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: 7238864
• 负责人: Eric R. Fearon
• 金额: $ 26.73万
• 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 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7238864
• 关键词: 26S proteasome; Address; Adenomatous Polyposis Coli; Adult; Affect; Behavior; Binding; Cancer Etiology; Cell Survival; Cell physiology; Cell surface; Cells; Clinical; Colon; Colon Carcinoma; Complex; Cyclin D1; Cyclins; Data; Defect; Development; Doctor of Philosophy; Epigenetic Process; Event; Family; Gene Amplification; Gene Expression; Gene Proteins; Gene Targeting; Genes; Genetic; Genus Cola; Glycogen Synthase Kinases; Growth; Human; In Vitro; Knock-out; LDL-Receptor Related Proteins; Life Style; Ligand Binding; Ligands; Low Density Lipoprotein Receptor; MDM2 gene; MDM2 gene; Malignant Neoplasms; Mediating; Modeling; Molecular; Mutation; N-terminal; Nuclear; Numbers; Oncogenes; Oncogenic; Pathogenesis; Pathway interactions; Phenotype; Phosphorylation; Phosphotransferases; Positioning Attribute; Process; Protein p53; Proteins; Proto-Oncogenes; Regulation; Research Personnel; Retinoblastoma; Role; Serine; Shapes; Signal Pathway; Signal Transduction; Structure; System; TCF Transcription Factor; TP53 gene; Threonine; Tissues; Transgenic Mice; Tumor Suppressor Genes; Tumor Suppressor Proteins; base; beta catenin; cancer cell; cell motility; gain of function mutation; insight; loss of function mutation; member; multicatalytic endopeptidase complex; novel diagnostics; novel therapeutics; programs; protein function; receptor; therapeutic target; trait; transcription factor; tumorigenesis

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 是高度保守的分泌蛋白家族，在发育过程中和成体组织中发挥关键作用，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 通路可以说是已发现的 Wnt 依赖性通路中最具特征的，并且经典通路中关键因子的突变与癌症的关系最明显。在经典途径中，β-连环蛋白是重要的效应子，某些 Wnt 配体（例如 Wnt-1）可起到稳定 β-连环蛋白的作用。糖原合酶激酶 3beta (GSK3beta) 蛋白与 Axin 和 APC（腺瘤性息肉病大肠杆菌）肿瘤抑制蛋白和其他激酶协同作用，磷酸化氨基 (N) 末端多个丝氨酸和苏氨酸残基的 β-连环蛋白。磷酸化的 β-连环蛋白迅速泛素化，然后 被26S蛋白酶体降解。 Wnt 配体与 Frizzled-LRP5/6 共受体复合物的结合导致 GSK3beta 抑制，从而导致 β-连环蛋白稳定。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 Axin1 肿瘤抑制因子的失活或激活（致癌）突变 β-连环蛋白的 N 末端磷酸化和降解基序。通过 Wnt 或癌症相关突变实现 β-连环蛋白的稳定会导致 β-连环蛋白核积累，并增强其与 T 细胞因子 (TCF) 转录因子家族的结合。反过来，β-连环蛋白/TCF 复合物调节一系列基因产物的表达，这些基因产物调节细胞命运、增殖和其他 流程。已经提供了涉及 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，例如 c-MYC 和细胞周期蛋白 D1。然而，对于 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了解还远未完成。鉴于此背景，我们提出以下目标：1）继续富有成效地努力识别下游基因 其表达受结肠和其他癌细胞中的 β-catenin/TCF 调节。 2) 利用强大的体外系统来评估选定的β-连环蛋白/TCF靶基因及其蛋白质产物在结肠癌和其他癌症表型改变中的作用。 3) 使用小鼠转基因和敲除模型，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。我们的研究将重点关注导致结肠癌和其他癌细胞表型特征改变的关键分子。还期望深入了解新的癌症诊断标志物以及新的治疗靶点和方法。