Signaling mechanisms by the rapamycin target: Tor kinase

雷帕霉素靶标的信号传导机制：Tor 激酶

基本信息

批准号：
7554129
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
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-03-17 至 2011-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7554129
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 FDA approved 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 Work Yeasts base cell growth chemotherapeutic agent chemotherapy histone acetyltransferase neoplastic cell novel programs promoter protein function research study response

项目摘要

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激酶是有效抗增生和免疫抑制药物雷帕霉素的靶标。雷帕霉素最近已被FDA批准为免疫抑制药物，而III期临床试验正在进行中，因为它用作新型化学疗法。在酵母菌和哺乳动物细胞中，雷帕霉素的作用是由其与肽基脯氨酰异构酶FKBP12的关联介导的。然后，雷帕霉素-FKBP12复合物与TOR激酶的功能结合并抑制了TOR激酶的功能，这些功能首先是通过酵母中的遗传研究鉴定出来的，随后在人类细胞中发现。 TOR激酶调节细胞增殖，翻译和转录以及对养分利用率的细胞反应，包括自噬，核糖体生物发生，细胞分化和交配。 TOR途径在调节核糖体蛋白（RP），核糖体RNA和TRNA基因表达中对养分的响应在酵母中起主要作用。此外，TOR控制营养利用基因的表达和应激反应基因。尽管对TOR调节营养利用率和应激反应基因表达的机制知之甚少，但对于TOR如何控制RP基因表达，知之甚少。我们已经表明，TOR活性有利于将ESA1组蛋白乙酰酶募集到与RP基因激活同时发生的RP基因启动子。最近，我们小组的研究和另一项研究表明，在响应养分时调节RP基因表达时，TOR和CAMP-PKA途径之间可能存在串扰。 TOR激酶的许多功能都是通过2A型蛋白磷酸酶（PP2A）介导的。在酵母中，PP2A样磷酸酶SIT4受其与TAP42的关联和四个相关蛋白的关联来调节。我们提出的研究试图定义SAP蛋白在TOR作用中的作用，以确定TOR和CAMP-PKA途径之间是否存在控制RP基因表达的串扰，并定义TOR信号控制ESA1募集ESA1对RP基因启动子的分子机制。我们的目标是阐明雷帕霉素作用的机制，其中许多作用是从酵母到哺乳动物的保守，因此为进一步开发雷帕霉素及其衍生物作为新型化学治疗剂提供了生化基础。