Elucidating the mechanism and consequences of aberrant cyclin D1 gene expression

阐明细胞周期蛋白 D1 基因表达异常的机制和后果

• 批准号: 10461000
• 负责人: Chioniso Patience Masamha
• 金额: $ 28.18万
• 依托单位: BUTLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10461000
• 关键词: 3' Untranslated Regions; Address; Affect; B lymphoid malignancy; B-Cell Acute Lymphoblastic Leukemia; B-Cell Lymphomas; B-Lymphocytes; Binding; Biological Markers; CCND1 gene; Case Study; Cell Line; Cell Nucleus; Cells; Characteristics; Chromosomal Instability; Chromosomal Rearrangement; Chromosomal translocation; Chromosome abnormality; Chronic; Clinical; Code; Cyclin D1; Cyclins; Cytoplasm; Data; Disease; Distal; Enhancers; Event; Frequencies; Gene Deletion; Gene Expression; Gene Fusion; Generations; Genes; Genetic; Genetic Enhancer Element; Genetic Transcription; Goals; Half-Life; Hematopoietic Neoplasms; Housekeeping; Human; Individual; Length; Lesion; Light; Lymphocyte; Lymphoma cell; Malignant Neoplasms; Mantle Cell Lymphoma; Measures; Messenger RNA; Molecular; Mutation; Nucleotides; Parents; Patients; Pattern; Phenotype; Physiological; Play; Poly(A) Tail; Polyadenylation; Process; Proteins; Publishing; RNA Splicing; Recurrence; Recurrent disease; Regulation; Research; Rest; Role; Sampling; Signal Transduction; Technology; Terminator Codon; Testing; Third Generation Sequencing; Transcript; Untranslated Regions; Work; cell motility; cell type; fusion gene; gene product; genome integrity; innovation; insight; knock-down; mRNA Precursor; molecular targeted therapies; novel; patient stratification; potential biomarker; premature; promoter; standard of care; transcriptome; tumorigenic

ABSTRACT Some genes take drastic measures to force their aberrant expression. As an example, the gene cyclin D1 which is not normally present in B-cell lymphocytes is expressed in the blood cancer Mantle Cell Lymphoma (MCL). MCL is the most aggressive of all B-cell malignancies and a chromosomal translocation event, that pre-dates the disease, activates the cyclin D1 promoter is the initiating lesion in the transformation of normal B-cells. Once expressed, the transcribed cyclin D1 message (pre-mRNA) undergoes further processing which enables it to shorten it's 3'untraslated region (3'UTR) thus increasing the half-life of the transcript. The expression of cyclin D1 in MCL facilitates a hyper-proliferative phenotype and increases the genetic instability and chromosomal abnormalities of B-cells. In our prior work we identified a novel fusion gene in MCL cell lines and patient samples where cyclin D1 is joined to another gene thus resulting in a truncated 3'UTR. The goal of this project is to determine the molecular mechanisms that drive the shortening of the 3'UTR of cyclin D1 as well as the effects of the cyclin D1 driven chromosomal translocation events. In this proposal we will determine how the sequences found in the pre-mRNA of cyclin D1 as well as proteins involved in 3'end processing play a role in optimizing the expression of cyclin D1 in MCL (Aim 1). We will also systematically identify fusion genes, which result from chromosomal translocation events, using third generation sequencing technology which allows us to get full length gene transcripts (Aim 2). Although chromosomal translocations are known to occur with a high degree of frequency in MCL, apart from serendipity discovery in individual case studies, little effort has been put into identifying fusion genes on a global scale making this type of research innovative. Furthermore, our study will determine the molecular basis of abnormal 3'end formation will answer a basic question in the field. This will have a positive impact by establishing better understanding of disease causing genes are expressed in human cells and will allow for more effective strategies to detect and treat disease.

抽象的 一些基因采取了巨大的措施来迫使其异常表达。例如，基因Cyclin D1 通常在B细胞淋巴细胞中不存在的，在血液癌地幔细胞淋巴瘤中表达 （MCL）。 MCL是所有B细胞恶性肿瘤中最具侵略性的事件，也是染色体易位事件， 预先疾病，激活细胞周期蛋白D1启动子是正常转化的启动病变 B细胞。一旦表达，转录的细胞周期蛋白D1消息（PRE-MRNA）将进行进一步的处理 这使其可以缩短其3'untraslated区域（3'UTR），从而增加了转录本的半衰期。 Cyclin D1在MCL中的表达促进了超增殖的表型并增加了遗传 B细胞的不稳定性和染色体异常。在我们先前的工作中，我们确定了一个新颖的融合基因 MCL细胞系和患者样品，其中细胞周期蛋白D1连接到另一个基因，从而导致截短 3'utr。该项目的目的是确定推动缩短缩短的分子机制 Cyclin D1的3'UTR以及Cyclin D1驱动的染色体易位事件的影响。在这个 提案我们将确定在细胞周期蛋白D1和蛋白的前MRNA中发现的序列如何 参与3'End加工在优化MCL中细胞周期蛋白D1的表达方面发挥了作用（AIM 1）。我们将 还使用第三 生成测序技术使我们能够获得全长基因转录本（AIM 2）。虽然 已知染色体易位在MCL中以高度的频率发生，除了 在个别案例研究中发现偶然性，几乎没有努力识别融合基因 全球规模使这种研究创新。此外，我们的研究将确定分子 异常3'E​​nd组的基础将回答该领域的基本问题。这将产生积极的影响 通过在人类细胞中表达对引起基因疾病基因的疾病的更好理解，将允许 有关检测和治疗疾病的更有效策略。