FBW7 loss promotes chromosomal instability and tumorigenesis via cyclin E1/CDK2–mediated phosphorylation of CENP-A

Mamoru Takada, Weiguo Zhang, Aussie Suzuki, Taruho S. Kuroda, Zhouliang Yu, Hiroyuki Inuzuka, Daming Gao, Lixin Wan, Ming Zhuang, Lianxin Hu, Bo Zhai, Christopher J. Fry, Kerry Bloom, Guohong Li, Gary H. Karpen, Wenyi Wei, Qing Zhang

研究成果: Article査読

42 被引用数 (Scopus)

抄録

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 CENPA, 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 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.

本文言語English
ページ(範囲)4881-4893
ページ数13
ジャーナルCancer Research
77
18
DOI
出版ステータスPublished - 2017 9 15

ASJC Scopus subject areas

  • 腫瘍学
  • 癌研究

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