Wnt signaling in Colon Cancer

结肠癌中的 Wnt 信号传导

• 批准号: 7616676
• 负责人: Marian L Waterman
• 金额: $ 27.5万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7616676
• 关键词: Address; Adenocarcinoma; Binding; Biological Assay; C-terminal; Cancer Etiology; Cell Nucleus; Cells; Colon; Colon Carcinoma; Commuting; DNA Binding; DNA Binding Domain; Development; Dominant-Negative Mutation; Enhancers; Family; Family member; Freezing; Gene Activation; Gene Expression; Gene Expression Regulation; Gene Targeting; Genes; Growth; Human; In Situ Hybridization; Individual; Ions; Laboratories; Lead; Length; Lymphoid; Lymphoid Cell; Malignant Neoplasms; Messenger RNA; Methods; Microarray Analysis; Modeling; Molecular Genetics; Molecular Profiling; Normal tissue morphology; Nuclear; Oncogenic; Paraffin Embedding; Pattern; Phenotype; Play; Protein Isoforms; Proteins; RNA Interference; RNA Splicing; Recombinants; Recruitment Activity; Regulation; Relative (related person); Reporting; Research Personnel; Reverse Transcriptase Polymerase Chain Reaction; Role; Signal Pathway; Signal Transduction; Specificity; TCF Transcription Factor; TCF7L2 gene; Tail; Testing; Tissues; Transcriptional Activation; Transfection; Tumor Tissue; Work; adenoma; base; cancer cell; cell growth; cell transformation; colon cancer cell line; colon carcinogenesis; genetic analysis; member; mutant; programs; protein expression; research study; stable cell line; t-complex polypeptide-1; transcription factor; tumor; tumor progression; tumorigenesis

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.

描述（申请人提供）：结肠癌分子遗传学分析证实Wnt信号通路参与肿瘤早期发展。将Wnt信号转换为靶基因表达变化的转录因子是淋巴细胞增强因子/T细胞因子（LEF/TCF）家族的成员。LEF/ tcf有全长激活型和截断型显性阴性型，也有选择性剪接型。根据以往的工作和其他实验室的结果，提出以下假设。首先，与正常组织相比，全长、激活的tcf亚型在结肠癌中占主导地位的假设将通过定义tcf在正常、腺瘤和腺癌中的表达模式来验证（Specific Aim 1）。其次，本文提出了两种不同的实验来验证先前报道的TCF异构体独特活性的机制（Specific Aim 2）。野生型和突变型TCF蛋白将在DNA结合试验中进行研究。第三，TCF家族成员和同种异构体携带独特的靶基因特异性，对癌症产生不同的影响，这一假设将通过两种不同的策略来测试，这些策略可以破坏结肠癌细胞中的TCF功能。效果将通过全球表达谱和细胞生长和活力测定来评估（Specific Aim 3）。总的来说，提出的工作将解决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。