Gastrointestinal Cell Proliferation and Cell Cycle

胃肠细胞增殖和细胞周期

• 批准号: 8052539
• 负责人: Lopa Mishra
• 金额: $ 2.22万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 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 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8052539
• 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因子。细胞周期蛋白依赖性激酶（cdks）和c-myc的tgf - β依赖性抑制与G1阻滞的信号传导和调节通过Smads发生。Smad2、SmadS和Smad4是参与胃肠道细胞增殖的关键蛋白。Smad2和Smad4的种系突变导致个体易患胃肠道癌。我们已经证明elf的破坏，β -幽灵素通过smad和Smad4破坏tgf - β信号。此外，elf和Smad4的双杂合子（elf+/-/Smad4+/-）更早发生胃增生和肿瘤。为了进一步了解elf/Smad4在细胞周期调节和肿瘤形成中的作用，我们建议：(1)对elf/~/Smad4+/-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、细胞衰老能力、胃细胞和成纤维细胞对凋亡刺激的易感性的影响；以及胃癌细胞和mef对癌基因转化的易感性。(2)确定elf/Smad4+/-小鼠对肿瘤发生易感性增强的分子基础，确定导致肿瘤形成的继发事件的性质。(3)利用elf+/-/Smad4+/-和Smad4+/-小鼠和p53缺失小鼠，研究elf/Smad4和p53通路之间的协同作用。(4)将Aim 1中描述的实验扩展到整个动物模型系统，确定elf/~/Smad4+/-和Smad4+/-小鼠在接受化学致癌物如MNU和/或DMBA以及幽门螺杆菌VacA毒素治疗后对肿瘤发展的易感性增强，并开展旨在确定elf/'/Smad4+/-和Smad4+/-小鼠肿瘤易感性增强的分子基础的实验。

项目成果

Identification of microRNAs specifically expressed in hepatitis C virus-associated hepatocellular carcinoma.

• DOI: 10.1002/ijc.28075
• 发表时间: 2013-08-15
• 期刊: INTERNATIONAL JOURNAL OF CANCER
• 影响因子: 6.4
• 作者: Diaz, Giacomo;Melis, Marta;Tice, Ashley;Kleiner, David E.;Mishra, Lopa;Zamboni, Fausto;Farci, Patrizia
• 通讯作者: Farci, Patrizia

Liver regeneration signature in hepatitis B virus (HBV)-associated acute liver failure identified by gene expression profiling.

• DOI: 10.1371/journal.pone.0049611
• 发表时间: 2012
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Nissim O;Melis M;Diaz G;Kleiner DE;Tice A;Fantola G;Zamboni F;Mishra L;Farci P
• 通讯作者: Farci P

TGF-β signaling in liver and gastrointestinal cancers.

肝脏和胃肠道癌中的TGF-β信号传导。

• DOI: 10.1016/j.canlet.2016.03.033
• 发表时间: 2016-09-01
• 期刊: CANCER LETTERS
• 影响因子: 9.7
• 作者: Katz, L. H.;Likhter, M.;Jogunoori, W.;Belkin, M.;Ohshiro, K.;Mishra, L.
• 通讯作者: Mishra, L.

Vitamin D Deficiency Promotes Liver Tumor Growth in Transforming Growth Factor-β/Smad3-Deficient Mice Through Wnt and Toll-like Receptor 7 Pathway Modulation.

• DOI: 10.1038/srep30217
• 发表时间: 2016-07-26
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Chen J;Katz LH;Muñoz NM;Gu S;Shin JH;Jogunoori WS;Lee MH;Belkin MD;Kim SB;White JC;Andricovich J;Tzatsos A;Li S;Kim SS;Shetty K;Mishra B;Rashid A;Lee JS;Mishra L
• 通讯作者: Mishra L