Regulation of Pre-mRNA Splicing in Tumorigenesis

肿瘤发生中前体 mRNA 剪接的调控

基本信息

批准号：
8234411
负责人：
Adrian R Krainer
金额：
$ 56.87万
依托单位：
COLD SPRING HARBOR LABORATORY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-01-01 至 2016-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8234411
关键词：
Address Algorithms Alternative Splicing Antisense Oligonucleotides Biochemical Bypass Cells Controlled Study Data Elements Epithelial Cells Exons Fibroblasts Genes Goals Hela Cells Human In Vitro Individual Instruction Laboratories Lymphomagenesis Malignant Neoplasms Malignant neoplasm of liver Malignant neoplasm of pancreas Mammary gland Measures Messenger RNA Metabolism Methods Morphogenesis Mutagenesis NCI Center for Cancer Research Normal Cell Nuclear Nude Mice Oncogene Proteins Oncogenes Oncogenic Pathway interactions Peptides Phosphotransferases Process Property Protein Family Protein Isoforms Proteins Proteomics Pyruvate Kinase RNA RNA Splicing RNA-Binding Proteins Regulation Rodent Role Series Signal Transduction Site Spliceosomes Structure System Trans-Activators Transcriptional Regulation Transgenic Mice Translating Untranslated Regions Warburg Effect acrosome stabilizing factor aerobic glycolysis c-myc Genes cancer cell cell transformation comparative gene function human FRAP1 protein insight keratinocyte mRNA Precursor malignant breast neoplasm member mouse model overexpression paralogous gene sarcoma small hairpin RNA therapeutic target tumor tumor growth tumorigenesis

项目摘要

PROJECT SUMMARY (See instructions): The central goal of Project 2 is to understand the role of alternative splicing in cancer. Cancer cells display extensive qualitative and quantitative dysregulation of splicing, and a subset of the isoforms that are inappropriately expressed can contribute to tumorigenesis. The mechanisms and pathways through which the splicing-factor oncoprotein SRSF1 and related members of the SR protein family transform cells will be investigated. Organotypic culture, as well as orthotopic and transgenic mouse models will be used to study transformation promoted by these splicing factors and their cooperation with other oncogenes in different cancer contexts. How these factors themselves are regulated in normal cells and upregulated in cancer will be addressed. High-throughput methods will be employed to systematically identify the splicing targets of SR proteins in human cells, and selected targets involved in tumorigenesis will be analyzed in detail. Splicing factors that contribute to the distinctive glycolytic metabolism of cancer cells will be identified and characterized, and alternative splicing of pyruvate kinase pre-mRNA will be investigated as a potential therapeutic target by specifically manipulating this process in tumors.

项目摘要（请参阅说明）：项目2的核心目标是了解替代剪接在癌症中的作用。癌细胞表现出广泛的定性和定量失调的剪接失调，并且不当表达的同工型的一部分可以导致肿瘤发生。将研究SR蛋白家族转化细胞的剪接因子癌蛋白SRSF1及相关成员的机制和途径。器官型培养物以及原位和转基因小鼠模型将用于研究这些剪接因子促进的转化及其在不同癌症情况下与其他癌基因的合作。这些因素本身如何在正常细胞中调节并在癌症中上调。将采用高通量方法来系统地识别人类细胞中SR蛋白的剪接靶标，并将详细分析参与肿瘤发生的选定靶标。将鉴定和表征有助于癌细胞的独特糖酵解代谢的剪接因子，并将通过在肿瘤中特异性操纵该过程来研究丙酮酸激酶前MRNA的替代剪接作为潜在的治疗靶靶标。