Regulation of c-myc translation by hnRNP A1: role in multiple myeloma tumor respo

描述(申请人提供)：该提案的长期目标是研究c-myc蛋白的帽子非依赖性翻译机制，假设其细胞功能是肿瘤细胞反应的关键决定因素，特别是对于恶性多发性骨髓瘤。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。多发性骨髓瘤细胞系、原代肿瘤细胞和异种移植模型将被用来利用A1/myc IRES调控调控获得的洞察力，以了解由于IL-6刺激而导致的骨髓瘤进展的机制以及尝试使用mTOR抑制剂治疗骨髓瘤时的治疗耐药。与公共卫生相关：该项目详细说明了多发性骨髓瘤癌细胞在一种名为白介素6(IL-6)的生长因子刺激下扩大数量的机制。这是这种恶性肿瘤在患者体内进展的重要途径。它还阐明了多发性骨髓瘤肿瘤细胞如何对被称为mTOR抑制剂的有希望的新治疗药物产生抗药性。

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 the malignancy multiple myeloma. 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. Multiple myeloma 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 myeloma progression due to IL-6 stimulation and myeloma therapy-resistance when treatment with mTOR inhibitors is attempted. PUBLIC HEALTH RELEVANCE: The project details the mechanism by which multiple myeloma cancer cells expand their numbers when they are stimulated by a growth factor called interleukin-6 (IL-6). This is an important pathway of progression of this malignancy in patients. It also elucidates how multiple myeloma tumor cells become resistant to promising new therapeutic agents called mTOR inhibitors.