Cyclin E deregulation impairs mitotic progression through premature activation of Cdc25C.
The cyclin E-cyclin-dependent kinase 2 (CDK2) complex accelerates entry into the S phase of the cell cycle and promotes polyploidy, which may contribute to genomic instability in cancer cells. The effect of low molecular weight isoforms of cyclin E (LMW-E) overexpression on mitotic progression and its link to genomic instability ... were the focus of this study. Here, we show that full-length cyclin E (EL) and LMW-E overexpression impairs the G(2)-M transition differently by targeting dual-specificity phosphatase Cdc25C activity. We identify Cdc25C as an interaction partner and substrate for cyclin E/CDK2 kinase. Specifically, the cyclin E/CDK2 complex phosphorylates Cdc25C on Ser(214), leading to its premature activation, which coincides with higher cyclin B/CDK1 and Polo-like kinase 1 (PLK1) activities in an S-phase-enriched population that result in faster mitotic entry. Whereas EL overexpression leads to hyperactivation of Cdc25C, cyclin B/CDK1, and PLK1 in a G(2)-M-enriched population, LMW-E overexpression causes premature inactivation of Cdc25C and PLK1, leading to faster mitotic exit. In addition, LMW-E-overexpressing cells showed a reduction in the mitotic index in the presence of a spindle poison and faster degradation of cyclin B, suggesting an increased rate of mitotic slippage and adaptation to the spindle checkpoint. Lastly, downregulation of Cdc25C inhibits LMW-E-mediated chromosome missegregation, anaphase bridges, and centrosome amplification. These results suggest that the high levels of LMW-E isoforms found in breast cancer may contribute to cellular transformation and genomic instability by impairing mitotic progression involving Cdc25C.
Mesh Terms:
Blotting, Western, Breast Neoplasms, Cell Cycle Proteins, Cell Division, Cell Line, Tumor, Centrosome, Chromosomal Instability, Cyclin B, Cyclin E, Cyclin-Dependent Kinase 2, Female, Fluorescent Antibody Technique, Humans, Immunoenzyme Techniques, Immunoprecipitation, Mitosis, Molecular Weight, Oncogene Proteins, Protein Serine-Threonine Kinases, Proto-Oncogene Proteins, RNA, Small Interfering, S Phase, cdc25 Phosphatases
Blotting, Western, Breast Neoplasms, Cell Cycle Proteins, Cell Division, Cell Line, Tumor, Centrosome, Chromosomal Instability, Cyclin B, Cyclin E, Cyclin-Dependent Kinase 2, Female, Fluorescent Antibody Technique, Humans, Immunoenzyme Techniques, Immunoprecipitation, Mitosis, Molecular Weight, Oncogene Proteins, Protein Serine-Threonine Kinases, Proto-Oncogene Proteins, RNA, Small Interfering, S Phase, cdc25 Phosphatases
Cancer Res
Date: Jun. 15, 2010
PubMed ID: 20530684
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