ASPP1/2-PP1 complexes are required for chromosome segregation and kinetochore-microtubule attachments.
ASPP1/2-PP1 complexes are required for chromosome segregation and kinetochore-microtubule attachments.
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ASPP1/2-PP1 复合物是染色体分离和着丝粒-微管附着所必需的
DOI：
10.18632/oncotarget.6355
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发表时间：
2015-12-08
期刊：
影响因子：
--
通讯作者：
Wang C
中科院分区：
文献类型：
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作者：
Zhang P;Zhang Y;Gao K;Wang Y;Jin X;Wei Y;Saiyin H;Wang D;Peng J;Ma J;Tang Y;Wumaier R;Yu H;Dong Y;Huang H;Yu L;Wang C
着丝粒和纺锤体微管之间的相互作用是维持染色体分离过程中基因组稳定性的关键。染色体分离缺陷是人类癌症中的普遍现象，被认为是肿瘤发生进展的燃料。肿瘤抑制蛋白ASPP 1和ASPP 2是p53凋亡刺激蛋白（apoptosis stimulating proteins of p53，ASPP）家族的两个成员，在人类肿瘤中表达下调。在这里，我们报告，ASPP 1/2所需的适当的有丝分裂进程。在ASPP 1/2共耗尽的细胞中，未对齐的染色体的持续存在和对齐染色体上的姐妹动粒之间的张力的降低导致持续的纺锤体组装检查点（SAC）激活。使用蛋白质亲和纯化方法，我们搜索了ASPP 1/2的功能伴侣，发现ASPP 1/2与一个动粒蛋白亚组（Hec 1，KNL-1和CENP-F）相关。研究发现ASPP 1/2作为PP 1靶向亚基促进PP 1和Hec 1之间的相互作用，并在有丝分裂晚期催化Hec 1（Ser 165）去磷酸化。这些观察结果揭示了ASPP 1/2在染色体分离和着丝粒-微管附着中的先前未被认识的功能，这可能有助于其在染色体稳定性和肿瘤抑制中的作用。
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.