Project 2

项目2的中心目标是了解选择性剪接在癌症中的作用。癌细胞表现出广泛的剪接定性和定量失调，并且不适当表达的亚型可以促进肿瘤发生。研究剪接因子癌蛋白SRSF1和SR蛋白家族相关成员转化细胞的机制和途径。器官型培养以及正位和转基因小鼠模型将用于研究这些剪接因子在不同癌症环境下促进的转化及其与其他癌基因的合作。这些因子本身如何在正常细胞中被调节，而在癌症细胞中被上调，将被解决。采用高通量方法系统鉴定SR蛋白在人细胞中的剪接靶点，并对选定的参与肿瘤发生的靶点进行详细分析。剪接因子有助于癌细胞独特的糖酵解代谢将被识别和表征，丙酮酸激酶前mrna的选择性剪接将被研究作为一个潜在的治疗靶点，通过在肿瘤中特异性地操纵这一过程。

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.