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Cancer Res. 2017 Sep 15;77(18):4881-4893. doi: 10.1158/0008-5472.CAN-17-1240. Epub 2017 Jul 31.

FBW7 Loss Promotes Chromosomal Instability and Tumorigenesis via Cyclin E1/CDK2-Mediated Phosphorylation of CENP-A.

Author information

1
Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
2
Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory and Department of Molecular and Cell Biology, University of California, Berkeley, California.
3
Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
4
Open Innovation Center Japan, Bayer Yakuhin, Ltd., Kita-ku, Osaka, Japan.
5
National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
6
Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts.
7
Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
8
St. Jude Children's Research Hospital, Memphis, Tennessee.
9
Cell Signaling Technology, Danvers, Massachusetts.
10
Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory and Department of Molecular and Cell Biology, University of California, Berkeley, California. Qing_Zhang@med.unc.edu ghkarpen@lbl.gov wwei2@bidmc.harvard.edu.
11
Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts. Qing_Zhang@med.unc.edu ghkarpen@lbl.gov wwei2@bidmc.harvard.edu.
12
Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina. Qing_Zhang@med.unc.edu ghkarpen@lbl.gov wwei2@bidmc.harvard.edu.
13
Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, North Carolina.

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 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 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. Cancer Res; 77(18); 4881-93. ©2017 AACR.

PMID:
28760857
PMCID:
PMC5743019
DOI:
10.1158/0008-5472.CAN-17-1240
[Indexed for MEDLINE]
Free PMC Article

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