CELLULAR PHARMACOLOGY OF RAPAMYCIN

描述：雷帕霉素是一种细菌衍生的大环内酯，目前 作为免疫抑制剂进行临床和临床前评价， 癌症化疗剂。 免疫抑制和抗癌 雷帕霉素的性质归因于抑制信号传导 增殖细胞从G1期进入S期所需的通路 相位 了解抗增殖机制的关键一步 雷帕霉素的鉴定是鉴定了功能是 当细胞暴露于这种药物时会受到抑制。 的哺乳动物靶标 雷帕霉素（Rapamycin，mTOR）是一种新的高分子量多肽家族的成员， 称为磷脂酰肌醇3-激酶相关激酶（PIKK）的激酶。 的 PIKK家族的成员在细胞周期调节中起关键作用， 染色体的维持，它们的功能障碍导致生长失调， 基因组不稳定和癌症。 本提案的总体目标 是定义由mTOR控制的信号通路，并确定 细胞周期相关的参数，决定敏感性或电阻 转化细胞对雷帕霉素的抗增殖作用。 的 初步研究提供了生化和遗传证据， 调节mRNA的翻译，mRNA的蛋白质产物需要 使细胞通过G1期进入S期。 本项目将扩大 本研究通过实施三个具体目标：（1）定义 PHAS-1在雷帕霉素抑制细胞生长中作用，（2）阐明 mTOR的上游调节因子在促分裂原刺激的细胞中起作用，（3） 研究mTOR依赖性信号通路与 非转化细胞和转化细胞的细胞周期控制机制。 这些目标的完成可能会极大地促进他们对 雷帕霉素的细胞药理学，并将促进发展， 靶向mTOR本身或其它的新的抗增殖剂 mTOR依赖性信号通路的组分。

DESCRIPTION: Rapamycin is a bacterially-derived macrolide that is currently undergoing clinical and preclinical evaluations as an immunosuppressant and cancer chemotherapeutic agent. Both the immunosuppressive and anticancer properties of rapamycin are attributed to the inhibition of a signaling pathway required for the passage of proliferating cells from G1 into S phase. A pivotal step toward understanding the anti-proliferative mechanism of rapamycin was the identification of the protein whose function is inhibited when cells are exposed to this drug. The mammalian Target of Rapamycin (mTOR) is a member of a novel family of high molecular weight kinases termed phosphatidylinositol 3-kinase-related kinases (PIKKs). The members of the PIKK family play crucial roles in cell-cycle regulation and chromosome maintenance, and their dysfunction leads to disregulated growth, genomic instability, and cancer. The overall objectives of this proposal are to define the signaling pathway governed by mTOR, and to identify the cell-cycle-related parameters that determine sensitivity or resistance of transformed cells to the anti-proliferative effects of rapamycin. The preliminary studies offer biochemical and genetic evidence that mTOR regulates the translation of mRNAs whose protein products are needed to drive the cell through G1 and into S phase. The current project will extend this research through implementation of three specific aims: (1) to define the role of PHAS-1 in cell growth inhibition by rapamycin, (2) to elucidate upstream regulators of mTOR function in mitogen-stimulated cells, (3) to investigate the interactions of the mTOR-dependent signaling pathway with the cell-cycle control machinery in nontransformed and transformed cells. The completion of these aims may significantly advance ther knowledge of the cellular pharmacology of rapamycin, and will facilitate the development of novel antiproliferative agents targeted against mTOR itself or other components of the mTOR-dependent signaling pathway.