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: 7595867
• 负责人: Estela Jacinto
• 金额: $ 27.79万
• 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/7595867
• 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; 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)：阐明允许细胞在不利生长条件下存活的机制对于了解癌细胞如何产生和持续存在至关重要。雷帕霉素的哺乳动物靶标(MTOR)是一种蛋白激酶，可被潜在的抗癌药物雷帕霉素抑制，并在生长和增殖中发挥核心作用。最近，我们发现mTOR是两个不同的蛋白质复合体的一部分，并且mTORC2(mTOR复合体2)在细胞存活中发挥着不被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，只有在应激条件下才是关键的。我们已经确定SIN1是mTORC2的一个组成部分。我们发现SIN1是Akt磷酸化所必需的。利用SIN1基因敲除细胞，我们的初步研究表明，当在mTORC2介导的位点上Akt的磷酸化被取消时，Akt的促凋亡靶标的磷酸化是有缺陷的，并且细胞对应激诱导的细胞凋亡变得敏感。我们现在将阐明mTORC2调节Akt如何促进细胞存活的机制。我们有初步的发现，在缺乏SIN1的情况下，Akt在应激诱导时更容易失稳。我们现在假设mTORC2调节蛋白质的稳定性，并且mTORC2的这一新功能是细胞在应激条件下生存所特需的。首先，我们将研究在没有SIN1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来调节Akt，或者SIN1是否作为允许Akt磷酸化的支架。第三，我们将阐明通过mTORC2介导的磷酸化来稳定Akt是如何促进细胞存活的。这些研究将促进我们对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作为药物靶点来具体抑制癌细胞的生存提供线索。与公共卫生相关：癌症的特征是不受控制的生长和增殖，尽管条件恶劣，这些异常细胞的生存能力仍在增加。我们的研究将探讨哺乳动物靶标雷帕霉素(MTOR)如何通过上调Akt来提高癌细胞的生存能力。Akt是一种在许多肿瘤中发现突变的蛋白质。