Mechanisms of AKT-dependent sensitivity to rapamycin

AKT 依赖性雷帕霉素敏感性机制

基本信息

批准号：
7409068
负责人：
JOSEPH F GERA
金额：
$ 19.49万
依托单位：
SEPULVEDA RESEARCH CORPORATION
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-07-15 至 2010-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7409068
关键词：
1-Phosphatidylinositol 3-Kinase Affect Antineoplastic Agents Binding Binding Sites Biogenesis CCI-779 Cell Cycle Cell Cycle Arrest Cell Cycle Progression Cell Cycle Proteins Cells Class Complex Cyclin D1 Cyclins Data Development Dissection Dissociation Elements Event Exhibits Exposure to Face G1 Arrest Genes Genetic Genetic Transcription Genetic Translation Genome Growth Factor Half-Life Human Hypersensitivity In Vitro Internal Ribosome Entry Site Lead Link MAP Kinase Signaling Pathways Malignant Neoplasms Mediating Messenger RNA Molecular Nutrient Pathway interactions Patients Peptide Initiation Factors Pharmaceutical Preparations Phosphoinositide-3-Kinase, Catalytic, Gamma Polypeptide Phosphorylation Phosphotransferases Post-Transcriptional Regulation Principal Investigator Process Protein Kinase Proto-Oncogene Proteins c-akt RNA-Binding Proteins Rate Recruitment Activity Regulation Reporter Reporting Research Personnel Resistance ST5 Protein ST5 gene Sampling Series Signal Pathway Signal Transduction Sirolimus Structure Testing Trans-Activators Transcript Transcriptional Regulation Translation Initiation Translational Regulation Translations Untranslated Regions Up-Regulation antitumor agent bone c-myc Genes clinical effect human MAPK14 protein inhibitor/antagonist mRNA Stability mitogen-activated protein kinase p38 neoplastic cell p27 Cell Cycle Protein p27 Enzyme Inhibitor pre-clinical programs promoter research study response thymidine 5&apos -triphosphate transcription factor tumor

项目摘要

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.

mTOR 抑制剂是一类新型药物，其临床前效果显示出巨大的潜力：癌症化疗。这些药物目前正在开发作为抗癌药物，可能很快就会可供临床医生使用。 mTOR 抑制剂以哺乳动物雷帕霉素靶点 (mTOR) 蛋白激酶为靶点，该蛋白激酶是 PI3 激酶/AKT 通路的下游靶点。 mTOR 的激活导致 p70S6 激酶和 4E-BP1 翻译抑制蛋白磷酸化，这两者都是细胞周期蛋白（例如 D 型细胞周期蛋白和 c-myc）翻译所必需的。 p70 的 mTOR 依赖性磷酸化诱导核糖体成分生物合成，4E-BP1 的磷酸化导致其与翻译起始因子 eIF-4E 解离。一旦释放，elF-4E 可以通过结合到 mRNA 5' 端的帽子结构来参与功能性翻译起始复合物的组装，从而促进依赖于上限的翻译。 Rapamycin/CCI-779 抑制这一过程，导致关键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已被证明对 mTOR 抑制剂的敏感性增强，并且我们已经确定了 AKT 依赖性敏感性的几个决定因素。该提案研究了 AKT 依赖性敏感性的机制以及肿瘤细胞对这些化合物的内在耐药性模式。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的 AKT 依赖性转录反应。在目标 2 和 3 中，该提案研究了控制 AKT 依赖性的转录后调控机制这些因素的帽独立翻译和 mRNA 稳定性。本次活动的总体目标建议了解调节肿瘤细胞对这些药物的 AKT 依赖性超敏反应的分子事件。