STRUCTURE/FUNCTION OF THE TARGETS OF RAPAMYCIN--THE

雷帕霉素是一种天然产物，具有抗微生物、免疫抑制、 通过其抑制信号的能力而具有抗肿瘤活性 转导。在酵母和哺乳动物细胞中，雷帕霉素的作用是 通过与多肽基丙氨酸异构酶FKBP12结合而介导。 FKBP12-雷帕霉素复合体抑制G1~5期细胞周期 但细胞周期停滞的机制尚不清楚。 酵母菌遗传学研究首次发现T0R1和T0R2基因 作为FKBP12-雷帕霉素复合体靶标的产品。最近，一位 哺乳动物的TOR同源基因(MTOR)已被鉴定。最高学位 的同源性位于与脂类同源的羧基末端结构域 和蛋白激酶。MTOR自动磷化，这一活性是 被FKBP12-雷帕霉素抑制，但只有一种其他候选底物 (PHAS-1)已被鉴定。TOR蛋白有三个已知的 功能。一个由TOR1和TOR2共享，是信令所需的 翻译启动与G1期细胞周期进程。此函数为 在哺乳动物细胞中保守，并导致p70S6K的激活。这个 TOR2的第二个功能是通过RH01和RH02 GTP酶控制， 细胞周期中肌动蛋白细胞骨架的极化分布。 最后，mTOR在防止细胞凋亡中的作用已经被提出 雷帕霉素加速癌细胞凋亡的研究。 然而，TOR蛋白在这些功能中的确切作用是 还不能很好地理解。候选人发现了一种新的有毒物质 TOR蛋白的结构域，并建议确定TOR蛋白的效应因子 酵母和哺乳动物细胞中的Tor蛋白及其作用机制的研究 TOR蛋白通过其调节细胞周期进程和细胞凋亡。 这类研究应提供关于#年的行动机制的信息。 新型TOR抑制剂雷帕霉素，从而提供了一种声音 进一步分析雷帕霉素和其他TOR的生化基础 作为新型化疗药物的抑制剂。

Rapamycin is a natural product with anti-microbial, immunosuppressive, and anti-neoplastic activities via its ability to inhibit signal transduction. In both yeast and mammalian cells, rapamycin action is mediated by association with the peptidyl proIy1 isomerase, FKBP12. The FKBP12-rapamycin complex inhibits G1 to 5 phase cell cycle progression, but the mechanisms of cell cycle arrest are unknown. Genetic studies in yeast first implicated the T0R1 and T0R2 gene products as targets of the FKBP12-rapamycin complex. Recently, a mammalian TOR homolog (mTOR) has been identified. The highest degree of identity resides in a carboxy terminal domain with homology to lipid and protein kinases. mTOR autophosphorylates, and this activity is inhibited by FKBP12-rapamycin, but only one other candidate substrate (PHAS-1) has been identified. The TOR proteins have three known functions. One, shared by TOR1 and TOR2, is required for signaling translation initiation and G1 cell cycle progression. This function is conserved in mammalian cells and leads to activation of p70s6k. The second function of TOR2, is the control, via the RH01 and RH02 GTPases, of polarized distribution of the actin cytoskeleton during the cell cycle. Finally, a role for mTOR in preventing apoptosis has been suggested by studies in which rapamycin accelerates apoptosis in cancer cells. However, the precise roles of the TOR proteins in these functions are not yet well understood. The candidate has identified a novel toxic domain of the TOR proteins and proposes to identify effectors of the TOR proteins in yeast and mammalian cells and to study the mechanisms by which the TOR proteins regulate cell cycle progression and apoptosis. Such studies should provide information on the mechanisms of action of the novel TOR inhibitor rapamycin and thereby provide a sound biochemical basis for further analysis of rapamycin and other TOR inhibitors as novel chemotherapy agents.