Zhang Pingzhao, Zhang Yuanyuan, Gao Kun, Wang Yuqi, Jin Xiaofeng, Wei Youheng, Saiyin Heige, Wang Dejie, Peng Jintao, Ma Jian, Tang Yan, Wumaier Reziya, Yu Hongxiu, Dong Yimin, Huang Haojie, Yu Long, Wang Chenji
State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, P.R. China.
Institute of Biomedical Science, Fudan University, Shanghai, P. R. China.
Oncotarget. 2015 Dec 8;6(39):41550-65. doi: 10.18632/oncotarget.6355.
Regulated interactions between kinetochores and spindle microtubules are critical for maintaining genomic stability during chromosome segregation. Defects in chromosome segregation are widespread phenomenon in human cancers that are thought to serve as the fuel for tumorigenic progression. Tumor suppressor proteins ASPP1 and ASPP2, two members of the apoptosis stimulating proteins of p53 (ASPP) family, are frequently down-regulated in human cancers. Here we report that ASPP1/2 are required for proper mitotic progression. In ASPP1/2 co-depleted cells, the persistence of unaligned chromosomes and the reduction of tension across sister kinetochores on aligned chromosomes resulted in persistent spindle assembly checkpoint (SAC) activation. Using protein affinity purification methods, we searched for functional partners of ASPP1/2, and found that ASPP1/2 were associated with a subset of kinetochore proteins (Hec1, KNL-1, and CENP-F). It was found that ASPP1/2 act as PP1-targeting subunits to facilitate the interaction between PP1 and Hec1, and catalyze Hec1 (Ser165) dephosphorylation during late mitosis. These observations revealed a previously unrecognized function of ASPP1/2 in chromosome segregation and kinetochore-microtubule attachments that likely contributes to their roles in chromosome stability and tumor suppression.
动粒与纺锤体微管之间的调控相互作用对于染色体分离过程中维持基因组稳定性至关重要。染色体分离缺陷是人类癌症中普遍存在的现象，被认为是肿瘤发生进展的驱动力。肿瘤抑制蛋白ASPP1和ASPP2是p53凋亡刺激蛋白（ASPP）家族的两个成员，在人类癌症中经常下调。在此我们报告，ASPP1/2是正常有丝分裂进程所必需的。在ASPP1/2共同缺失的细胞中，未对齐染色体的持续存在以及对齐染色体上姐妹动粒间张力的降低导致纺锤体组装检查点（SAC）持续激活。我们使用蛋白质亲和纯化方法寻找ASPP1/2的功能伙伴，发现ASPP1/2与一部分动粒蛋白（Hec1、KNL-1和CENP-F）相关。研究发现，ASPP1/2作为靶向PP1的亚基，促进PP1与Hec1之间的相互作用，并在有丝分裂后期催化Hec1（Ser165）去磷酸化。这些观察结果揭示了ASPP1/2在染色体分离和动粒-微管附着中一种以前未被认识的功能，这可能有助于它们在染色体稳定性和肿瘤抑制中的作用。
