Cdx2 modulates beta-catenin activity in intestinal cells

Cdx2 调节肠细胞中的 β-连环蛋白活性

• 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
• 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

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 150,000 每年都会新诊断出患有这种疾病的人，其中三分之一最终会死亡 来自他们的疾病。 p-连环蛋白水平和功能的异常调节通常发生在 结肠癌发生。 p-连环蛋白是一种多功能蛋白质，已知在增强 增殖，抑制肠细胞分化和凋亡，调节细胞间粘附， 血管生成和细胞迁移。因此，p-连环蛋白的失调可以赋予癌细胞 结肠癌发生所必需的许多特征。其分子机制 正常肠道细胞调节β-连环蛋白功能，而癌细胞则通过该功能消除这种功能 监管，不理解。同源域转录因子 Cdx2 是经过充分研究的 肠道特异性基因表达的调节因子。其具有促进肠细胞分化和 调节增殖已得到认可，但其机制仍有待阐明。我们的研究 专门研究了这些过程。我们发现 Cdx2 抑制 p-catenin/TCF 转录活性。此外，癌细胞对 Cdx2 的作用相对有抵抗力。 p-连环蛋白/TCF。此外，我们还开发了一种细胞培养系统来模拟 Cdx2 诱导 人类结肠细胞中的极化柱状细胞形态，这是一种新机制 cdx2。这种效应需要功能性的E-钙粘蛋白/β-连环蛋白复合物，以及伴随的后- p-连环蛋白的翻译修饰。该提案旨在表征 Cdx2 介导对增殖和细胞粘附的生物效应，并将测试以下内容 总体假设：Cdx2 抑制结肠细胞增殖并促进形态学 通过调节 B-连环蛋白转录和细胞间粘附活性来成熟。这个假设 将通过以下相互关联的具体目标来追求：（1）研究 p- 的抑制作用 连环蛋白通过 Cdx2 介导的增殖，以及结肠癌中对此抑制作用的抵抗 细胞； (2) 表征 Cdx2 介导的细胞间粘附的分子机制和 柱状形态发生。因此，本提案探讨了 Cdx2 在调节中的新作用 细胞与细胞粘附的相互依赖过程，获得极化和柱状 结肠细胞内的形态和细胞增殖。了解这些机制将 极大地提高我们对控制正常结肠细胞生物学的分子事件的了解，并且 同时，为散发性结肠癌的分子发病机制提供新的见解。作为 因此，潜在的新型靶向疗法也可能出现。