INTERACTION OF APC AND P53 IN COLORECTAL CARCINOGENESIS

点击翻译按钮获取中文摘要

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.