FBW7 Loss Promotes Chromosomal Instability and Tumorigenesis via Cyclin E1/CDK2-Mediated Phosphorylation of CENP-A.
FBW7 Loss Promotes Chromosomal Instability and Tumorigenesis via Cyclin E1/CDK2-Mediated Phosphorylation of CENP-A.
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DOI：
10.1158/0008-5472.can-17-1240
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发表时间：
2017-09-15
期刊：
影响因子：
11.2
通讯作者：
Zhang Q
中科院分区：
文献类型：
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作者：
Takada M;Zhang W;Suzuki A;Kuroda TS;Yu Z;Inuzuka H;Gao D;Wan L;Zhuang M;Hu L;Zhai B;Fry CJ;Bloom K;Li G;Karpen GH;Wei W;Zhang Q
着丝粒调节染色体分离，其功能障碍与染色体不稳定性有关。然而，对于着丝粒功能障碍是如何在癌症中发生的，我们知之甚少。在这里，我们定义了Cyclin E1/CDK2对着丝粒相关蛋白CENP-A的保守Ser18残基磷酸化的后果，CENP-A是一种指定着丝粒身份的基本组蛋白H3变体。细胞中Ser18的过度磷酸化发生在FBW7缺失时，FBW7是一种肿瘤抑制因子，其失活导致染色体不稳定（CIN）。这一事件降低了CENP-A的着丝点定位，增加了CIN，促进了非锚定生长和异种移植物肿瘤的形成。总的来说，我们的研究结果揭示了Cyclin E1/CDK2激活与FBW7缺失通过cenp - a介导的着丝粒功能障碍促进CIN和肿瘤进展的途径。
The centromere regulates proper chromosome segregation and its dysfunction is implicated in chromosomal instability (CIN). However, relatively little is known about how centromere dysfunction occurs in cancer. Here we define the consequences of phosphorylation by Cyclin E1/CDK2 on a conserved Ser18 residue of centromere-associated protein CENP-A, an essential histone H3 variant that specifies centromere identity. Ser18 hyperphosphorylation in cells occurred upon loss of FBW7, a tumor suppressor whose inactivation leads to chromosomal instability (CIN). This event on CENP-A reduced its centromeric localization, increased CIN and promoted anchorage-independent growth and xenograft tumor formation. Overall, our results revealed a pathway that Cyclin E1/CDK2 activation coupled with FBW7 loss promotes CIN and tumor progression via CENP-A-mediated centromere dysfunction.