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INTERACTION OF APC AND P53 IN COLORECTAL CARCINOGENESIS

APC 和 P53 在结直肠癌发生中的相互作用

基本信息

批准号：
6350294
负责人：
SATYA NARAYAN
金额：
$ 19.36万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-01-01 至 2003-01-31
项目状态：
已结题

项目摘要

Colon cancer is the second most frequent cancer diagnosed in the United States, with an estimated 95,600 new cases and 47,700 deaths in the year 1998 (American Cancer Society - Cancer Facts and Figures; February 6, 1998). The association of altered expression of adenomatous polyposis coli (APC) tumor suppressor gene with poor prognosis in colon cancer patients is well established; however, little is known about APC's biological functions, and virtually nothing is known concerning the regulation of APC gene expression. The long-term goal of this project is to understand the mechanisms by which the APC gene is regulated, and the function of its product in normal and cancer cells. Development of colon cancer is a multistep process that frequently involves mutations in both the APC and p53 genes. Our preliminary results indicate that expression of APC mRNA is transcriptionally activated in a p53-dependent manner by the DNA-alkylating agent N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). The objective of this study is to elucidate the mechanisms of p53-dependent transcriptional regulation of APC by agents that damage DNA. Based on our prior studies and the work of others, we propose that, in response to signals generated by genotoxic agents, levels of phosphorylated p53 protein increase and form transcriptionally active p53/TFIIH complex that enhance the rate of APC transcription, resulting in APC-mediated cell cycle arrest or apoptosis of colon cancer cells. This hypothesis will be tested by: 1) characterizing the assembly of the DNA damage-induced, p53-mediated transcriptional complex on the APC promoter and evaluating its functions by using a chloramphenicol acetyl transferase (CAT)-reporter expression; and 2) analyzing the mechanisms of APC gene regulation by p53 in an in vitro run-off transcription system. Our results are expected to establish a functional link between APC and p53, the two most frequently mutated tumor suppressor genes involved in cell cycle arrest and apoptosis in colon cancer. Therefore, novel therapeutic strategies may emerge with respect to potential new targets for chemotherapeutic intervention in colon cancer.

结肠癌是美国第二常见的癌症各州，今年预计新增病例 95,600 例，死亡 47,700 例 1998 年（美国癌症协会 - 癌症事实和数据；2 月 6 日， 1998）。腺瘤性息肉病表达改变的关联大肠杆菌（APC）抑癌基因与结肠癌预后不良患者已建立良好的基础；然而，人们对 APC 知之甚少生物学功能，而实际上对它一无所知 APC 基因表达的调控。本项目的长期目标是为了了解 APC 基因的调节机制，以及其产品在正常细胞和癌细胞中的功能。发展结肠癌是一个多步骤的过程，经常涉及突变存在于 APC 和 p53 基因中。我们的初步结果表明 APC mRNA 的表达在 p53 依赖性细胞中被转录激活 DNA烷化剂N-甲基-N'-硝基-N-亚硝基胍的方式（MNNG）。本研究的目的是阐明其机制损伤因子对 APC 的 p53 依赖性转录调控脱氧核糖核酸。根据我们之前的研究和其他人的工作，我们建议响应于基因毒剂产生的信号，磷酸化 p53 蛋白增加并形成转录活性 p53/TFIIH 复合物可增强 APC 转录率，从而产生 APC 介导的结肠癌细胞的细胞周期停滞或凋亡。该假设将通过以下方式进行检验：1）表征 APC 上 DNA 损伤诱导、p53 介导的转录复合物启动子并使用乙酰氯霉素评估其功能转移酶（CAT）-报告基因表达； 2）分析机制体外径流转录中 p53 对 APC 基因的调控系统。我们的结果预计将在两者之间建立功能联系 APC 和 p53，两个最常突变的抑癌基因参与结肠癌的细胞周期停滞和细胞凋亡。所以，关于潜在的新治疗策略可能会出现结肠癌化疗干预的目标。