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：
7230526
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 2009-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7230526
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抑制剂是一类新的药物癌症的化学治疗药。这些代理商目前正在作为抗癌药物中发育，很快就可以为临床医生提供。 MTOR抑制剂靶向雷帕霉素（MTOR）蛋白激酶的哺乳动物靶标，该蛋白是PI3-激酶/AKT途径的下游靶标。 MTOR的激活导致p70s6kinase和4E-BP1转化抑制剂的磷酸化，这两者都是细胞周期蛋白（如D型细胞周期蛋白和C-MYC）的翻译所必需的。 p70的MTOR依赖性磷酸化诱导核糖体成分生物发生和4E-BP1的磷酸化导致其与翻译起始因子ELF-4E的解离。一旦解放，ELF-4E可以通过与mRNA的5'末端结合，参与功能翻译启动复合物的组装，促进帽子依赖性翻译。雷帕霉素/CCI-779抑制了这一过程，并导致关键凯尔特循环成分和G1停滞的水平降低。肿瘤细胞的Akt活性水平升高已显示出对MTOR抑制剂的敏感性增强，我们已经确定了AKT依赖性敏感性的几种决定因素。该提案研究了依赖Akt依赖性灵敏度的机制以及肿瘤细胞对这些化合物的内在耐药性的模式。在AIM 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依赖性转录响应。在目标2和3中，该提案研究了控制Akt依赖性的转录后调节机制这些因素的无帽非依赖性翻译和mRNA稳定性。这个广泛的目标建议理解分子事件，这些事件调节肿瘤细胞对这些药物的过敏性过敏。