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

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

该项目的主要目标是为 c-myc IRES 的未来治疗靶向提供理论依据它介导多发性骨髓瘤细胞中帽独立的翻译。 IRES 依赖的 myc 翻译是在此肿瘤模型中，ER应激期间对于肿瘤细胞的存活至关重要。目的包括研究机制 MNK 激酶、hnRNP A1 ITAF 和核糖体蛋白 RPS25 介导 IRES 功能；这 myc 诱导 A1 和 RPS25 表达的机制和重要性以及抑制剂的潜力 IRES 在骨髓瘤中发挥作用。骨髓瘤细胞的活力与死亡及其实现 c-myc 的能力将研究体外翻译和 IRES 活性。此外，c-myc 驱动的骨髓瘤小鼠模型将用于确定 hnRNPA1 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。