1. FBW7 Loss Promotes Chromosomal Instability and Tumorigenesis via Cyclin E1/CDK2-Mediated Phosphorylation of CENP-A.
- Author
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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, and Zhang Q
- Subjects
- Apoptosis, Biomarkers, Tumor metabolism, Breast Neoplasms genetics, Breast Neoplasms metabolism, Cell Cycle, Cell Proliferation, Cell Transformation, Neoplastic genetics, Cell Transformation, Neoplastic metabolism, Centromere, Centromere Protein A, Colonic Neoplasms genetics, Colonic Neoplasms metabolism, F-Box-WD Repeat-Containing Protein 7, Female, Histones metabolism, Humans, Phosphorylation, Tumor Cells, Cultured, Autoantigens metabolism, Breast Neoplasms pathology, Cell Cycle Proteins metabolism, Cell Transformation, Neoplastic pathology, Chromosomal Instability, Chromosomal Proteins, Non-Histone metabolism, Colonic Neoplasms pathology, Cyclin E metabolism, Cyclin-Dependent Kinase 2 metabolism, F-Box Proteins metabolism, Oncogene Proteins metabolism, Ubiquitin-Protein Ligases metabolism
- 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 ., (©2017 American Association for Cancer Research.)
- Published
- 2017
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