Nuclear functions of the tumor suppressor protein APC

肿瘤抑制蛋白APC的核功能

• 批准号: 7236715
• 负责人: KRISTI L NEUFELD
• 金额: $ 24.18万
• 依托单位: UNIVERSITY OF KANSAS LAWRENCE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-16 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7236715
• 关键词: A Mouse; Adenomatous Polyposis Coli; Adenomatous Polyposis Coli Protein; Adenomatous Polyps; Affect; Animals; Binding; Biological Models; Cell Cycle; Cell Line; Cell Nucleus; Cell Proliferation; Cell division; Cells; Cessation of life; Colon; Colorectal; Colorectal Cancer; Condition; Confocal Microscopy; Cultured Cells; Cytoplasmic Protein; DNA; Defect; Development; Embryo; Endoderm; Epithelial Cell Proliferation; Epithelial Cells; Event; Exhibits; Fluorochrome; Gene Targeting; Generations; Genus Cola; Germ Layers; Growth; Health; Human; Incidence; Intercellular Junctions; Intestines; Knowledge; Large Intestine Carcinoma; Location; Malignant Neoplasms; Malignant neoplasm of lung; Mesoderm; Microtubules; Mitotic; Modeling; Mus; Mutation; Normal Cell; Nuclear; Nuclear Localization Signal; Numbers; Oncogene Proteins; Pathologic; Pattern; Phosphorylation; Physiological; Polyps; Pongidae; Population; Proliferation Marker; Proteins; Rate; Regulation; Relative (related person); Research; Research Personnel; Role; Stem cells; Testing; Therapeutic Intervention; Time; Tissues; Tube; Tumor Suppression; Tumor Suppressor Genes; Tumor Suppressor Proteins; United States; base; beta catenin; carcinogenesis; crypt cell; homologous recombination; improved; indexing; innovation; intestinal crypt; intracellular protein transport; mutation carrier; polyposis; programs; protein distribution; protein function; protein localization location; stem; tumor; tumorigenesis

DESCRIPTION (provided by applicant): Colorectal cancer is the second deadliest malignancy in the United States. Mutation of the adenomatous polyposis coil (Apc) tumor suppressor gene initiates most colorectal carcinomas. However, it is not known how Apc mutation predisposes a cell to polyp development and colorectal carcinogenesis. Although APC is found at cell-cell junctions, binding to microtubules, and in the nuclei, little is known about nuclear APC function. We discovered increased cytoplasmic APC as human colon tissue progressed from normal, to polyp, to tumor. In cultured cells, APC localization responded to cell proliferation and phosphorylation. Furthermore, using this model we found that nuclear APC regulated the activity of the oncoprotein beta-catenin. We hypothesize changes in APC localization, initiated by mutation of the APC nuclear localization signals, will result in concomitant alterations in beta-catenin regulation, proliferation and differentiation at the cellular level, and polyp formation at the tissue level. We will inactivate APC's nuclear localization signals in mouse embryo-derived stem (ES) cells and whole animals to study nuclear APC function under physiological conditions. We will use these two innovative model systems to test directly if nuclear APC is involved in beta-catenin regulation (Aim 1), cellular proliferation (Aim 2), and differentiation (Aim 3). We will perform pathologic examinations on mice lacking nuclear APC to test if nuclear APC functions in tumor suppression (Aim 4). Greater knowledge of APC function in normal cells will improve our understanding of APC's role in tumorigenesis and ultimately illuminate new points for therapeutic intervention.

描述（由申请人提供）：结直肠癌是美国第二大致命恶性肿瘤。腺瘤性息肉病线圈 (Apc) 抑癌基因的突变会引发大多数结直肠癌。然而，目前尚不清楚 Apc 突变如何使细胞容易发生息肉发展和结直肠癌。尽管 APC 存在于细胞与细胞连接处、与微管结合以及细胞核中，但人们对核 APC 功能知之甚少。我们发现，随着人类结肠组织从正常发展为息肉、发展为肿瘤，细胞质 APC 增加。在培养细胞中，APC 定位对细胞增殖和磷酸化作出反应。此外，使用该模型我们发现核 APC 调节癌蛋白 β-连环蛋白的活性。我们假设由 APC 核定位信号突变引发的 APC 定位变化将导致 β-连环蛋白调节、细胞水平上的增殖和分化以及组织水平上息肉形成的伴随改变。 我们将灭活小鼠胚胎干细胞和整个动物中 APC 的核定位信号，以研究生理条件下 APC 的核功能。我们将使用这两个创新模型系统直接测试核 APC 是否参与 β-catenin 调节（目标 1）、细胞增殖（目标 2）和分化（目标 3）。我们将对缺乏核APC的小鼠进行病理检查，以测试核APC是否具有抑制肿瘤的功能（目标4）。对正常细胞中 APC 功能的更多了解将提高我们对 APC 在肿瘤发生中的作用的理解，并最终阐明治疗干预的新观点。