Project 2: Regulation of Pre-mRNA Splicing in Tumorigenesis

项目摘要--项目2 项目2的中心目标是了解选择性剪接在癌症中的各种作用，并利用 这一过程具有癌症特有的特点，以开发有针对性的治疗方法。癌细胞展示 广泛的定性和定量剪接失调，以及许多亚型的子集，这些亚型是 不适当的表达有助于肿瘤的发生或细胞代谢的改变。机制和 剪接因子癌蛋白SRSF2和SRSF1转化细胞的途径将继续 调查过了。细胞培养模型以及原位和遗传小鼠模型将用于研究 在不同的癌症环境中，这些剪接因子通过突变或过度表达促进肿瘤的发生 重点是髓系发育不良的反复突变。高通量RNA测序和 计算分析将被用来识别和比较这些SR蛋白的剪接靶标 将对不同的癌症背景和选定的靶点进行表征和操作，以评估其 对肿瘤发生的贡献以及作为治疗靶点或生物标志物的潜力。一个关键事件，可供选择 拼接控制癌细胞独特的糖酵解新陈代谢的丙酮酸激酶前体mRNA，将 作为潜在的治疗靶点进行彻底的研究，通过在体内特别地操纵这一过程， 利用反义技术和小鼠脑胶质瘤和肝细胞癌模型。

PROJECT SUMMARY - PROJECT 2 The central goal of Project 2 is to understand the various roles of alternative splicing in cancer, and to exploit cancer-specific features of this process to develop targeted-therapeutic approaches. Cancer cells display extensive qualitative and quantitative dysregulation of splicing, and a subset of the numerous isoforms that are inappropriately expressed contribute to tumorigenesis or altered cell metabolism. The mechanisms and pathways through which the splicing-factor oncoproteins SRSF2 and SRSF1 transform cells will continue to be investigated. Cell-culture models, as well as orthotopic and genetic mouse models will be used to study tumorigenesis promoted by these splicing factors upon mutation or overexpression in different cancer contexts, with an emphasis on recurrent mutations in myeloid dysplasias. High-throughput RNA-sequencing and computational analysis will be employed to identify and compare the splicing targets of these SR proteins in different cancer contexts, and selected targets will be characterized and manipulated to evaluate their contributions to tumorigenesis and potential as therapeutic targets or biomarkers. One key event, alternative splicing of pyruvate kinase pre-mRNA, which controls the distinctive glycolytic metabolism of cancer cells, will be thoroughly investigated as a potential therapeutic target, by specifically manipulating this process in vivo, using antisense technology and mouse models of glioma and hepatocellular carcinoma.