Mechanisms of Akt-dependent sensitivity to rapamycin

描述(申请人提供)：该提案的长期目标是研究c-myc蛋白的帽非依赖性翻译机制，假设其细胞功能是肿瘤细胞反应的关键决定因素，特别是对中枢神经系统恶性肿瘤。更具体地说，该提案将阐明hnRNP A1(A1)如何作为反式作用蛋白与c-myc转录本5‘UTR中的内部核糖体进入位点(IRES)结合，从而促进依赖IRES的myc翻译。此外，它将集中在Akt和MAPK级联调控A1翻译促进活性的能力，测试A1对IRES-退火活性的影响，对IRES-核糖体结合的影响，以及对A1/IRES亚细胞定位的影响。将利用胶质瘤细胞系、原代肿瘤细胞和异种移植模型，利用A1/myc IRES调控机制的洞察力，以了解mTOR抑制剂治疗胶质瘤细胞耐药的机制。与公共卫生相关：该项目详细说明了胶质瘤细胞对被称为mTOR抑制剂的有前景的新治疗药物产生抗药性的机制。将研究细胞对这些化合物的内在耐药性的机制，以及在体外和体内模型中联合靶向治疗胶质瘤的临床前评估。

DESCRIPTION (provided by applicant): The long range goal of the proposal is to investigate the mechanism of cap-independent translation of the c- myc protein with the assumption that its cellular function is a key determinant of tumor cell responses, especially for CNS malignancies. More specifically, the proposal will elucidate how hnRNP A1 (A1) functions as a trans-acting protein that binds to the internal ribosome entry site (IRES) in the 5' UTR of the c-myc transcript, thus facilitating IRES-dependent translation of myc. Furthermore, it will focus on the ability of Akt and MAPK cascades to regulate this A1 translation-promoting activity, testing effects on the IRES-annealing activity of A1, effects on IRES-ribosome binding and effects on A1/IRES subcellular localization. Glioma cell lines, primary tumor cells and xenograft models will be used to exploit the insight gained on A1/myc IRES regulatory controls to understand mechanisms of glioma cell resistance whe treatment with mTOR inhibitors is attempted. PUBLIC HEALTH RELEVANCE: The project details the mechanisms by which glioma tumor cells become resistant to promising new therapeutic agents called mTOR inhibitors. The mechanisms of cell intrinsic resistance to these compounds will be investigated, as well as, the pre-clinical evaluation of combination targeted therapies in glioma in vitro and in vivo models.