调节

• 批准号: 7778874
• 负责人: Estela Jacinto
• 金额: $ 27.51万
• 依托单位: UNIV OF MED/DENT NJ-R W JOHNSON MED SCH
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7778874
• 关键词: Abnormal Cell; Address; Affect; Antineoplastic Agents; Apoptosis; Apoptotic; Biochemical; Biological Assay; Cell Survival; Cells; Co-Immunoprecipitations; Collaborations; Complex; Drug Delivery Systems; Embryo; Fibroblasts; Growth; In Vitro; Knock-out; Knowledge; Label; Malignant Neoplasms; Measures; Mediating; Metabolic; Microscopy; Mus; Mutagenesis; Mutate; Pathway interactions; Phosphorylation; Phosphorylation Site; Physiologic pulse; Play; Protein Kinase; Proteins; Proto-Oncogene Proteins c-akt; Regulation; Role; Signal Pathway; Signal Transduction; Sirolimus; Site; Stress; Ubiquitination; Up-Regulation; base; cancer cell; cell growth; fluorescence imaging; human FRAP1 protein; immunocytochemistry; mTOR protein; novel; protein complex; protein degradation; public health relevance; response; scaffold; stress activated protein kinase; tumor

DESCRIPTION (provided by applicant): Elucidating the mechanisms that allow cells to survive under adverse growth conditions is crucial for understanding how cancer cells arise and persist. The mammalian target of rapamycin (mTOR) is a protein kinase that is inhibited by the potential anti-cancer drug, rapamycin, and plays a central role in growth and proliferation. Recently, we discovered that mTOR is part of two distinct protein complexes and that mTORC2 (mTOR Complex 2) performs a novel function in cell survival that is not inhibited by rapamycin. This novel function of mTORC2 involves phosphorylation of Akt/PKB and is critical only under stress conditions. We have identified SIN1 as an integral component of mTORC2. We found that SIN1 is required for phosphorylation of Akt. Using SIN1 knockout cells, our initial studies indicate that when Akt phosphorylation is abolished at the mTORC2-mediated site, phosphorylation of the pro- apoptotic targets of Akt is defective and cells become susceptible to stress-induced apoptosis. We will now elucidate the mechanism of how Akt regulation by mTORC2 can promote cell survival. We have preliminary findings that in the absence of SIN1, Akt is destabilized more readily upon stress induction. We now hypothesize that mTORC2 regulates protein stability and that this novel function of mTORC2 is required specifically for cell survival under stress conditions. First, we will examine Akt turnover and degradation in the absence of SIN1. Second, we will investigate if mTORC2 can regulate Akt by phosphorylation or if SIN1 serves as a scaffold to allow Akt phosphorylation. Third, we will elucidate how Akt stabilization by mTORC2-mediated phosphorylation can promote cell survival. These studies will advance our knowledge on how mTOR can regulate cell growth and survival pathways and will provide clues as to how mTORC2 can be exploited as a drug target to specifically inhibit the survival of cancer cells. PUBLIC HEALTH RELEVANCE: Cancer is characterized by uncontrolled growth and proliferation and the increased viability of these abnormal cells despite hostile conditions. Our studies will examine the mechanisms of how the mammalian target of rapamycin (mTOR) can enhance survival capacity of cancer cells via upregulation of Akt, a protein that is found mutated in a number of tumors.

描述（由申请人提供）：阐明细胞在不利生长条件下生存的机制对于理解癌细胞如何产生和持续存在至关重要。哺乳动物雷帕霉素靶标 (mTOR) 是一种蛋白激酶，可被潜在抗癌药物雷帕霉素抑制，在生长和增殖中发挥核心作用。最近，我们发现 mTOR 是两种不同蛋白质复合物的一部分，并且 mTORC2（mTOR 复合物 2）在细胞存活中发挥着不受雷帕霉素抑制的新功能。 mTORC2 的这一新功能涉及 Akt/PKB 的磷酸化，并且仅在应激条件下才至关重要。我们已确定 SIN1 是 mTORC2 的一个组成部分。我们发现 SIN1 是 Akt 磷酸化所必需的。使用 SIN1 敲除细胞，我们的初步研究表明，当 mTORC2 介导位点的 Akt 磷酸化被消除时，Akt 促凋亡靶点的磷酸化就会出现缺陷，细胞变得容易受到应激诱导的凋亡的影响。我们现在将阐明 mTORC2 调节 Akt 如何促进细胞存活的机制。我们初步发现，在缺乏 SIN1 的情况下，Akt 在应激诱导时更容易不稳定。我们现在假设 mTORC2 调节蛋白质稳定性，并且 mTORC2 的这种新功能是细胞在应激条件下生存所必需的。首先，我们将检查在 SIN1 缺失的情况下 Akt 的周转和降解。其次，我们将研究 mTORC2 是否可以通过磷酸化调节 Akt，或者 SIN1 是否充当允许 Akt 磷酸化的支架。第三，我们将阐明 mTORC2 介导的磷酸化对 Akt 的稳定作用如何促进细胞存活。这些研究将增进我们对 mTOR 如何调节细胞生长和生存途径的了解，并将为如何利用 mTORC2 作为药物靶点来特异性抑制癌细胞的生存提供线索。 公共卫生相关性：癌症的特点是不受控制的生长和增殖，以及这些异常细胞在恶劣条件下的活力增加。我们的研究将探讨哺乳动物雷帕霉素靶标 (mTOR) 如何通过上调 Akt（一种在许多肿瘤中发现突变的蛋白质）来增强癌细胞的生存能力。