Gastrointestinal Cell Proliferation and Cell Cycle

胃肠细胞增殖和细胞周期

• 批准号: 7615576
• 负责人: Lopa Mishra
• 金额: $ 29.21万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2010-03-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7615576
• 关键词: Adaptor Signaling Protein; Age; Animal Model; Animals; Antineoplastic Agents; Apoptotic; Biological Assay; Biological Models; Breeding; C-terminal; Carcinogens; Carcinoma; Cell Cycle; Cell Cycle Kinetics; Cell Cycle Progression; Cell Cycle Regulation; Cell Proliferation; Cells; Chemical Agents; Collaborations; Cyclin A; Cyclin-Dependent Kinases; Cyclins; Cytoplasmic Tail; Defect; Development; Down-Regulation; Embryo; Epithelial; Event; Exhibits; Fibroblasts; G1 Arrest; Gastric mucosa; Genes; Germ-Line Mutation; Growth; Haploidy; Helicobacter pylori; Hematopoietic; Heterozygote; Human; Hyperplasia; Individual; Intestinal Cancer; Intestines; Lead; Longevity; Lymphocyte; Malignant Neoplasms; Mammalian Cell; Mediating; Mesenchymal; Methylnitrosourea; Modeling; Molecular; Mouse Strains; Mus; Mutant Strains Mice; Mutation; Nature; Neoplasms; Neoplastic Cell Transformation; Nuclear Translocation; Oncogenes; Pathway interactions; Phase; Phenotype; Phosphorylation; Predisposition; Primary carcinoma of the liver cells; Principal Investigator; Property; Protein p53; Proteins; Regulation; Resistance; Role; Signal Transduction; Smad Proteins; Smad protein; Spectrin; Stimulus; Stomach; Stomach Carcinoma; Stomach Neoplasms; TP53 gene; Testing; Time; Toxin; Transforming Growth Factor beta; base; beta Spectrin; blastomere structure; c-myc Genes; cancer cell; carcinogenesis; chemical carcinogen; cyclin D2; cyclin D3; dimethylbenzanthracene; gastrointestinal; gastrointestinal carcinoma; insight; interest; mutant; null mutation; overexpression; p53 Signaling Pathway; polymerization; programs; receptor; relating to nervous system; research study; response; senescence; treatment strategy; tumor; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): TGF-beta is an important regulator of G1/S cell cycle progression of mammalian cells in culture. Signaling and modulation of TGF-beta dependent inhibition of cyclin-dependent kinases (cdks) and c-myc with G1 arrest, occurs through Smads. Smad2, SmadS and Smad4 are key proteins involved in gastrointestinal cell proliferation. Germline mutations in Smad2 and Smad4 result in a predisposition of the individuals to the development of gastrointestinal carcinoma. We have shown that disruption of elf, a beta-Spectrin disrupts TGF-beta signaling through SmadS and Smad4. Moreover, double heterozygotes of elf and Smad4 (elf+/-/Smad4+/-) develop earlier gastric hyperplasia and tumors. To gain further insight into the role of elf/Smad4 in cell cycle regulation and neoplasia, we propose: (1) to carry out a detailed characterization of gastric cells and mouse embryonic fibroblasts (MEFs) derived from elf/~/Smad4+/- mice to determine the effect of loss of ELF on cell cycle kinetics, ability of these cells to undergo senescence, susceptibility of gastric cells and fibroblasts to apoptotic stimuli; and susceptibility of gastric cells and MEFs to neoplastic transformation by oncogenes. (2) To determine the molecular basis for the enhanced susceptibility of the elf/Smad4+/- mice to the development of tumors and determine the nature of secondary events that lead to tumor formation. (3) To investigate the collaboration between the elf/Smad4 and p53 pathways, using elf+/-/Smad4+/- and Smad4+/- mice and mice deficient in p53. (4) To extend experiments described in Aim 1 to whole animal model systems by determining enhanced susceptibility of the elf/~/Smad4+/- and Smad4+/- mice to the development of carcinomas following treatment with chemical carcinogens such as MNU and/or DMBA, and H. pylori VacA toxin, and carrying out experiments aimed at determining the molecular basis for enhanced susceptibility to neoplasia in the elf/'/Smad4+/- and Smad4+/- mice.

描述（由申请人提供）：TGF-β是培养的哺乳动物细胞G1/S细胞周期进程的重要调节剂。信号传导和调节TGF-β依赖性抑制细胞周期蛋白依赖性激酶（cdks）和c-myc与G1期阻滞，发生通过Smads。Smad 2、SmadS和Smad 4是参与胃肠道细胞增殖的关键蛋白。Smad 2和Smad 4的生殖系突变导致个体发生胃肠道癌的易感性。我们已经证明，elf的破坏，β-Spectrin通过SmadS和Smad 4破坏TGF-β信号传导。此外，elf和Smad 4的双杂合子（elf+/-/Smad 4 +/-）更早地发生胃增生和肿瘤。为了进一步了解elf/Smad 4在细胞周期调控和肿瘤形成中的作用，我们提出：（1）对elf/~/Smad 4 +/-小鼠的胃细胞和小鼠胚胎成纤维细胞（MEFs）进行详细的表征，以确定ELF缺失对细胞周期动力学、这些细胞经历衰老的能力、胃细胞和成纤维细胞对凋亡刺激的敏感性的影响;以及胃细胞和MEFs对癌基因引起的肿瘤转化的易感性。(2)确定elf/Smad 4 +/-小鼠对肿瘤发展的易感性增强的分子基础，并确定导致肿瘤形成的继发事件的性质。(3)使用elf+/-/Smad 4 +/-和Smad 4 +/-小鼠和p53缺陷小鼠研究elf/Smad 4和p53通路之间的协作。(4)通过测定elf/~/Smad 4 +/-和Smad 4 +/-小鼠在用化学致癌物如MNU和/或DMBA和H. pylori VacA毒素，并进行旨在确定在elf/Smad 4 +/-和Smad 4 +/-小鼠中对瘤形成的增强的易感性的分子基础的实验。