Function of the rapamycin targets: The TOR kinases

雷帕霉素靶点的功能：TOR 激酶

• 批准号: 6458912
• 负责人: MARIA E CARDENAS-CORONA
• 金额: $ 15.26万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6458912
• 关键词: SDS polyacrylamide gel electrophoresis; ammonium compounds; autoradiography; biological signal transduction; cell line; fungal genetics; gene deletion mutation; gene expression; gene induction /repression; gene targeting; genetic regulation; genetic screening; glutamine; immunoprecipitation; northern blottings; nutrient interaction; phosphoprotein phosphatase; phosphorylation; polymerase chain reaction; posttranslational modifications; protein kinase; protein protein interaction; protein structure function; ribosomal proteins; sirolimus; western blottings

DESCRIPTION (provided by applicant): Rapamycin is a microbial product with potent antiproliferative and immunosuppressive activities via its ability to inhibit signal transduction. Rapamycin has recently been approved by the FDA as an immunosuppressive drug, and phase II clinical trials in cancer patients are in progress as a novel chemotherapy agent. In both yeast and mammalian cells, rapamycin action is mediated by its association with the peptidyl prolyl isomerase FKBP12. The rapamycin-FKBP12 targets were first identified as the highly homologous TOR1 and TOR2 genes by genetic studies in yeast, and subsequently, a mammalian ortholog (mTOR) was discovered. The TOR proteins have a C-terminal domain with similarity to protein and lipid kinases. Detailed studies have revealed the TOR proteins have an intrinsic protein kinase activity. The FKBP12-rapamycin complex inhibits the TOR kinases, which regulate cell proliferation, translation and transcription and cell responses to nutrient availability, including authophagy, ribosome biogenesis and cell mating. In both yeast and mammalian cells the TOR proteins regulate translation initiation and G1 to S phase cell cycle progression. Recent studies have revealed a novel role for the TOR pathway in yeast in regulating ribosomal protein, ribosomal RNA, and tRNA gene expression in response to nutrients. In addition, TOR controls expression of nitrogen utilization genes. The precise mechanisms of this regulation are unknown but recent evidence has indicated that the role of TOR in these processes is largely mediated via control of type 2A protein phosphatases (PP2A). Although studies in both yeast and mammalian cells have indicated that the TOR kinases signal in response to nutrients and mitogens, little is known about the mechanisms by which TOR is activated. Our proposed studies seek to define the role of PP2A in TOR action, to determine the molecular mechanisms by which nutrient signals activate the TOR kinases, and to explore the role of the TOR pathway in regulating expression of genes encoding ribosomal proteins. These studies will provide information about the mechanisms of rapamycin action, which has been conserved from yeast to mammals, and thereby provide the biochemical basis for further development of rapamycin and derivatives as novel chemotherapeutic agents.

描述（由申请方提供）：雷帕霉素是一种微生物产品， 有效的抗增殖和免疫抑制活性， 抑制信号转导。雷帕霉素最近已被FDA批准 作为一种免疫抑制药物，以及癌症患者的II期临床试验 作为一种新的化疗药物正在开发中。在酵母和哺乳动物中 细胞，雷帕霉素的作用是通过其与肽基的结合介导的 脯氨酰异构酶FKBP 12。雷帕霉素-FKBP 12靶标首先被鉴定为 通过酵母中的遗传学研究，认为是高度同源的TOR 1和TOR 2基因， 随后，发现了哺乳动物直系同源物（mTOR）。TOR蛋白 具有与蛋白质和脂质激酶相似的C-末端结构域。 详细的研究表明，TOR蛋白具有一种内在蛋白质， 激酶活性FKBP 12-雷帕霉素复合物抑制TOR激酶， 调节细胞增殖、翻译和转录以及细胞反应 对营养有效性的影响，包括自噬、核糖体生物合成和细胞 交配在酵母和哺乳动物细胞中，TOR蛋白调节 翻译起始和G1至S期细胞周期进展。 最近的研究揭示了TOR通路在酵母中的新作用， 调节核糖体蛋白、核糖体RNA和tRNA基因表达， 对营养的反应。此外，TOR控制氮的表达， 利用基因这种调节的确切机制尚不清楚， 最近的证据表明，职权范围在这些过程中的作用， 主要通过控制2A型蛋白磷酸酶（PP 2A）介导。虽然 在酵母和哺乳动物细胞中的研究表明，TOR激酶 在响应营养素和有丝分裂原的信号，很少有人知道 这是TOR被激活的机制。我们建议的研究旨在界定 PP 2A在TOR作用中的作用，以确定 营养信号激活TOR激酶，并探讨TOR的作用 核糖体蛋白编码基因表达的调控途径。这些 研究将提供关于雷帕霉素作用机制的信息， 从酵母到哺乳动物都是保守的，从而提供了 进一步开发雷帕霉素及其衍生物作为 新的化疗剂。