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

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)4881-4893
Number of pages13
JournalCancer Research
Volume77
Issue number18
DOIs
StatePublished - Sep 15 2017
Externally publishedYes

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Chromosomal Instability
Cyclins
Centromere
Carcinogenesis
Phosphorylation
Neoplasms
Chromosome Segregation
Heterografts
Histones
centromere protein A
Growth
Proteins

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

FBW7 loss promotes chromosomal instability and tumorigenesis via cyclin E1/CDK2–mediated phosphorylation of CENP-A. / Takada, Mamoru; Zhang, Weiguo; Suzuki, Aussie; Kuroda, Taruho S.; Yu, Zhouliang; Inuzuka, Hiroyuki; Gao, Daming; Wan, Lixin; Zhuang, Ming; Hu, Lianxin; Zhai, Bo; Fry, Christopher J.; Bloom, Kerry; Li, Guohong; Karpen, Gary H.; Wei, Wenyi; Zhang, Qing.

In: Cancer Research, Vol. 77, No. 18, 15.09.2017, p. 4881-4893.

Research output: Contribution to journalArticle

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 2017, 'FBW7 loss promotes chromosomal instability and tumorigenesis via cyclin E1/CDK2–mediated phosphorylation of CENP-A', Cancer Research, vol. 77, no. 18, pp. 4881-4893. https://doi.org/10.1158/0008-5472.CAN-17-1240
Takada, Mamoru ; Zhang, Weiguo ; Suzuki, Aussie ; Kuroda, Taruho S. ; Yu, Zhouliang ; Inuzuka, Hiroyuki ; Gao, Daming ; Wan, Lixin ; Zhuang, Ming ; Hu, Lianxin ; Zhai, Bo ; Fry, Christopher J. ; Bloom, Kerry ; Li, Guohong ; Karpen, Gary H. ; Wei, Wenyi ; Zhang, Qing. / FBW7 loss promotes chromosomal instability and tumorigenesis via cyclin E1/CDK2–mediated phosphorylation of CENP-A. In: Cancer Research. 2017 ; Vol. 77, No. 18. pp. 4881-4893.
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abstract = "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.",
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AU - Gao, Daming

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AU - Zhai, Bo

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