GKLF/Beta-catenin crosstalk in the intestine

GKLF/β-连环蛋白在肠道中的串扰

• 批准号: 7985874
• 负责人: CHUNMING LIU
• 金额: $ 25.47万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7985874
• 关键词: Address; Adenomatous Polyposis Coli; Binding; Binding Proteins; Biological Assay; C-terminal; Cancer Etiology; Casein Kinase Ialpha; Cell Adhesion; Cell Differentiation process; Cell Nucleus; Cell Proliferation; Cells; Cessation of life; Chromatin Structure; Clinical; Clinical Markers; Colon Carcinoma; Colorectal Cancer; Complex; Cyclin D1; DNA; Data; Development; Disease; Down-Regulation; E-Cadherin; Epithelial Cells; Family; GKLF protein; Gene Targeting; Genes; Genetic Transcription; Glycogen Synthase Kinase 3; Hand; Health; Homeostasis; Human; In Vitro; Intestines; Kruppel-like transcription factors; Lead; Malignant Neoplasms; Mammalian Cell; Membrane; Messenger RNA; Methods; Molecular; Mus; Mutation; Natural regeneration; Neoplasm Metastasis; Nuclear Translocation; Nude Mice; Oncogenes; Pathway interactions; Phosphorylation; Process; Proliferating; Proteins; Proto-Oncogene Proteins c-myc; Publishing; Recruitment Activity; Repression; Research Personnel; Role; Sampling; Signal Pathway; Signal Transduction; Signaling Molecule; Stem cells; TCF Transcription Factor; Testing; Therapeutic Agents; Tissues; Transact; Transcription Coactivator; Tumor Suppressor Proteins; Up-Regulation; base; beta catenin; c-myc Genes; cancer cell; colon cancer cell line; colon carcinogenesis; economic cost; gastrointestinal; insight; mouse model; multidisciplinary; novel therapeutics; overexpression; programs; research study; tumor; tumor growth; tumor progression; tumor xenograft; tumorigenesis; ubiquitin ligase

DESCRIPTION (provided by applicant): The majority of colorectal cancers have mutations of the ARC (adenomatous polyposis coli) tumor supressor gene or the ?-catenin oncogene, causing ?-catenin accumulation that activates other oncogenes. This project will investigate the interaction of ?-catenin and other signaling molecules in the intestine. Gut-enriched Kr¿ppel-like transcriptional factor (GKLF, now called KLF4) is down-regulated in many colon cancer cells and considered to be a candidate tumor suppressor protein; it inhibits intestinal cell proliferation and induces cell differentiation. In contrast, ?-catenin induces intestinal cell proliferation and inhibits differentiation. KLF4 expression is APC-dependent, and its function and expression are inversely correlated with those of ?-catenin. The central hypothesis of this project is that KLF4 inhibits ?-catenin signaling in the differentiated cells; conversely, ?-catenin inhibits KLF4 expression in proliferating cells, so KLF4/??-catenin crosstalk defines the proliferating and differentiating compartments in the intestine. Up- regulation of ?-catenin and down-regulation of KLF4 together contribute to the initiation of colon cancers. To address this hypothesis, we will pursue three Specific Aims, to: 1) Delineate the mechanisms by which KLF4 inhibits ?-catenin signaling using cell-based assays or in vitro-binding assays; 2) Determine the mechanisms of APC-regulated KLF4 expression in colon cancer cells and in the intestines of APC-deleted mice; and 3) assess the functional effects of KLF4/??-catenin interactions in human colorectal cancers and in nude mice injected with colon cancer cells with altered KLF4/??-catenin signaling. These experiments should elucidate the role of this important signaling axis in the development and progression of colorectal cancers, and eventually lead to new clinical markers and treatment approaches for this important class of cancers. Health Relevance: Colorectal cancer is the second leading cause of cancer-related deaths in the U.S., with -150,000 new cases and 57,000 deaths annually (about 10% of all cancer deaths), at an estimated annual economic cost greater than $3.5 billion. A better understanding of the signaling pathways contributing to colorectal cancer progression should provide targets for novel therapeutic agents to treat this disease.

描述（由适用提供）：大多数有色癌症具有弧菌（腺瘤性息肉大肠杆菌）肿瘤supressor基因或？ - 卡坦蛋白癌基因的突变，引起激活其他癌基因的钙蛋白积累。该项目将研究肠道中的？ - 蛋白质和其他信号分子的相互作用。在许多结肠癌细胞中，含肠含量的kr¿ppel样转录因子（GKLF，现在称为KLF4）被下调，被认为是候选肿瘤抑制蛋白。它抑制肠细胞增殖并抑制细胞分化。相比之下，？ - 蛋白质会诱导肠细胞增殖并抑制分化。 KLF4表达与APC依赖性，其功能和表达与-Catenin的功能和表达成反比。该项目的中心假设是klf4抑制了分化细胞中的 - 蛋白酶信号传导。相反，？ - 蛋白质抑制了增殖细胞中的KLF4表达，因此KLF4/?? - catenin串扰定义了肠中的增殖和区分隔室。 klf4的 - 蛋白质和下调的上调共同有助于结肠癌的倡议。为了解决这一假设，我们将追求三个特定的目的，以：1）描述KLF4使用基于细胞的测定或体外结合测定的机制抑制KLF4的机制； 2）确定在结肠癌细胞和APC缺失小鼠的肠中受APC调节的KLF4表达的机制； 3）评估人类结直肠癌中KLF4/?? - catenin相互作用的功能效应，以及注入了klf4/?? - catenin信号传导的结肠癌细胞的裸小鼠中。这些实验应阐明这一重要信号轴在有色癌症的发展和发展中的作用，并最终导致这种重要类癌症类别的新临床标记和治疗方法。健康相关性：结直肠癌是美国与癌症相关死亡的第二大主要原因，每年为-150,000例新病例和57,000例死亡（约占所有癌症死亡的10％），年度经济成本估计超过35亿美元。更好地了解导致大肠癌进展的信号通路应为新型治疗剂提供治疗该疾病的靶标。