Mechanisms of AKT-dependent sensitivity to rapamycin

mTOR抑制剂是一类新的药物，其临床前作用显示出巨大潜力， 癌症的化疗药物。这些药物目前正在开发作为抗癌药物，并可能很快成为临床医生可用。mTOR抑制剂靶向雷帕霉素（mTOR）蛋白激酶的哺乳动物靶标，其是PI 3-激酶/AKT途径的下游靶标。mTOR的激活导致p70 S6激酶和4 E-BP 1翻译阻遏物的磷酸化，这两者都是细胞周期蛋白如D型细胞周期蛋白和c-myc的翻译所需的。p70的mTOR依赖性磷酸化诱导核糖体组分生物合成，4 E-BP 1的磷酸化导致其从翻译起始因子eIF-4 E解离。一旦释放，eIF-4 E可以通过结合mRNA 5'端的帽结构参与功能性翻译起始复合物的组装，促进翻译起始复合物的合成。 cap-dependent翻译雷帕霉素/CCI-779抑制这一过程，并导致关键细胞周期组分和G1期阻滞水平降低。具有升高水平的AKT活性的肿瘤细胞已经显示出对mTOR抑制剂具有增强的敏感性，并且我们已经鉴定了AKT依赖性敏感性的几个决定因素。该提案研究了肿瘤细胞对这些化合物的AKT依赖性敏感性和内在抗性模式的机制。在目标1中，该提案检查了雷帕霉素/CCI-779暴露后这些决定簇的AKT依赖性转录反应。在目标2和3中，该提案研究了转录后调节控制AKT依赖性的细胞凋亡的机制。 帽非依赖性翻译和mRNA的稳定性这些因素。其主要目标是 建议是了解调节肿瘤细胞对这些试剂的AKT依赖性超敏反应的分子事件。

mTOR inhibitors are a new class of drugs whose pre-clinical effects indicate great potential as chemotherapeutics for cancer. These agents are currently in development as anti-cancer drugs and may soon become available for clinicians. mTOR inhibitors target the mammalian target of rapamycin (mTOR) protein kinase which is a downstream target of the PI3-kinase/AKT pathway. Activation of mTOR results in phosphorylation of the p70S6kinase and the 4E-BP1 translational represser, both of which are required for translation of cell cycle proteins such as D-type cyclins and c-myc. The mTOR-dependent phosphorylation of p70 induces ribosomal component biogenesis and the phosphorylation of 4E-BP1 causes its dissociation from the translation initiation factor elF-4E. Once liberated, elF-4E can participate in assembly of a functional translation initiation complex by binding to the cap structure at the 5' end of mRNAs, promoting cap-dependent translation. Rapamycin/CCI-779 inhibits this process and results in reduced levels of critical celt cycle components and G1 arrest. Tumor cells with elevated levels of AKT activity have been shown to have enhanced sensitivty to mTOR inhibitiors and we have identified several determinants of AKT-dependent sensitivity. This proposal investigates the mechanisms of AKT-dependent sensitivity and modes of intrinsic resistance of tumor cells to these compounds. In aim 1, the proposal examines the AKT-dependent transcriptional responses of these determinants following rapamycin/CCI-779 exposure. In aims 2 and 3 the proposal investigates the mechanisms of post-transcriptional regulation controling AKT-dependent cap-independent translation and mRNA stability of these factors. The broad objective of this proposal is understand the molecular events which regulate AKT-dependent hypersensitivity of tumor cells to these agents.