p53与RCC2反馈调节网络研究及其对结肠癌转移的影响

p53, a potent tumor suppressor, exerts its function through transcriptional activation or suppression of its target genes by binding to their response elements (RE) within promoter regions. Our previous work identified a new potential target gene named RCC2, which may be regulated by p53 through a non-canonical RE and play an important role in repressing epithelial-mesenchymal transition (EMT) process during metastasis of colon cancer. Furthermore, we found that p53 and RCC2 can interact with each other at protein level and this interaction helps to maintain p53 expression level, which indicates a special feed-forward loop between these two proteins. In this proposal, we will take advantage of RCC2 conditional knockout mice model and molecular biological techniques to investigate the molecular network between p53 and RCC2 and evaluate its role in the tumorigenesis and metastasis of colon cancer, with the purpose of illuminating p53's function in the regulation of EMT process through protein-coding genes. Meanwhile we will identify a novel RE recognized by p53 and its role in p53 regulation pathway. Accomplishment of this project will improve our understanding the p53 regulation network and provide theoretic foundation for individual therapy strategy and prognosis of colon cancer.

p53是最著名的抑癌基因，可与下游靶基因的启动子区反应元件结合，从转录水平调节基因表达水平。我们的前期实验发现p53可通过非经典反应元件结构调控一个新的靶基因RCC2，并预测其在结肠癌转移的EMT过程中发挥抑制作用。此外，RCC2蛋白还可与p53蛋白结合并促进其表达，显示两蛋白间可能形成独特的正反馈调节回路。本项目将利用分子生物学手段以及RCC2基因敲除小鼠等动物模型对RCC2和p53开展深入研究，旨在揭示p53与RCC2间的新的分子调控网络并评价其对结肠癌形成及转移的影响，进一步扩展对p53通过蛋白编码基因参与调控EMT过程的研究认识。我们还将鉴定出p53可识别的一个特殊反应元件结构并明确其对p53调控的作用。预期此项研究将完善p53调控网络并为结肠癌的个体化治疗及预后评价提供理论依据。