Signaling mechanisms by the rapamycin target: Tor kinase

描述(申请人提供)：Tor激酶是一种有效的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，其作为一种新型化疗药物的第三阶段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的结合而介导的。然后，雷帕霉素-FKBP12复合体结合并抑制Tor激酶的功能，这种功能最初是通过在酵母中的遗传学研究确定的，后来在人类细胞中发现。Tor激酶调节细胞的增殖、翻译和转录，以及细胞对营养物质供应的反应，包括自噬、核糖体生物发生、细胞分化和交配。在酵母中，Tor途径在调节核糖体蛋白(RP)、核糖体RNA和tRNA基因表达以响应营养方面起着重要作用。此外，Tor还控制营养利用基因和胁迫反应基因的表达。虽然人们对Tor调控养分利用和胁迫反应基因表达的机制知之甚少，但对Tor如何调控RP基因表达知之甚少。我们发现，Tor活性有利于Esa1组蛋白乙酰化酶向与RP基因激活一致的RP基因启动子募集。最近，我们和另一个小组的研究表明，在调节RP基因表达以响应营养的过程中，Tor和cAMP-PKA通路之间可能存在串扰。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受其与Tap42和一组被称为SAP的四种相关蛋白的联合调节。 我们的研究试图确定SAP蛋白在Tor作用中的作用，确定Tor和cAMP-PKA信号通路之间是否存在控制RP基因表达的串扰，并确定Tor信号控制Esa1向RP基因启动子招募的分子机制。我们的目标是阐明雷帕霉素的作用机制，其中许多作用从酵母到哺乳动物都是保守的，从而为进一步开发雷帕霉素及其衍生物作为新型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.