Signaling mechanisms by the rapamycin target: Tor kinase

描述（由申请人提供）：Tor激酶是有效的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批准为一种免疫抑制药物，其作为一种新型化疗药物的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酸异构酶FKBP12的关联介导的。rapamycin-FKBP12复合物随后结合并抑制Tor激酶的功能，Tor激酶最初是在酵母的遗传研究中发现的，随后在人类细胞中被发现。Tor激酶调节细胞增殖、翻译和转录以及细胞对营养物质的反应，包括自噬、核糖体生物发生、细胞分化和交配。Tor通路在酵母对营养物质的反应中调控核糖体蛋白（RP）、核糖体RNA和tRNA基因的表达中起着重要作用。此外，Tor还控制养分利用基因和胁迫应答基因的表达。虽然我们对Tor调控营养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基因表达知之甚少。我们已经证明，Tor的活性有利于Esa1组蛋白乙酰化酶在RP基因激活时向RP基因启动子募集。最近，我们和另一个小组的研究表明，Tor和cAMP-PKA通路之间可能存在串扰，在营养反应中调节RP基因的表达。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，类似pp2a的磷酸酶Sit4受其与Tap42和一组四种相关蛋白Saps的关联所调节。

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.