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: 8257976
• 负责人: JOSEPH F GERA
• 金额: $ 26.5万
• 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/8257976
• 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; Health; 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; 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; response; trafficking; translation factor; tumor; tumor growth; tumor xenograft

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.

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。