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

hnRNP A1 对 c-myc 翻译的调节：在多发性骨髓瘤肿瘤反应中的作用

• 批准号: 7727057
• 负责人: JOSEPH F GERA
• 金额: $ 27.58万
• 依托单位: BRENTWOOD BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7727057
• 关键词: 5' Untranslated Regions; Address; Affect; Binding; Biological Assay; Cell Line; Cell Nucleus; Cell Proliferation; Cell physiology; Cells; Clinical; Complex; Cytoplasm; Data; Development; Down-Regulation; Event; Future; G1 Arrest; Genetic Transcription; Goals; Growth; Growth Factor; Interleukin-6; Internal Ribosome Entry Site; MAP Kinase Gene; MAPK14 gene; Maintenance; Malignant Neoplasms; Mediating; Mediator of activation protein; Messenger RNA; Minority; Mitogen-Activated Protein Kinase Inhibitor; Molecular; Molecular Conformation; Monoclonal gammopathy of uncertain significance; Multiple Myeloma; Newly Diagnosed; Nuclear; Paralysed; Pathway interactions; Patients; Phosphorylation; Phosphotransferases; Point Mutation; Premalignant; Primary Neoplasm; Protein Binding; Proteins; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-myc; RNA; RNA annealing; RNA-Binding Proteins; Regulation; Research; Resistance; Ribosomes; Role; Sampling; Scientist; Serine; Signal Pathway; Sirolimus; Site; Structure; Syndrome; Talents; Testing; Therapeutic; Therapeutic Agents; Transcript; Translating; Translations; Transport Process; Untranslated Regions; Up-Regulation; Xenograft Model; c-myc Genes; cancer cell; falls; follow-up; hnRNP A1; in vivo; insight; mRNA Stability; mTOR Inhibitor; mTOR inhibition; neoplastic cell; novel therapeutics; pre-clinical; prevent; protein expression; public health relevance; response; trafficking; translation factor; tumor; tumor growth

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.

描述（由申请人提供）：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应答的关键决定因素，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转录本5' UTR中的内部核糖体进入位点（IRES）结合，从而促进IRES依赖的myc翻译。此外，它将集中在Akt和MAPK级联调节这种A1促增殖活性的能力，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、原发性肿瘤细胞和异种移植模型将用于利用A1/myc IRES调控控制获得的见解，以了解当尝试使用mTOR抑制剂治疗时，由于IL-6刺激和骨髓瘤治疗抗性导致的骨髓瘤进展机制。公共卫生相关性：该项目详细说明了多发性骨髓瘤癌细胞在受到一种称为白细胞介素-6（IL-6）的生长因子刺激时扩大其数量的机制。这是患者中这种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称为mTOR抑制剂的有前途的新治疗药物产生耐药性。