ASPP1/2-PP1复合体通过调控纺锤体装配检验点沉默参与肿瘤细胞染色体稳定的分子机制研究

ASPP1和ASPP2 是两个在多种肿瘤中都显著下调的肿瘤抑制基因。目前已知ASPP1/2 的主要作用是激活p53 的促凋亡功能，但多项研究表明ASPP1/2具有不依赖于p53 的抑制肿瘤作用。我们通过亲和纯化得到了细胞内源ASPP1/2蛋白复合体，发现ASPP1/2可以和多个动粒相关蛋白（如Ndc80、 KNL-1 和CENP-F 等）相互作用，并且干扰ASPP1/2的表达可造成肝癌细胞有丝分裂期纺锤体装配检验点持续激活、动粒-微管的连接和染色体的分离过程出现障碍。我们还发现ASPP1/2作为一个接头蛋白，能在有丝分裂中期促进磷酸酯酶PP1对这些动粒蛋白的去磷酸化。本项研究将探讨ASPP1/2在肿瘤中下调导致染色体不稳定性的具体分子机制，和在肿瘤发生发展过程中的重要意义。

ASPP1 and ASPP2 are two tumor suppressors which are significantly downregulated in various tumors. The well-known function ASPP1/2 is to stimulate p53 pro-apoptotic function. However, many studies also indicated that ASPP1/2 can exert tumor suppression function independent of p53. We successfully isolated endogenous ASPP1/2 protein complex by two-step affinity purification. Unexpectedly, we found many kinetochore proteins such as Ndc80、KNL-1 and CENP-F existed in ASPP1/2 complex. ASPP1/2 knockdown in HCC cells impaired the kinetochore-tubulin connection and chromosome segregation, caused persistent spindle assembly checkpoint activation. One possible explanation is that ASPP1/2 promote phosphatase PP1-mediated dephosphorylation of kinetochore proteins. The aim of this project is to investigate the molecular mechanism and clinic impact of chromosomal instability caused by ASPP1/2 downregulation in tumors.