Expression of Simian Virus 40 T antigens in Intestine

猿猴病毒40 T抗原在肠道中的表达

• 批准号: 7231473
• 负责人: JAMES M PIPAS
• 金额: $ 30.87万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7231473
• 关键词: Age; Antigen Targeting; Antigens; Apoptosis; Binding; Carcinoma; Cell Cycle; Cell Death; Cell Proliferation; Cells; Cessation of life; Complex; Cyclin A; Development; Dysplasia; Enterocytes; Exhibits; Family; Genes; Genetic Transcription; Goals; Growth; Hyperplasia; Intestinal Intraepithelial Neoplasia; Intestines; Large T Antigen; Lead; Length; Mesenchyme; Mus; Mutation; Numbers; Oncogene Proteins; Pathway interactions; Pattern; Phase; Phosphoric Monoester Hydrolases; Play; Population; Proliferating; Protein p53; Proteins; Range; Regulation; Repression; Research Personnel; Retinoblastoma Protein; Role; Series; Simian virus 40; Small T Antigen; Stem cells; System; TP53 gene; Tissues; Transcriptional Activation; Transgenic Mice; Transgenic Organisms; Tumor Suppressor Proteins; Villus; Viral Tumor Antigens; Virus; cell growth; cell type; cellular targeting; genetic regulatory protein; intestinal crypt; intestinal villi; mRNA Expression; member; mutant; novel; research study; response; sialosyl-T antigen; size; tool; transcription factor; tumorigenesis

DESCRIPTION (provided by applicant): We have been using the 708 large T antigen encoded by simian virus 40 (SV40) to probe mechanisms of cell proliferation and death. T antigen is sufficient to induce transformation in a number of cell-types in culture. However, in transgenic mouse systems the effect of T antigen expression is cell-type dependent with responses ranging from induction of hyperplasia or carcinoma to cell death. Furthermore, T antigen possesses multiple transforming functions and which function(s) is(are) required for transformation also depends on the cell-type. We have been studying the mouse intestine to explore the regulation of cellular growth control. The intestine consists of the crypts, which contain stem cells and a proliferating cell population, and the villi, which are composed of growth-arrested, terminally differentiated cells. Expression of large T antigen in enterocytes induces their reentry into the cell cycle resulting in an intestinal hyperplasia that is dependent upon the interaction of T antigen with the Rb-family of tumor suppressors. Furthermore, an amino-terminal fragment of T antigen (dl1137) that inactivates Rb but is missing the p53 interaction domain, also induces hyperplasia. We conclude that the induction of enterocyte proliferation requires an interaction of T antigen with one or more members of the Rb-family. Interestingly, while the intestines of mice expressing dl1137 remain at hyperplasia, those expressing wild-type T antigen progress with age to dysplasia. Thus, dysplasia requires carboxy-terminal of T antigen. We have shown that T antigen interaction with p53 does not play a role in either induction of hyperplasia or dysplasia. In this application, we seek to: (1) understand the mechanism of T antigen-induced hyperplasia; and, (2) identify the T antigen target and cellular pathway(s) required for progression to dysplasia.

描述（由申请人提供）：我们一直在使用由猿猴病毒40（SV 40）编码的708大T抗原来探测细胞增殖和死亡的机制。T抗原足以在培养物中的许多细胞类型中诱导转化。然而，在转基因小鼠系统中，T抗原表达的作用是细胞类型依赖性的，反应范围从诱导增生或癌细胞死亡。此外，T抗原具有多种转化功能，并且转化所需的功能也取决于细胞类型。我们一直在研究小鼠肠道，以探索细胞生长控制的调节。肠由含有干细胞和增殖细胞群的隐窝和由生长停滞的终末分化细胞组成的绒毛组成。肠上皮细胞中大T抗原的表达诱导它们重新进入细胞周期，导致肠增生，这依赖于T抗原与Rb家族的肿瘤抑制因子的相互作用。此外，使Rb失活但缺失p53相互作用结构域的T抗原的氨基末端片段（dl 1137）也诱导增生。我们得出结论，肠上皮细胞增殖的诱导需要T抗原与Rb家族的一个或多个成员的相互作用。有趣的是，虽然表达dl 1137的小鼠的肠道仍处于增生状态，但表达野生型T抗原的小鼠随着年龄的增长而发育不良。因此，发育异常需要T抗原的羧基末端。我们已经表明，T抗原与p53的相互作用不起作用，无论是诱导增生或异型增生。在本申请中，我们寻求：（1）了解T抗原诱导的增生机制;和（2）鉴定进展为发育不良所需的T抗原靶标和细胞途径。