Regulation of TCF3 by Wnt signaling

Wnt 信号传导对 TCF3 的调节

• 批准号: 8077039
• 负责人: Sergei Sokol
• 金额: $ 41.41万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8077039
• 关键词: Adult; Attention; Biochemical; Biological; Biological Assay; Cell Death; Cell Differentiation process; Cell Proliferation; Cell Proliferation Regulation; Cells; Colon Carcinoma; Complex; Cutaneous Melanoma; DNA; Determination of Death; Development; Disease; Ectoderm Cell; Embryo; Embryonic Development; Family; Gene Activation; Gene Expression; Gene Expression Regulation; Gene Targeting; Genetic; Genetic Transcription; Goals; Homeostasis; Human; Knowledge; Lead; Ligands; Malignant Neoplasms; Mammalian Cell; Mediating; Modification; Molecular; Pathway interactions; Pattern; Phosphorylation; Play; Post-Translational Protein Processing; Preclinical Drug Evaluation; Protein Kinase; Proteins; Regulation; Research; Role; Signal Pathway; Signal Transduction; Site; Skin Neoplasms; TCF Transcription Factor; TCF3 gene; Testing; Therapeutic; Tissues; Transcription Repressor/Corepressor; Vertebrates; Wnt proteins; Xenopus; base; blastomere structure; cell behavior; cell fate specification; cofactor; egg; expression cloning; gene repression; homeodomain; loss of function; member; mutant; novel; overexpression; receptor; research study; response; tumor; tumorigenesis

DESCRIPTION (provided by applicant): The T-cell factor (TCF) family plays key roles in the control of gene expression in response to secreted Wnt proteins. Wnt pathways operate to modulate cell proliferation, migratory behavior, cell fate determination and cell death. This proposal aims to study the regulation of TCF3, a transcriptional repressor which has been implicated in Wnt signaling during cell differentiation and tumorigenesis. Our preliminary experiments in Xenopus ectoderm and mammalian cells identified a specific post-translational change in TCF3 protein mobility that correlates with Wnt target gene activation. This effect has been demonstrated to involve homeodomain-interacting protein kinase (HIPK), leading to a hypothesis that Wnt proteins act via HIPK2 and TCF3 to regulate their transcriptional targets. This hypothesis will be tested in mammalian cells and Xenopus eggs, in which biochemical and cell biological approaches can be combined with rapid functional analysis of underlying mechanisms. To investigate roles of TCF3 postranslational modification for Wnt-dependent activation of target genes, non- phosphorylatable and phosphomimetic TCF3 mutant proteins will be compared in morphological and molecular assays. Other experiments will elucidate how Wnt signals activate HIPK and trigger TCF3 post-translational modifications that are critical for target gene regulation. These studies will help characterize basic signaling networks normally leading to cell proliferation and differentiation, but which are misregulated during disease. Given the association of Wnt pathways with cancer, the knowledge of how TCF3 is regulated will serve as a basis for new drug screens and should lead to the development of crucial therapeutic strategies. PUBLIC HEALTH RELEVANCE: This application concerns the function of TCF3, a Wnt-dependent transcriptional repressor that is essential for the regulation of cell proliferation. Since Wnt pathways have been found activated in a variety of tumors, the proposed studies are highly relevant to human cancer.

描述（由申请人提供）：T细胞因子（TCF）家族在响应分泌的Wnt蛋白的基因表达控制中起关键作用。Wnt途径调节细胞增殖、迁移行为、细胞命运决定和细胞死亡。该提案旨在研究TCF 3的调节，TCF 3是一种转录抑制因子，在细胞分化和肿瘤发生期间参与Wnt信号传导。我们在非洲爪蟾外胚层和哺乳动物细胞中的初步实验确定了与Wnt靶基因激活相关的TCF 3蛋白迁移率的特定翻译后变化。这种效应已被证明涉及同源域相互作用蛋白激酶（HIPK），从而导致Wnt蛋白通过HIPK2和TCF 3调节其转录靶点的假设。这一假设将在哺乳动物细胞和非洲爪蟾卵中进行测试，其中生物化学和细胞生物学方法可以与潜在机制的快速功能分析相结合。为了研究TCF 3翻译后修饰对靶基因的Wnt依赖性活化的作用，将在形态学和分子测定中比较不可磷酸化的和磷酸化模拟的TCF 3突变蛋白。其他实验将阐明Wnt信号如何激活HIPK并触发对靶基因调控至关重要的TCF 3翻译后修饰。这些研究将有助于表征通常导致细胞增殖和分化的基本信号网络，但这些网络在疾病期间被错误调节。鉴于Wnt通路与癌症的关联，TCF3如何调节的知识将作为新药筛选的基础，并应导致关键治疗策略的开发。 公共卫生相关性：本申请涉及TCF 3的功能，TCF 3是一种Wnt依赖性转录抑制因子，对细胞增殖的调节至关重要。由于已发现Wnt通路在多种肿瘤中被激活，因此拟议的研究与人类癌症高度相关。