Signaling mechanisms by the rapamycin target: Tor kinase

雷帕霉素靶标的信号传导机制：Tor 激酶

• 批准号: 7367851
• 负责人: MARIA E CARDENAS-CORONA
• 金额: $ 25.96万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-03-17 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7367851
• 关键词: Actins; Apoptosis; Autophagocytosis; Binding; Biochemical; Biogenesis; Cell Cycle; Cell Differentiation process; Cell Proliferation; Cell Survival; Cell Wall; Cells; Complex; Couples; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Cytoskeleton; Development; Gene Activation; Gene Expression; Genes; Genetic; Genetic Transcription; Goals; Growth; Human; Immunosuppressive Agents; Mammalian Cell; Mammals; Mediating; Modeling; Molecular; Molecular Mechanisms of Action; Mutation; Nitrogen; Nutrient; Partner in relationship; Pathway interactions; Peptidylprolyl Isomerase; Pharmaceutical Preparations; Phase III Clinical Trials; Phosphoric Monoester Hydrolases; Phosphotransferases; Play; Preparation; Protein phosphatase; Proteins; Repression; Research Personnel; Resistance; Ribosomal Proteins; Ribosomal RNA; Ribosomes; Role; Signal Transduction; Signal Transduction Pathway; Sirolimus; Stress; Tacrolimus Binding Protein 1A; Transfer RNA; Translation Initiation; Translations; United States Food and Drug Administration; Work; Yeasts; base; cell growth; chemotherapeutic agent; chemotherapy; histone acetyltransferase; neoplastic cell; novel; programs; promoter; protein function; research study; response

DESCRIPTION (provided by applicant): The Tor kinases are the targets of the potent antiproliferative and immunosuppressive drug rapamycin. Rapamycin has recently been approved by the FDA as an immunosuppressive drug, and phase III clinical trials are in progress for its use 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 complex then binds to and inhibits the functions of the Tor kinases, which were first identified by genetic studies in yeast and subsequently discovered in human cells. The Tor kinases regulate cell proliferation, translation and transcription as well as cellular responses to nutrient availability, including autophagy, ribosome biogenesis, cell differentiation, and mating. The Tor pathway plays a major role in yeast in regulating ribosomal protein (RP), ribosomal RNA, and tRNA gene expression in response to nutrients. In addition, Tor controls expression of nutrient utilization genes and stress responsive genes. Although much is known about the mechanisms by which Tor regulates the expression of nutrient utilization and stress responsive genes, very little is known about how Tor controls RP gene expression. We have shown that Tor activity favors the recruitment of the Esa1 histone acetylase to RP gene promoters coincident with RP gene activation. More recently, studies from our group and another have suggested a possible crosstalk between the Tor and cAMP-PKA pathways in regulating RP gene expression in response to nutrients. Many of the functions of the Tor kinases are mediated via type 2A protein phosphatases (PP2A). In yeast the PP2A-like phosphatase, Sit4, is regulated by its association with Tap42 and a set of four related proteins known as the Saps. Our proposed studies seek to define the roles of the Sap proteins in Tor action, to determine if there is crosstalk between the Tor and cAMP-PKA pathways to control RP gene expression, and to define the molecular mechanisms by which Tor signaling controls recruitment of Esa1 to RP gene promoters. Our goal is to elucidate the mechanisms of rapamycin action, many of which are conserved from yeast to mammals, and thereby, provide the biochemical basis for further development of rapamycin and its derivatives as novel chemotherapeutic agents.

描述（由申请人提供）：Tor 激酶是强效抗增殖和免疫抑制药物雷帕霉素的靶标。雷帕霉素最近被 FDA 批准为免疫抑制药物，作为新型化疗药物的 III 期临床试验正在进行中。在酵母和哺乳动物细胞中，雷帕霉素的作用是通过其与肽基脯氨酰异构酶 FKBP12 的结合介导的。然后雷帕霉素-FKBP12 复合物与 Tor 激酶结合并抑制其功能，Tor 激酶首先通过酵母基因研究发现，随后在人类细胞中发现。 Tor 激酶调节细胞增殖、翻译和转录以及细胞对营养可用性的反应，包括自噬、核糖体生物发生、细胞分化和交配。 Tor 通路在酵母中发挥重要作用，调节核糖体蛋白 (RP)、核糖体 RNA 和 tRNA 基因表达以响应营养物质。此外，Tor 控制养分利用基因和应激反应基因的表达。尽管人们对 Tor 调节养分利用和应激反应基因表达的机制了解很多，但对 Tor 如何控制 RP 基因表达却知之甚少。我们已经表明，Tor 活性有利于将 Esa1 组蛋白乙酰化酶招募到 RP 基因启动子，同时 RP 基因激活。最近，我们小组和另一个小组的研究表明，Tor 和 cAMP-PKA 通路在调节 RP 基因表达以响应营养物质方面可能存在串扰。 Tor 激酶的许多功能是通过 2A 型蛋白磷酸酶 (PP2A) 介导的。在酵母中，PP2A 样磷酸酶 Sit4 通过与 Tap42 和一组称为 Saps 的四种相关蛋白的关联来调节。 我们提出的研究旨在确定 Sap 蛋白在 Tor 作用中的作用，确定 Tor 和 cAMP-PKA 通路之间是否存在串扰来控制 RP 基因表达，并确定 Tor 信号传导控制 Esa1 募集的分子机制至 RP 基因启动子。我们的目标是阐明雷帕霉素的作用机制，其中许多机制从酵母到哺乳动物都是保守的，从而为雷帕霉素及其衍生物作为新型化疗药物的进一步开发提供生化基础。