Coordinately regulated alternative splicing in DNA damage and cancer

DNA 损伤和癌症中协调调节的选择性剪接

基本信息

批准号：
7890944
负责人：
Dawn S Chandler
金额：
$ 26.89万
依托单位：
RESEARCH INST NATIONWIDE CHILDREN'S HOSP
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2015-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7890944
关键词：
Adult Affinity Chromatography Age Alternative Splicing Astrocytoma B-Cell Lymphomas B-Lymphocytes Binding Binding Proteins Binding Sites Biochemical Pathway Biological Assay Breast Calculi Cell Lineage Cells Cellular Stress DNA Damage Data Dependence Development Developmental Process Dominant-Negative Mutation Event Frequencies Gene Expression Generations Genetic Genetic Techniques Genotoxic Stress Glioma Goals Human Lead Length Lung Lymphoma MDM2 gene Malignant Childhood Neoplasm Malignant Neoplasms Mass Spectrum Analysis Mediating Molecular Molecular Genetics Molecular Profiling Mus Mutagens Mutation Nuclear Extract Oncogenic Outcome Ovary Pathway interactions Phenotype Play Polypyrimidine Tract-Binding Protein Primary Neoplasm Protein Binding Protein Isoforms Protein p53 Proteins Publishing RNA RNA Binding RNA Splicing RNA-Binding Proteins Regulation Regulatory Element Relative (related person)Research Rhabdomyosarcoma Role Sampling Signal Transduction Stress System TP53 gene Testing Therapeutic Intervention Transcript Transgenes Transgenic Mice Tumor Suppressor Genes Tumor Suppressor Proteins Work cancer therapy carcinogenesis cell growth cell transformation design drug discovery human disease inhibitor/antagonist interest liposarcoma mRNA Precursor mouse model novel novel therapeutic intervention prevent public health relevance recombinase research study response tumor tumorigenesis tumorigenic

项目摘要

DESCRIPTION (provided by applicant): One of the most elegant and tightly regulated mechanisms for gene expression is alternative pre-mRNA splicing. Despite the undisputed importance of regulated splicing in several developmental processes and human disease, relatively little is known about the mechanisms by which specific alternative splice choices are regulated. Importantly, the identification of numerous alternatively spliced isoforms in cancer highlights the potential role of the spliceome in the tumor phenotype. Recently, we have shown that specific types of cell stress initiate coordinated alternative splicing of the p53 modulators mdm2 and mdm4 (mdmx). The predominant activity of the mdm2 alternative transcripts is to activate the p53 pathway by inhibiting MDM2 in a dominant negative fashion. These same alternative transcripts have been identified in numerous human tumors. We are interested in studying the regulation of mdm2 splicing to gain a better understanding of 1) regulation of the p53 pathway by alternative splicing in cancer 2) the relationship between the cancer spliceome and the cancer phenotype and 3) the role of the resultant spliced forms in the induction of cancer. Our data suggest that some transformed cells provide a constant signal to activate p53 through sustained expression of mdm2 alternatively spliced transcripts. The proposed research will elucidate the molecular connection between RNA splicing, the p53 response, and ultimately cancer. Unraveling this pathway will undoubtedly lead to the discovery of novel therapeutic intervention points and thus be a crucial stepping-stone for drug discovery. PUBLIC HEALTH RELEVANCE: p53 is one of the most important tumor suppressor genes whose normal function is to prevent inappropriate cell growth and proliferation. The proposed research will decipher the role of alternative splicing in transformation and disruption of the p53 pathway. Since activation of the p53 tumor suppressor pathway is a central target for cancer therapy, understanding the way that splicing contributes to its silencing could lead to novel therapies to reactive the p53 tumor suppressor activity.

描述（由申请人提供）：基因表达最优雅且受严格调控的机制之一是选择性前 mRNA 剪接。尽管调控剪接在多种发育过程和人类疾病中的重要性无可争议，但人们对特定选择性剪接选择的调控机制知之甚少。重要的是，癌症中众多选择性剪接亚型的鉴定凸显了剪接组在肿瘤表型中的潜在作用。最近，我们发现特定类型的细胞应激会启动 p53 调节剂 mdm2 和 mdm4 (mdmx) 的协调选择性剪接。 mdm2 替代转录物的主要活性是通过以显性负向方式抑制 MDM2 来激活 p53 通路。这些相同的替代转录物已在许多人类肿瘤中被发现。我们有兴趣研究 mdm2 剪接的调节，以便更好地了解 1) 癌症中选择性剪接对 p53 通路的调节 2) 癌症剪接组与癌症表型之间的关系以及 3) 所得剪接形式的作用在诱发癌症方面。我们的数据表明，一些转化细胞通过 mdm2 选择性剪接转录物的持续表达提供恒定信号来激活 p53。拟议的研究将阐明 RNA 剪接、p53 反应和最终癌症之间的分子联系。解开这条途径无疑将导致新的治疗干预点的发现，从而成为药物发现的关键垫脚石。公共健康相关性：p53 是最重要的肿瘤抑制基因之一，其正常功能是防止不适当的细胞生长和增殖。拟议的研究将破译选择性剪接在 p53 通路转化和破坏中的作用。由于 p53 肿瘤抑制通路的激活是癌症治疗的核心目标，了解剪接导致其沉默的方式可能会导致开发出反应 p53 肿瘤抑制活性的新疗法。