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）：T（4; 14）在20％的多发性骨髓瘤（MM）病例中发现的染色体易位导致已经无法治愈的疾病的存活率较短。从T（4; 14）易位WHSC1（MMSET）过表达的候选癌基因无法自行转化培养细胞或驱动小鼠的肿瘤发生。对T（4; 14）断点周围2 MB区域的检查表明，125 bp的孤儿H/ACA类非编码RNA ACA11的过表达，该ACA11已确认在T（4; 14; 14; 14）mm细胞系和患者样品中上调。进一步的初步研究表明，作为小核核糖核蛋白（SNRNP）复合物的一部分，ACA11定位于核仁。此外，ACA11的过表达降低了对氧化应激的反应性氧（ROS）的水平，并在化学治疗剂的存在下增加细胞存活。我们假设t（4; 14）mm中ACA11的过表达降低了ROS诱导的细胞死亡，导致MM的发展和/或进展。该提案的最终目标是阐明ACA11对ROS诱导的细胞周期抑制作用和细胞死亡的抑制作用的机制（4; 14）mm细胞系。我们假设t（4; 14）mm中ACA11 snORNA的过表达导致涉及细胞响应ROS的特定RNA转录本的剪接改变。这些选定的转录物将编码对于MM中B细胞存活至关重要的RNA或蛋白质。因此，ACA11及其相关的SNRNP将是MM治疗或诊断的潜在新目标。 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应力诱导的P53调节的ROS产生