Function of the rapamycin targets: The TOR kinases

描述(申请人提供)：雷帕霉素是一种微生物产品，具有 强大的抗增殖和免疫抑制活性，通过其能力 抑制信号转导。雷帕霉素最近获得了FDA的批准 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进行中。在酵母和哺乳动物中 细胞，雷帕霉素的作用是通过它与多肽的结合来介导的 Prolyl异构酶FKBP12。首次确定了雷帕霉素-FKBP12靶点 通过遗传研究，在酵母中发现高度同源的TOR1和TOR2基因，以及 随后，发现了一个哺乳动物直系同源基因(MTOR)。TOR蛋白 有一个与蛋白质和脂类激酶相似的C-末端结构域。 详细的研究表明，TOR蛋白具有一种固有的蛋白质 激活酶活性。FKBP12-雷帕霉素复合体抑制TOR激酶，后者 调节细胞增殖、翻译、转录和细胞反应 对养分的有效性，包括自噬作用、核糖体生物发生和细胞 交配。在酵母和哺乳动物细胞中，TOR蛋白调节 翻译起始与G1~S期细胞周期进程。 最近的研究揭示了TOR途径在酵母中的一个新的作用 调节核糖体蛋白、核糖体RNA和tRNA基因的表达 对营养的反应。此外，TOR还控制氮的表达 利用基因。这一规定的确切机制尚不清楚，但 最近的证据表明，TOR在这些过程中的作用是 主要通过控制2A型蛋白磷酸酶(PP2A)来调节。虽然 在酵母和哺乳动物细胞中的研究表明，TOR激酶 信号响应营养物质和有丝分裂原，人们对此知之甚少 启动TOR的机制。我们建议的研究旨在界定 PP2A在TOR作用中的作用，以确定其分子机制 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，因此提供了 进一步开发雷帕霉素及其衍生物的生物化学基础 新型化疗药物。

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.