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、 和抗肿瘤活性，通过其抑制信号传导的能力， 转导在酵母和哺乳动物细胞中，雷帕霉素的作用是 通过与肽基脯氨酸异构酶FKBP 12的结合介导。 FKBP 12-雷帕霉素复合物抑制G1至5期细胞周期 进展，但细胞周期停滞的机制是未知的。 酵母中的遗传研究首先涉及T0 R1和T0 R2基因 作为FKBP 12-雷帕霉素复合物的靶点。 近日一 哺乳动物TOR同源物（mTOR）已被鉴定。 程度最高 同一性的一部分位于与脂质同源的羧基末端结构域 和蛋白激酶。 mTOR自磷酸化，这种活性是 受FKBP 12-雷帕霉素抑制，但仅受一种其他候选底物抑制 （PHAS-1）已被识别。 TOR蛋白有三种已知的 功能协调发展的 一个由TOR 1和TOR 2共享，用于信令 翻译起始和G1细胞周期进展。 此功能 在哺乳动物细胞中是保守的，并导致p70 s6 k的激活。 的 TOR 2的第二个功能是通过RH 01和RH 02 GTP酶， 肌动蛋白细胞骨架在细胞周期中的极化分布。 最后，mTOR在预防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 还没有很好地理解。 候选人发现了一种新的有毒物质 结构域的TOR蛋白，并提出确定效应的 酵母和哺乳动物细胞中的TOR蛋白，并研究其机制 TOR蛋白通过其调节细胞周期进程和凋亡。 这类研究应提供资料，说明 新TOR抑制剂雷帕霉素，从而提供了一种可靠的 进一步分析雷帕霉素和其他TOR的生化基础 抑制剂作为新的化疗剂。

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.