p53在肿瘤发生发展中发挥极为重要作用，Mdm2是p53最重要的负性调节因子。传统观点认为Mdm2通过自身泛素化调节其稳定性。但申请人通过色谱分离和质谱鉴定发现SCF(FBXO22)作为外源的E3泛素连接酶具有修饰Mdm2的功能。我们在体外纯蛋白水平已证实SCF(FBXO22)可以泛素化Mdm2，但两者在细胞内相互作用机制尚不清楚。进一步研究发现FBXO22可以抑制乳腺癌细胞的体内转移。据此提出科学假说：以FBXO22为中心形成SCF(FBXO22)复合物，其中FBXO22通过其Mdm2蛋白识别域，与Mdm2特异性结合，调控Mdm2泛素化，进而影响p53表达，最终影响乳腺癌转移。本课题拟利用我们构建的多种细胞、动物和人群模型研究SCF(FBXO22)通过调控Mdm2泛素化影响乳腺癌转移的分子机制。本研究的开展将对理解Mdm2的稳定性具有重要创新意义，因此可能为肿瘤的基因治疗开辟崭新的途径。

The p53 tumor suppressor plays a crucial role in preventing tumorigenesis. Mdm2 is the most important negative regulator of p53. It was previously believed that Mdm2 regulated its own stability by autoubiquitination. But we identified SCF(FBXO22) as an alternative Mdm2 E3 ubiquitin ligase by chromatographic separation and mass spectrometry. Then we proved that purified SCF(FBXO22) protein could ubiquitinate Mdm2 in vitro. But the interaction between SCF(FBXO22) and Mdm2 in vivo is still unclear. Our recent data showed that FBXO22 inhibited the metastasis of breast cancer cells in vivo. On the basis of these findings, we propose the hypothesis that FBXO22 is formed in the center of SCF complex. This complex regulates Mdm2 ubiquitination, thereby affecting the expression of p53, and ultimately affect breast cancer cell metastasis. This project intends to study the mechanism that SCF(FBXO22) regulates breast cancer metastasis via a variety of cell and animal models we constructed. The success of this project will provide a new insight of the Mdm2 stability. And FBXO22 could be a new therapeutic target for breast cancer.