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质量和数量上的剪接异常，而不适当表达的亚型亚型可能有助于肿瘤的发生。剪接因子癌蛋白SRSF1和SR蛋白家族的相关成员转化细胞的机制和途径将被研究。器官类型培养，以及原位和转基因小鼠模型将被用来研究这些剪接因子促进的转化以及它们在不同癌症背景下与其他癌基因的合作。这些因素本身是如何在正常细胞中调节的，以及在癌症中如何上调的，将被解决。高通量方法将被用来系统地鉴定人类细胞中SR蛋白的剪接靶标，并将对参与肿瘤发生的选定靶标进行详细分析。有助于癌细胞独特的糖酵解代谢的剪接因子将被识别和表征，丙酮酸激酶前体mRNA的选择性剪接将被研究为通过在肿瘤中具体操作这一过程而成为潜在的治疗靶点。

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.