The Role of Beta-catenin/Tcf Pathway Defects in Cancer

β-连环蛋白/Tcf 通路缺陷在癌症中的作用

• 批准号: 6985089
• 负责人: Eric R. Fearon
• 金额: $ 28.36万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-06-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6985089
• 关键词: cadherins; cell line; clinical research; colon neoplasms; disease /disorder model; gene expression; gene induction /repression; gene mutation; genetically modified animals; human tissue; in situ hybridization; laboratory mouse; microarray technology; neoplasm /cancer genetics; neoplastic transformation; transcription factor

DESCRIPTION (provided by applicant): The Wnts are a highly conserved family of secreted proteins with critical roles during development and in adult tissues, including functions in regulating cell fate determination, proliferation, cell survival, and motility. Wnts bind to cognate frizzled receptor and LDL-Receptor-Related Protein (LRP) co-receptor complexes on the cell surface and mediate intracellular signaling events through distinct pathways. The "canonical" Wnt pathway is arguably the best characterized of the Wnt-dependent pathways uncovered, and mutations in key factors in the canonical pathway have been most clearly implicated in cancer. In the canonical pathway, the beta-catenin protein is a vital effector, with certain Wnt ligands (e.g., Wnt-1) acting to stabilize beta-catenin. The glycogen synthase kinase 3beta (GSK3beta) protein functions in concert with the Axin and APC (adenomatous polyposis coli) tumor suppressor proteins and other kinases to phosphorylate (-catenin at multiple serine and threonine residues in its amino (N)-terminus. The phosphorylated beta-catenin is rapidly ubiquitinated and then degraded by the 26S proteasome. Wnt ligand binding to the Frizzled-LRP5/6 co- receptor complex leads to GSK3beta inhibition, with resultant beta-catenin stabilization. Mutational mechanisms with major roles in dysregulating beta-catenin in human cancer, include inactivation of the APC or Axin1 tumor suppressors or activating (oncogenic) mutations in beta-catenin's N-terminal phophorylation and degradation motif. Stabilization of beta-catenin via Wnts or cancer-related mutations leads to beta-catenin nuclear accumulation and its enhanced binding to T cell factor (TCF) family of transcription factors. In turn, beta-catenin/TCF complexes regulate expression of the panoply of gene products that regulate cell fate, proliferation, and other processes. Data implicating beta-catenin/TCF in the regulation of specific target genes, including key growth promoting genes, such as c-MYC and cyclin D1, have been offered. However, understanding of the role of beta- catenin/TCF pathway defects in the pathogenesis of colon and other cancers remains far from complete. Given this background, we propose the following aims: 1) To continue productive efforts to identify downstream genes whose expression is regulated by beta-catenin/TCF in colon and other cancer cells. 2) To utilize robust in vitro systems to assess the role of selected beta-catenin/TCF target genes and their protein products in the altered phenotype of colon and other cancers. 3) To continue successful efforts to assess the role of beta-catenin/TCF and selected downstream target genes in tumorigenesis, using mouse transgenic and knockout models. Our studies will highlight critical molecules contributing to the altered phenotypic traits of colon and other cancer cells. Insights into new diagnostic markers and novel therapeutic targets and approaches for cancer are also expected.

描述（由申请人提供）：Wnt是一个高度保守的分泌蛋白家族，在发育和成体组织中具有关键作用，包括调节细胞命运决定、增殖、细胞存活和运动的功能。Wnt与细胞表面上的同源卷曲受体和LDL受体相关蛋白（LRP）共受体复合物结合，并通过不同的途径介导细胞内信号传导事件。“经典”Wnt途径可以说是最好的Wnt依赖性途径的特点，在经典途径中的关键因素的突变已最清楚地涉及癌症。在经典途径中，β-连环蛋白是重要的效应子，具有某些Wnt配体（例如，Wnt-1）起稳定β-连环蛋白的作用。糖原合成酶激酶3 β（GSK 3 β）蛋白与Axin和APC（腺瘤性结肠息肉病）肿瘤抑制蛋白和其它激酶协同作用，以在β-连环蛋白氨基（N）末端的多个丝氨酸和苏氨酸残基处磷酸化β-连环蛋白。磷酸化的β-连环蛋白被迅速泛素化，然后被26 S蛋白酶体降解。Wnt配体与卷曲-LRP 5/6共受体复合物的结合导致GSK 3 β抑制，并产生β-连环蛋白稳定化。在人类癌症中β-连环蛋白失调中起主要作用的突变机制包括APC或Axin 1肿瘤抑制因子的失活或β-连环蛋白的N-末端磷酸化和降解基序中的激活（致癌）突变。通过Wnt或癌症相关突变稳定β-连环蛋白导致β-连环蛋白核积累及其与T细胞因子（TCF）家族转录因子的结合增强。反过来，β-连环蛋白/TCF复合物调节基因产物的表达，这些基因产物调节细胞命运、增殖和其他过程。已经提供了暗示β-连环蛋白/TCF调节特定靶基因的数据，包括关键的生长促进基因，如c-MYC和细胞周期蛋白D1。然而，对β-连环蛋白/TCF通路缺陷在结肠癌和其他癌症发病机制中的作用的理解仍然远未完成。在此背景下，我们提出了以下目标：1）继续进行富有成效的努力，以确定结肠和其他癌细胞中表达受β-连环蛋白/TCF调控的下游基因。2)利用稳健的体外系统评估选定的β-连环蛋白/TCF靶基因及其蛋白产物在结肠癌和其他癌症改变的表型中的作用。3)使用小鼠转基因和基因敲除模型，继续成功评估β-连环蛋白/TCF和选定的下游靶基因在肿瘤发生中的作用。我们的研究将突出有助于改变结肠和其他癌细胞的表型性状的关键分子。对癌症的新诊断标志物和新治疗靶点和方法的见解也是值得期待的。