Regulation of c-myc translation by hnRNP A1: Role in multiple myeloma tumor responses

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: 9884542
• 负责人: ALAN K LICHTENSTEIN
• 金额: $ 28.82万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-17 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9884542
• 关键词: 5' Untranslated Regions; Acute; Binding; Bortezomib; Categories; Cell Nucleus; Cell Proliferation; Cell Survival; Cells; Cessation of life; Complex; Cytoplasm; DNA; Data; Depressed mood; Development; Drug usage; Event; FRAP1 gene; Feedback; Funding; Future; Genetic Transcription; Goals; Hybrids; Initiator Codon; Interleukin-6; Internal Ribosome Entry Site; Libraries; Malignant - descriptor; Malignant Neoplasms; Mediating; Messenger RNA; Modeling; Modification; Molecular Conformation; Multiple Myeloma; Oncoproteins; Pathway interactions; Phosphorylation; Phosphotransferases; Plasma Cells; Production; Proteins; RNA-Binding Proteins; Regulation; Ribosomal Proteins; Ribosomes; Risk; Role; Testing; Therapeutic; Trans-Activators; Translations; Work; Yeasts; c-myc Genes; design; drug development; endoplasmic reticulum stress; experimental study; hnRNP A1; in vitro activity; in vivo; inhibitor/antagonist; mTOR Inhibitor; mouse model; neoplastic cell; prevent; protein expression; recruit; response; small molecule inhibitor; therapeutic target; transcription factor; tumor; tumor progression

The main objective of this project is to provide a rationale for future therapeutic targeting of the c-myc IRES which mediates cap-independent translation in multiple myeloma cells. IRES-dependent myc translation is critical for tumor cell survival during ER stress in this tumor model. The aims include studying the mechanism by which the MNK kinase, the hnRNP A1 ITAF and the ribosomal protein RPS25 mediate IRES function; the mechanism and importance of myc inducing A1 and RPS25 expression and the potential for an inhibitor of IRES function in myeloma. The viability versus death of myeloma cells as well as their ability to achieve c-myc translation and IRES activity in vitro will be studied. In addition, a murine model of c-myc-driven myeloma will be exploited to determine the in vivo roles of hnRNPA1 and IRES activity in tumor progression as well as the potential efficacy of our IRES inhibitors.

本项目的主要目的是为将来c-myc IRES的靶向治疗提供理论基础 其在多发性骨髓瘤细胞中介导帽非依赖性翻译。IRES依赖的myc翻译是 在该肿瘤模型中，ER应激对肿瘤细胞存活至关重要。研究的目的包括： MNK激酶、hnRNPA 1 ITAF和核糖体蛋白RPS 25通过其介导IRES功能; myc诱导A1和RPS 25表达的机制和重要性以及myc抑制剂的潜力 骨髓瘤中的IRES功能。骨髓瘤细胞的存活与死亡以及它们获得c-myc的能力 将研究体外翻译和IRES活性。此外，c-myc驱动的骨髓瘤的鼠模型将 可用于确定hnRNPA 1和IRES活性在肿瘤进展中的体内作用以及 我们的IRES抑制剂的潜在功效。