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

• 批准号: 8447373
• 负责人: Dawn S Chandler
• 金额: $ 24.52万
• 依托单位: RESEARCH INST NATIONWIDE CHILDREN'S HOSP
• 依托单位国家: 美国
• 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/8447373
• 关键词: Adult; Affinity Chromatography; Age; Alanine Transaminase; Alternative Splicing; Astrocytoma; B-Cell Lymphomas; B-Lymphocytes; Binding; Binding Proteins; Binding Sites; Biochemical Pathway; Biological Assay; Breast; CD19 gene; Calculi; Cell Lineage; Cell Proliferation; 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; 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; Spectrometry; Stress; System; 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

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.

描述（由申请人提供）：基因表达最优雅和最严格调控的机制之一是选择性前mrna剪接。尽管调节剪接在几个发育过程和人类疾病中具有无可争议的重要性，但对于特定的替代剪接选择被调节的机制却知之甚少。重要的是，在癌症中大量选择性剪接异构体的鉴定突出了剪接体在肿瘤表型中的潜在作用。最近，我们已经表明，特定类型的细胞应激启动p53调节剂mdm2和mdm4 （mdmx）的协调选择性剪接。mdm2替代转录本的主要活性是通过以显性负向方式抑制mdm2来激活p53通路。在许多人类肿瘤中已经发现了这些相同的替代转录本。我们有兴趣研究mdm2剪接的调控，以更好地理解1)癌症中通过选择性剪接对p53通路的调控2)癌症剪接体与癌症表型之间的关系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，一些转化的细胞通过持续表达mdm2的选择性剪接转录物来提供一个恒定的信号来激活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。解开这一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重要基石。