CPEB2-p53负反馈环路在肾癌中的作用及机制研究

p53是重要的抑癌基因，研究p53如何被调控对了解癌症的发病机理和防治具有重要意义。申请者经微阵列芯片筛选并证实RNA结合蛋白CPEB2是p53直接靶基因，同时CPEB2高表达显著抑制p53；CPEB2在肾癌组织中明显高表达且与患者生存期呈负相关，能显著促进肾癌细胞增殖。据此提出科学假说：p53转录激活CPEB2，CPEB2通过影响mRNA稳定性从而抑制p53，形成CPEB2-p53负反馈调控环路，在肾癌发生发展中发挥着重要作用。本项目拟利用我们构建的多种细胞、动物和人群模型研究揭示CPEB2-p53负反馈环调节的具体分子机制及调控肾癌生长和转移的作用及机制。本研究的开展将为阐明肿瘤细胞p53的调控机制提供新的角度，对肾癌的发生发展及治疗研究提供新的思路。

p53 is one of the most important tumor suppressor. A better understanding of the mechanism underlying p53 regualtion is of great significance for cancer etiology and prevention of cancer. We have previously found that CPEB2 is a candidate gene targeted by p53 through a microarray screening. Surprisingly, overexpression of CPEB2 substantialy suppress p53 expression. CPEB2 is a RNA binding protien which is upregulated in renal cancer tissues and is negatively correlated with overall survival in patients with renal cancer, and significantly promotes renal cancer cell proliferation. On the basis of these findings, we propose the hypothesis that p53 transactivates downstream target gene CPEB2. In contrast, CPEB2 binds to p53 mRNA and negatively regulates p53 expression, thus forming the CPEB2-p53 negative feedback loop, which plays an important role in the development of renal cancer. Through this proposal, we will further characterize the mechanism of mutual regulation between CPEB2 and p53, and identify the function of CPEB2-p53 loop in regulating renal cancer growth and metastasis via a variety of cell and animal models. This study will provide a new perspective to elucidate the regulatory mechanism of p53 in tumor cells, and offer new ideas for the development and treatment of renal cancer.