Journal
CANCER RESEARCH
Volume 77, Issue 18, Pages 4881-4893Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-17-1240
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Funding
- NIHK99/R00 [CA160351]
- V Scholar Award
- Kimmel Scholar Award
- Susan G. Komen Career Catalyst Award
- University Cancer Research Fund
- NIHR01 [GM094777, GM119011]
- Grants-in-Aid for Scientific Research [16K15811] Funding Source: KAKEN
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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. (C)2017 AACR.
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