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

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

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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）：基因表达的最优雅和严格调节的机制之一是替代性mRNA剪接。尽管在几种发育过程和人类疾病中受到调节的剪接的重要性无可争议，但对调节特定替代剪接选择的机制知之甚少。重要的是，在癌症中鉴定许多剪接的同工型突出了剪接组在肿瘤表型中的潜在作用。最近，我们已经表明，特定类型的细胞应力启动了p53调节剂MDM2和MDM4（MDMX）的协调替代剪接。 MDM2替代转录本的主要活性是通过以显性负面方式抑制MDM2来激活p53途径。这些相同的替代转录本已在许多人类肿瘤中鉴定出来。我们有兴趣研究MDM2剪接的调节以更好地了解1）通过在癌症中进行替代剪接来调节p53途径2）癌症剪接组与癌症表型之间的关系和3）由此产生的剪接形式在癌症诱导中的作用。我们的数据表明，某些转化的细胞通过持续的MDM2剪接转录本的持续表达提供了恒定信号，以激活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。揭开这一途径无疑会导致发现新型治疗干预点，从而成为毒品发现的至关重要的垫脚石。公共卫生相关性：p53是最重要的肿瘤抑制基因之一，其正常功能是防止细胞的生长和增殖不当。拟议的研究将破译替代剪接在p53途径变化和破坏中的作用。由于p53肿瘤抑制途径的激活是癌症治疗的核心靶标，因此了解剪接有助于其沉默的方式可能导致新的疗法使p53肿瘤抑制剂活性反应。