权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Cdx2 modulates beta-catenin activity in intestinal cells

Cdx2 调节肠细胞中的 β-连环蛋白活性

基本信息

批准号：
7898167
负责人：
JOHN P. LYNCH
金额：
$ 1.11万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-20 至 2010-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7898167
关键词：
Apoptosis Binding Biological Biological Models Biology Cancer Etiology Cell Adhesion Cell Culture System Cell Differentiation process Cell Line Cell Proliferation Cell model Cell-Cell Adhesion Cells Cellular Morphology Colon Carcinoma Columnar Cell Complex Deletion Mutagenesis Disease E-Cadherin Engineering Event Gene Expression Growth Human In Vitro Intestines Knowledge Mediating Modeling Molecular Morphogenesis Morphology Mus Mutate Newly Diagnosed PTPN1 gene Pathogenesis Phosphorylation Phosphorylation Site Polyps Post-Translational Protein Processing Process Proteins Regulation Research Research Personnel Resistance Role SCID Mice Site Testing Transgenic Mice Tyrosine Phosphorylation United States Xenograft procedure adenoviral-mediated angiogenesis base beta catenin cancer cell carbonate dehydratase cell motility colon carcinogenesis domain mapping homeodomain improved in vivo inhibitor/antagonist insight migration mortality neoplastic new therapeutic target novel overexpression programs protein protein interaction transcription factor tumor growth tumor progression

项目摘要

Colon cancer is an important cause of cancer mortality. In the United States, over 150,000 people are newly diagnosed with this disease each year, and one-third of them will ultimately die from their disease. Abnormal regulation of p-catenin levels and function commonly occur during colon carcinogenesis. p-catenin is a multifunctional protein with known roles in enhancing proliferation, inhibiting intestinal cell differentiation and apoptosis, and regulating cell-cell adhesion, angiogenesis, and cell migration. Dysregulation of p-catenin can thus endow a cancer cell with many of the features necessary for colon carcinogenesis. The molecular mechanisms by which normal intestinal cells regulate p-catenin function, and by which cancer cells abrogate this regulation, are not understood. The homeodomain transcription factor Cdx2 is a well-studied regulator of intestine-specific gene expression. Its role in promoting intestinal cell differentiation and regulating proliferation is recognized but the mechanisms remain to be elucidated. Our research has specifically investigated these processes. We have found that Cdx2 inhibits p-catenin/TCF transcriptional activity. Moreover, cancer cells were relatively resistant to Cdx2's effect on p-catenin/TCF. In addition, we have developed a cell culture system to model Cdx2 induction of a polarized, columnar cell morphology in human colonocytes, a novel mechanism attributable to Cdx2. This effect requires a functional E-cadherin/p-catenin complex, and accompanying post- translational modifications of p-catenin. This proposal is directed towards characterizing Cdx2 mediated biological effects upon proliferation and cell-adhesion and will test the following overarching hypothesis: Cdx2 inhibits colonocvte proliferation and promotes morphologic maturation by modulating B-catenin transcriptional and cell-cell adhesion activity. This hypothesis will be pursued by the following inter-related Specific Aims: (1) To investigate the inhibition of p- catenin mediated proliferation by Cdx2, and the resistance to this inhibitory effect in colon cancer cells; and, (2) To characterize the molecular mechanisms for Cdx2-mediated cell-cell adhesion and columnar morphogenesis. This proposal therefore explores the novel roles for Cdx2 in regulating the interdependent processes of cell-cell adhesion, acquisition of a polarized and columnar morphology, and cell-proliferation within the colonocyte. Understanding these mechanisms will improve greatly our knowledge of the molecular events governing normal colonocyte biology, and simultaneously, provide new insights into the molecular pathogenesis of sporadic colon cancer. As a result, potential novel targeted therapeutics mayalso emerge.

结肠癌是癌症死亡的重要原因。在美国，超过15万