Wnt signaling in Colon Cancer

描述（由申请人提供）：结肠癌的分子遗传学分析已经确定Wnt信号通路参与早期肿瘤发展。 将Wnt信号转换为靶基因表达变化的转录因子是类淋巴细胞增强因子/T细胞因子（LEF/TCF）家族的成员。 LEF/TCF有全长激活型和截短显性负性形式以及选择性剪接亚型。 根据以前的工作和其他实验室的结果，提出了以下假设。 首先，将通过定义TCF在正常、腺瘤和腺癌中的表达模式来检验TCF的全长活化亚型在结肠癌中占主导地位的假设（具体目标1）。 其次，实验提出了两个不同的假设，以测试机制的基础上先前报道的独特活动的TCF亚型（具体目标2）。 将在DNA结合试验中研究野生型和突变型TCF蛋白。 第三，TCF家族成员和同种型携带独特的靶基因特异性以在癌症中赋予不同的作用的假设将通过两种不同的破坏结肠癌细胞中TCF功能的策略来测试。 将通过总体表达谱和细胞生长和活力试验（特定目标3）评估效应。 总的来说，这项工作将解决TCF蛋白在指导Wnt信号向细胞转化和癌症进展中所起作用的重要未知因素。

DESCRIPTION (provided by applicant): Molecular genetic analysis of colon cancers has established that Wnt signaling pathway is involved in early tumor development. The transcription factors that commute Wnt signals into changes in target gene expression are members of the Lymphoid Enhancer Facto/T Cell Factor (LEF/TCF) family. There are full-length activating, and truncated dominant negative forms of LEF/TCFs as well as alternatively spliced isoforms. Based on previous work and results from other laboratories the following hypotheses are proposed. First, the hypothesis that full-length, activating isoforms of TCFs predominate in colon cancer as compared to normal tissue will be tested by defining the expression patterns of TCFs in normal, adenoma and adenocarcinomas (Specific Aim 1). Second, experiments are proposed to test two different hypotheses for the mechanism underlying previously reported unique activities of TCF isoforms (Specific Aim 2). Wild type and mutant TCF proteins will be studied in DNA binding assays. Third, the hypothesis that TCF family members and isoforms carry unique target gene specificities to impart distinct effects in cancer will be tested by two different strategies that disrupt TCF function in colon cancer cells. Effects will be assessed by global expression profiles and cell growth and viability assays (Specific Aim 3). Collectively, the work proposed will address important unknowns about the role that TCF proteins play in directing Wnt signals toward cell transformation and cancer progression.