Regulation of Pre-mRNA Splicing in Tumorigenesis

选择性剪接是转录后控制基因表达的一种广泛的机制，并且 占蛋白质组多样性的很大一部分。这一过程在癌症中也经常被错误调控， 并且似乎促成了与转变相关的各种变化。这个项目探索了 两个保守的RNA结合蛋白家族成员的分子机制 调控选择性剪接，并在以下背景下控制前mRNA靶标的范围 转型。这些因子的过度表达可以促进肿瘤的发生，并显然绕过了 通过控制几个键的特定异构体的表达来实现癌基因合作的要求 癌基因和肿瘤抑制网络的成员。这一机制在肿瘤中的流行 将研究不同类型人类癌症的发展情况，并剖析其具体特征。 并通过对细胞培养中剪接因子的遗传操作和在不同环境中的比较 B细胞淋巴瘤、肝细胞癌和乳腺癌的模型。PRE的显著特点 还将研究剪接机器识别的mrna靶标，以了解 这一过程的机制和特异性，并有助于癌症突变的分类- 导致基因和蛋白质缺陷的易感基因。 通过探索肿瘤发展的新途径，这项研究可能定义有助于早期 检测导致癌症的基因损伤，还可能发现癌症的新靶点 心理治疗。对导致RNA剪接缺陷的突变的改进预测将为治疗提供信息 对于有癌症遗传易感性的个人的决定。

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.