INTERACTION OF APC AND P53 IN COLORECTAL CARCINOGENESIS

APC 和 P53 在结直肠癌发生中的相互作用

• 批准号: 2748995
• 负责人: SATYA NARAYAN
• 金额: $ 19.29万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-01-01 至 2001-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2748995
• 关键词: N methyl N' nitro N nitrosoguanidine; apoptosis; carcinogen testing; chemical carcinogenesis; chloramphenicol acetyltransferase; colorectal neoplasms; enzyme activity; enzyme induction /repression; gene interaction; gene mutation; genetic promoter element; human genetic material tag; mutagen testing; mutagens; neoplasm /cancer genetics; p53 gene /protein; phosphoproteins; tissue /cell culture; tumor suppressor genes; tumor suppressor proteins

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。 估计该年有95，600例新病例和47，700例死亡 1998年（美国癌症协会-癌症事实和数字; 2月6日， 1998年）。 腺瘤性息肉病的表达改变 大肠杆菌（APC）抑癌基因与结肠癌预后不良的关系 患者是公认的;然而，对APC的知之甚少 生物功能，几乎没有什么是已知的， APC基因表达的调控。 这个项目的长期目标是 是了解APC基因的调控机制， 其产物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， 在APC和p53基因中。 我们的初步结果表明， APC mRNA的表达在p53依赖性的转录激活中被激活。 通过DNA烷基化剂N-甲基-N '-硝基-N-亚硝基胍 （MNNG）.本研究的目的是阐明 p53依赖性APC转录调控的损伤因子 DNA. 基于我们以前的研究和其他人的工作，我们建议 在对遗传毒性物质产生的信号的反应中， 磷酸化p53蛋白增加并形成转录活性 p53/TFIIH复合物增强APC转录速率，导致 在APC介导的细胞周期阻滞或结肠癌细胞凋亡中。 这一假设将通过以下方式进行检验：1）表征 APC上DNA损伤诱导的p53介导的转录复合物 启动子和用乙酰氯霉素评价其功能 转移酶（CAT）-报告基因表达;和2）分析机制 p53在体外转录中对APC基因调控的研究 系统 我们的研究结果有望建立一个功能之间的联系， APC和p53，两个最常突变的肿瘤抑制基因 参与结肠癌的细胞周期停滞和凋亡。 因此，我们认为， 新的治疗策略可能会出现在潜在的新的 结肠癌化疗干预的靶点。