Signaling mechanisms by the rapamycin target: Tor kinase

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点。雷帕霉素最近已被FDA批准为免疫抑制药物，其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FKBP 12的结合来介导的。雷帕霉素-FKBP 12复合物然后结合并抑制Tor激酶的功能，Tor激酶首先通过酵母中的遗传研究鉴定，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途径在酵母中调节核糖体蛋白（RP）、核糖体RNA和tRNA基因表达以响应营养物中起主要作用。此外，Tor控制营养利用基因和胁迫响应基因的表达。尽管对Tor调控营养利用和胁迫响应基因表达的机制了解很多，但对Tor如何控制RP基因表达知之甚少。我们已经表明，Tor活性有利于招募的Esa 1组蛋白乙酰化酶RP基因启动子与RP基因激活一致。最近，来自我们小组和另一个小组的研究表明，Tor和cAMP-PKA通路在响应营养物调节RP基因表达中可能存在串扰。Tor激酶的许多功能通过2A型蛋白磷酸酶（PP 2A）介导。在酵母中，PP 2A样磷酸酶Sit 4通过与Tap 42和一组称为Saps的四种相关蛋白的结合来调节。 我们提出的研究旨在确定Tor作用中Sap蛋白的作用，以确定Tor和cAMP-PKA通路之间是否存在串扰以控制RP基因表达，并确定Tor信号传导控制Esa 1招募到RP基因启动子的分子机制。我们的目标是阐明雷帕霉素的作用机制，其中许多是保守的从酵母到哺乳动物，从而为进一步开发雷帕霉素及其衍生物作为新的化疗药物提供生化基础。

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.