GKLF/Beta-catenin crosstalk in the intestine

GKLF/β-连环蛋白在肠道中的串扰

基本信息

批准号：
8107647
负责人：
CHUNMING LIU
金额：
$ 24.96万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-01 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8107647
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 Clinical Treatment 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 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 overexpression programs research study tumor tumor growth tumor progression tumor xenograft tumorigenesis ubiquitin ligase

项目摘要

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（由申请人提供）：大多数结直肠癌具有 ARC（腺瘤性结肠息肉病）肿瘤抑制基因或 β-连环蛋白致癌基因的突变，导致 β-连环蛋白积累，从而激活其他癌基因。该项目将研究 ? 连环蛋白的相互作用。 -肠道中富含连环蛋白和其他信号分子。 ppel 样转录因子（GKLF，现在称为 KLF4）在许多结肠癌细胞中下调，被认为是候选肿瘤抑制蛋白；它抑制肠细胞增殖并诱导细胞分化，相反，β-连环蛋白诱导肠细胞。 KLF4 的表达是 APC 依赖性的，并且其功能和表达与 β-catenin 的功能和表达呈负相关。该项目的中心假设是 KLF4 抑制 β-catenin 信号转导。分化细胞；相反，β-连环蛋白抑制增殖细胞中的 KLF4 表达，因此 KLF4/β-连环蛋白串扰定义了肠道中的增殖和分化区室。为了解决这一假设，我们将追求三个具体目标：1) 描述 KLF4 抑制 β-连环蛋白的机制。使用基于细胞的测定或体外结合测定进行信号传导；2) 确定结肠癌细胞和 APC 缺失小鼠肠道中 APC 调节的 KLF4 表达的机制；以及 3) 评估 KLF4/?? 的功能作用。 -连环蛋白在人类结直肠癌和注射了具有改变的 KLF4/β-连环蛋白信号传导的结肠癌细胞的裸鼠中的相互作用，这些实验应该阐明这一重要信号传导轴在发育中的作用。结直肠癌的发生和进展，并最终为这一类重要癌症带来新的临床标志物和治疗方法。健康相关性：结直肠癌是美国癌症相关死亡的第二大原因，有 -150,000 例新病例和 57,000 例死亡。每年（约占所有癌症死亡的 10%），估计每年的经济成本超过 35 亿美元。治疗这种疾病的新治疗剂。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Quantification of trans-2,6-difluoro-4'-N,N-dimethylaminostilbene in rat plasma: application to a pharmacokinetic study.

大鼠血浆中反式 2,6-二氟-4-N,N-二甲氨基芪的定量：在药代动力学研究中的应用。

DOI：
发表时间：
2013-01
期刊：
影响因子：
0
作者：
Lin, Hai-Shu;Sviripa, Vitaliy M.;Watt, David S.;Liu, Chunming;Xiang, Tian-Xiang;Anderson, Bradley D.;Ong, Pei Shi;Ho, Paul C.
通讯作者：
Ho, Paul C.

Regulation of the potential marker for intestinal cells, Bmi1, by β-catenin and the zinc finger protein KLF4: implications for colon cancer.

β-连环蛋白和锌指蛋白 KLF4 对肠细胞潜在标记物 Bmi1 的调节：对结肠癌的影响。

DOI：
发表时间：
2012-02-03
期刊：
影响因子：
0
作者：
Yu, Tianxin;Chen, Xi;Zhang, Wen;Colon, Deannon;Shi, Jiandang;Napier, Dana;Rychahou, Piotr;Lu, Wange;Lee, Eun Y;Weiss, Heidi L;Evers, B Mark;Liu, Chunming
通讯作者：
Liu, Chunming

Kruppel-like factor 4 regulates intestinal epithelial cell morphology and polarity.

Kruppel 样因子 4 调节肠上皮细胞形态和极性。