MOLECULAR BASIS OF CELL GROWTH CONTROL BY THE TOR KINASE

雷帕霉素是一种有效的免疫抑制药物，可以阻止细胞周期 IL-2激活的T细胞在G1期的进展 肿瘤细胞 线条和酵母中。雷帕霉素的主要细胞靶点，作用 在……里面 SITE作为一种与其结合蛋白(FKBP-12)的复合体，是一种新的 280 KDa 多肽，首先在酵母中被鉴定为TOR，随后在 哺乳动物细胞。Tor是一种磷酸化磷脂酰基的激酶 肌苷，可能还有蛋白质，在结构上与 这个 共济失调-血管扩张症基因产物。 酵母TOR位于液泡的细胞质表面。 雷帕霉素处理酵母会使TOR从液泡中分离出来，并且 诱导出与两者缺失的表型相同的表型 树 基因，这与营养物质的反应非常相似 剥夺； 具体地说，蛋白质合成的启动是快速和强烈的 抑制，然后是G1期停滞。在哺乳动物细胞中，雷帕霉素， 演戏 通过mTOR，快速抑制40 S的磷酸化 核糖体蛋白S6(通过抑制p70 S6激酶)和 阴性的eIF-4E-BP1的磷酸化和失活 调整器 MRNA帽结合蛋白，eIF-4E。这两个动作都是 相伴 通过选择性抑制信使核糖核酸的翻译，这似乎表明 基础 抑制细胞周期进程。 提出的研究将揭示生理和生化方面的。 MTOR参与监管的机制 哺乳动物细胞 通过向翻译机构发出信号来实现增长。蜂窝手机 将定义mTOR的本地化，以及负责的域 对于ITS 本地化映射。细胞结合部位将是 特色化的。 MTOR相关激酶的调节及其特性 催化作用 将定义活动。结合在一起的细胞蛋白 MTOR将 被隔离并检查它们作为mTORs效应者的作用 信令 功能。MTOR调节的蛋白激酶或磷酸酶活性在 EIF- 4E-BP1将被寻找，p70 S6激酶对 这个 MTOR信号转导的雷帕霉素敏感成分将是 已经成立了。 这些研究将定义一种新的信号转导途径 控管 淋巴样细胞和其他细胞中的细胞生长。

Rapamycin is a potent immunosuppressive drug that halts cell cycle progression in the G1 phase in IL-2 activated T-cells, certain tumor cell lines and in yeast. The major cellular target of rapamycin, acting in situ as a complex with its binding protein (FKBP-12), is a novel 280 KDa polypeptide, first identified in yeast as TOR, and subsequently in mammalian cells. TOR is a kinase that phosphorylates phosphatidyl inositides and perhaps proteins, and is homologous in structure to the Ataxia-Teleangiectasia gene product. Yeast TOR is situated on the cytoplasmic surface of the vacuole. Rapamycin treatment of yeast delocalizes TOR from the vacuole, and elicits a phenotype equivalent to that seen with deletion of both TOR genes, and which resembles closely the response to nutrient deprivation; specifically, protein synthesis initiation is quickly and strongly inhibited, followed by G1 arrest. In mammalian cells, rapamycin, acting through mTOR, rapid inhibits both the phosphorylation of the 40 S ribosomal protein S6 (by inhibiting the p70 S6 kinase) and the phosphorylation and inactivation of eIF-4E-BP1, a negative regulator of the mRNA Cap binding protein, eIF-4E. Both these actions are accompanied by a selective inhibition in mRNA translation, which appears to underlie the inhibition of cell cycle progression. The studies proposed will uncover the physiologic and biochemical mechanisms by which mTOR participates in the regulation of mammalian cell growth by signalling to the translational apparatus. The cellular localization of mTOR will be defined, and the domains responsible for its localization mapped. The cellular binding site will be characterized. The regulation and properties of the mTOR-associated kinase catalytic activities will be defined. The cellular proteins that bind to mTOR will be isolated and examined for their role as effectors of mTORs signalling function. mTOR-regulated protein kinases or phosphatases active on eIF- 4E-BP1 will be sought, and the contribution of the p70 S6 kinase to the rapamycin-sensitive components of mTOR signalling will be established. These studies will define a new signal transduction pathway controlling cell growth in lymphoid and other cells.