ROLE OF ACA11, AN ORPHAN SMALL NUCLEOLAR RNA IN RESISTANCE TO CANCER CHEMOTHERAPY

孤儿小核仁 RNA ACA11 在抵抗癌症化疗中的作用

基本信息

批准号：
8477547
负责人：
MICHAEL H TOMASSON
金额：
$ 31.54万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-05-01 至 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8477547
关键词：
4p16.3 Antibodies B-Lymphocytes Binding Biochemical Biological Biological Assay Boxing Cell Cycle Inhibition Cell Death Cell Line Cell Nucleolus Cell Survival Cells Chemotherapy-Oncologic Procedure Chromosomal translocation Chromosomes Chromosomes, Human, Pair 4 Clinical Complementary DNA Complex Custom Data Development Diagnosis Disease Etiology Functional RNA Genes Goals Grant Growth Guide RNA Health Immunologic Techniques Introns Laboratories Malignant Neoplasms Mediator of activation protein Modeling Molecular Morphology Multiple Myeloma Mus Nuclear Extract Oncogenes Orphan Oxidative Stress Patients Phenotype Plasma Process Production Proteins Publishing RNA RNA Splicing Reactive Oxygen Species Resistance Ribosomal Proteins Ribosomal RNA Role Sampling Small Nuclear Ribonucleoproteins Small Nucleolar RNA Stress Survival Rate Testing Therapeutic Transcript Transformed Cell Line WHSC1 gene base biological adaptation to stress cell growth cell transformation chemotherapeutic agent chemotherapy deep sequencing histone methyltransferase knock-down mRNA Expression member mutant new therapeutic target novel overexpression research study response tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): The t(4;14) chromosomal translocation found in 20% of multiple myeloma (MM) cases leads to a shorter survival rate in an already incurable disease. The candidate oncogene overexpressed from the t(4;14) translocation, WHSC1 (MMSET), is unable to transform cells in culture or drive tumorigenesis in mice on its own. Examination of a 2 MB region around the t(4;14) breakpoint revealed the overexpression of a 125 bp orphan H/ACA class non-coding RNA, ACA11, which was confirmed to be up-regulated in t(4;14) MM cell lines and patient samples. Further preliminary studies demonstrate ACA11 localizes to the nucleolus as part of an small nuclear ribonucleoprotein (snRNP) complex. In addition, ACA11 overexpression reduces the levels of reactive oxygen species (ROS) in response to oxidative stress and increases cell survival in the presence of chemotherapeutic agents. We hypothesize that the overexpression of ACA11 in t(4;14) MM reduces ROS-induced cell death leading to the development and/or progression of MM. The ultimate goal of this proposal is to elucidate the mechanism by which ACA11 exerts its inhibitory effects on ROS-induced cell cycle inhibition and cell death in t(4;14) MM cell lines. We hypothesize that the overexpression of the ACA11 snoRNA in t(4;14) MM results in the altered splicing of specific RNA transcripts involved in the cellular response to ROS. These selected transcripts will encode either RNA or proteins critical for B-cell survival in MM. Therefore, ACA11 and its associated snRNP's will be potential novel targets for MM treatment or diagnosis. Three specific aims of the grant are proposed: Aim 1: To test the hypothesis that ACA11 must interact with snRNPs to exert its inhibition of oxidative stress induced cell death Aim 2: To test the hypothesis that ACA11 regulates ROS levels through modulating splicing of snoRNAs from ribosomal protein transcripts Aim 3: To test the hypothesis that overexpression of ACA11 leads to an inhibition of nucleolar stress-induced, p53-regulated ROS production

描述（由申请人提供）：在 20% 的多发性骨髓瘤 (MM) 病例中发现的 t(4;14) 染色体易位会导致本已无法治愈的疾病的生存率缩短。 t(4;14) 易位过表达的候选癌基因 WHSC1 (MMSET) 无法自行转化培养细胞或驱动小鼠肿瘤发生。对 t(4;14) 断点周围 2 MB 区域的检查揭示了 125 bp 孤儿 H/ACA 类非编码 RNA ACA11 的过度表达，该 RNA 经证实在 t(4;14) MM 中上调细胞系和患者样本。进一步的初步研究表明，ACA11 作为小核核糖核蛋白 (snRNP) 复合物的一部分定位于核仁。此外，ACA11 过表达会降低响应氧化应激的活性氧 (ROS) 水平，并增加化疗药物存在下的细胞存活率。我们假设 t(4;14) MM 中 ACA11 的过度表达减少了 ROS 诱导的细胞死亡，从而导致 MM 的发生和/或进展。该提案的最终目标是阐明 ACA11 对 t(4;14) MM 细胞系中 ROS 诱导的细胞周期抑制和细胞死亡发挥抑制作用的机制。我们假设 t(4;14) MM 中 ACA11 snoRNA 的过度表达导致参与细胞对 ROS 反应的特定 RNA 转录本的剪接改变。这些选定的转录物将编码对 MM 中 B 细胞存活至关重要的 RNA 或蛋白质。因此，ACA11 及其相关 snRNP 将成为 MM 治疗或诊断的潜在新靶标。该资助计划提出了三个具体目标：目标 1：检验 ACA11 必须与 snRNP 相互作用才能抑制氧化应激诱导的细胞死亡的假设目标 2：检验 ACA11 通过调节 snoRNA 剪接来调节 ROS 水平的假设核糖体蛋白转录物目标 3：检验 ACA11 过度表达会抑制核仁应激诱导的 p53 调节的假设活性氧生产