Regulation of Pre-mRNA Splicing in Tumorigenesis

肿瘤发生中前体 mRNA 剪接的调控

• 批准号: 7225417
• 负责人: Adrian R Krainer
• 金额: $ 54.69万
• 依托单位: COLD SPRING HARBOR LABORATORY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-01-01 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7225417
• 关键词: 5' Splice Site; Accounting; Alternative Splicing; Apoptosis; B-Cell Lymphomas; Bladder; Breast Carcinoma; Bypass; Cancer-Predisposing Gene; Cell Cycle Regulation; Cells; Classification; Colorectal; Consensus; Cultured Cells; Development; Early Diagnosis; Epithelial Cells; Family; Fibroblasts; Gene Expression; Gene Expression Regulation; Genetic; Genetic Predisposition to Disease; Genomic Instability; Heterogeneous Nuclear RNA; Heterogeneous-Nuclear Ribonucleoprotein Group A-B; Human; Individual; Lesion; Link; Lung; Lymphomagenesis; Maintenance; Malignant Neoplasms; Mediating; Messenger RNA; Modeling; Modification; Molecular; Mutation; Oncogene Proteins; Oncogenes; Oncogenic; Pathway interactions; Positioning Attribute; Post-Transcriptional Regulation; Predisposition; Prevalence; Primary carcinoma of the liver cells; Process; Protein Isoforms; Protein Overexpression; Proteins; Proteomics; Proto-Oncogenes; RNA Splicing; RNA-Binding Proteins; Range; Regulation; Role; Signal Pathway; Specificity; Structure; Transcript; Tumor Suppressor Genes; Tumor-Derived; Tumorigenicity; U1 small nuclear RNA; Up-Regulation; base; cancer therapy; cell growth regulation; cell transformation; genetic manipulation; hnRNP A1; improved; loss of function; mRNA Precursor; malignant breast neoplasm; member; mouse model; novel; tumor; tumorigenesis

Alternative splicing is a widespread mechanism for post-transcriptional control of gene expression, and accounts for a large fraction of proteomic diversity. This process is also frequently misregulated in cancer, and appears to contribute to various changes associated with transformation. This project explores the molecular mechanisms through which the members of two conserved families of RNA-binding proteins regulate alternative splicing, and the range of pre-mRNA targets each of them controls in the context of transformation. Overexpression of these factors can promote tumorigenesis, and apparently bypass the requirement for oncogene cooperation by controlling the expression of specific isoforms of several key members of oncogene and tumor-suppressor networks. The prevalence of this mechanism for tumor development in different types of human cancer will be studied, and its specific features will be dissected and compared in different contexts by genetic manipulation of the splicing factors in cell culture and in models of B-cell lymphoma, hepatocellular carcinoma,and breast carcinoma. Distinctive features ofpre- mRNA targets recognized by the splicing machinery will also be studied, both to understand the mechanism and specificity of this process and to facilitate the classification of mutations in cancer- susceptibility genes that result in defective mRNA and protein. By exploring a new pathway for tumor development,this study may define markers that facilitate early detection of genetic lesions leading to cancer, and it may also potentially uncover novel targets for cancer therapy. Improved prediction of mutations that cause defective RNA splicing will inform treatment decisions for individuals with genetic predisposition to cancer.

选择性剪接是基因表达的转录后控制的广泛机制， 占蛋白质组多样性的很大一部分。这个过程在癌症中也经常被错误调节， 并且似乎促成了与转变相关的各种变化。这个项目探讨了 两个保守的RNA结合蛋白家族成员的分子机制 调节选择性剪接，并且它们各自控制的前体mRNA靶向的范围， 转型这些因子的过度表达可促进肿瘤发生，并明显绕过肿瘤细胞的增殖。 通过控制几个关键基因的特定亚型的表达， 癌基因和肿瘤抑制网络的成员。这种机制在肿瘤中的流行率 将研究不同类型人类癌症的发展，并剖析其具体特征 并通过在细胞培养物中和细胞培养物中对剪接因子进行遗传操作， B细胞淋巴瘤、肝细胞癌和乳腺癌的模型。预处理的显著特征 还将研究剪接机制识别的mRNA靶点，以了解剪接机制的作用。 这一过程的机制和特异性，并促进癌症突变的分类- 导致mRNA和蛋白质缺陷的易感基因。 通过探索肿瘤发展的新途径，这项研究可能会定义促进早期肿瘤发生的标志物。 检测导致癌症的遗传病变，还可能发现癌症的新靶点 疗法改善导致缺陷RNA剪接的突变预测将为治疗提供信息 对有癌症遗传易感性的个体做出决定。