Mechanisms of AKT-dependent sensitivity to rapamycin

MTOR抑制剂是一类新的药物，其临床前疗效显示出很大的潜力 癌症的化疗药物。这些药物目前正在开发中，作为抗癌药物，可能很快就会提供给临床医生。MTOR抑制剂针对哺乳动物靶点雷帕霉素(MTOR)蛋白激酶，它是PI3-激酶/AKT通路的下游靶点。MTOR的激活导致p70S6激酶和4E-BP1翻译抑制物的磷酸化，这两者都是翻译细胞周期蛋白(如D-型细胞周期蛋白和c-myc)所必需的。依赖mTOR的p70的磷酸化诱导核糖体成分的生物合成，而4E-BP1的磷酸化导致其与翻译起始因子ELF-4E解离。一旦被释放，ELF-4E可以通过与mRNAs 5‘端的帽子结构结合，促进 依赖大小写的翻译。雷帕霉素/CCI-779抑制这一过程，并导致关键的细胞周期成分水平降低和G1期停滞。AKT活性水平升高的肿瘤细胞被证明对mTOR抑制剂的敏感性增强，我们已经确定了几个AKT依赖敏感性的决定因素。该方案研究了AKT依赖的肿瘤细胞对这些化合物的敏感性和内在耐药模式的机制。在目标1中，该提案检查了雷帕霉素/CCI-779暴露后这些决定因素依赖AKT的转录反应。在目标2和目标3中，建议研究转录后调控控制AKT依赖的机制 这些因子的帽子非依赖性翻译和mRNA稳定性。这样做的总体目标是 建议了解调节AKT依赖的肿瘤细胞对这些药物的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.