Mps1是纺锤体组装检查点（SAC）的必需基因，在多种肿瘤中高表达；降低其表达或者抑制其活性均导致肿瘤细胞死亡，该蛋白已成为新的抗癌药物靶标。但是Mps1高表达的形成机制及其如何促进肿瘤细胞增殖目前并不清楚。在前期研究中我们发现将Mps1的一个介导蛋白互作的LXXLL基序突变会导致SAC维持缺陷；而引起缺陷的原因是Mps1的LXXLL基序突变体在SAC维持时就发生完全降解。此外我们还发现抑制Mps1活性所引起的肿瘤细胞死亡也是因为SAC维持缺陷所造成的。据此我们提出一个假设：肿瘤细胞存在某些与Mps1LXXLL基序结合的蛋白，这些蛋白在肿瘤细胞中高表达或特异性表达促进了Mps1稳定性和SAC活性，进而维持了肿瘤细胞高增值活力。本项目将分析和鉴定能与Mps1的LXXLL基序结合并对于维持Mps1的高水平和SAC活力起至关重要的功能蛋白，进而研究其与Mps1共同调节肿瘤细胞增殖的分子机制。

Mps1 kinase is an essential component of spindle assembly checkpoint(SAC), the high levels of which are protective of aneuploidy in many types of cancer. The majority of Mps1 stably function through cell cycle and only a small partial of it are prone to degradation upon the disappearance of SAC signal in mitosis. Despite the significance of the partial degradation of Mps1 in tumor cells survival, the mechanism underlying however is not clear. Recently, we uncovered that the failure of SAC maintenance via treating cells with reversine, a specific inhibitor of Mps1 kinase, caused polyploidization and cell death. Similarly, the cells reconstructed with a muted Mps1 at LXXLL motif also failed to maintain the SAC signal upon exposure to nocodazole. Notably, Unlike the wild type of Mps1 which degraded partially, Mps1 LXXLL mutant underwent a rapid and complete degradation upon SAC maintenance. Based on these findings, we formed a speculation: the high levels of Mps1 are beneficial for SAC maintenance and thereby tumor survival; to achieve that, Mps1 binds to some regulators via its LXXLL motif and prevent from degradation mediated by proteosome. In case of the approval of this proposal, we will test these hypothesis by using a combinational method of quantitative cell biology，genetics and biochemistry.