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

描述（由申请人提供）：该提案的长期目标是研究c-myc蛋白cap无关翻译的机制，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）如何作为一种反式作用蛋白，与c-myc转录物5' UTR中的内部核糖体进入位点（IRES）结合，从而促进myc的IRES依赖性翻译。此外，我们将重点关注Akt和MAPK级联调控A1翻译促进活性的能力，测试对A1的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、原发肿瘤细胞和异种移植物模型将用于利用对A1/myc IRES调控控制的见解，以了解在尝试使用mTOR抑制剂治疗时，由于IL-6刺激和骨髓瘤治疗抵抗而导致骨髓瘤进展的机制。公共卫生相关性：该项目详细描述了多发性骨髓瘤癌细胞在一种叫做白细胞介素-6 （IL-6）的生长因子刺激下增殖的机制。这是患者恶性肿瘤进展的重要途径。它还阐明了多发性骨髓瘤肿瘤细胞如何对有希望的新型治疗药物mTOR抑制剂产生耐药性。

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.