RRC ID 1950
Author Sugihara E, Kanai M, Saito S, Nitta T, Toyoshima H, Nakayama K, Nakayama KI, Fukasawa K, Schwab M, Saya H, Miwa M.
Title Suppression of centrosome amplification after DNA damage depends on p27 accumulation.
Journal Cancer Res
Abstract The centrosome plays a fundamental role in cell division, cell polarity, and cell cycle progression. Centrosome duplication is mainly controlled by cyclin-dependent kinase 2 (CDK2)/cyclin E and cyclin A complexes, which are inhibited by the CDK inhibitors p21Cip1 and p27Kip1. It is thought that abnormal activation of CDK2 induces centrosome amplification that is frequently observed in a wide range of aggressive tumors. We previously reported that overexpression of the oncogene MYCN leads to centrosome amplification after DNA damage in neuroblastoma cells. We here show that centrosome amplification after gamma-irradiation was caused by suppression of p27 expression in MYCN-overexpressing cells. We further show that p27-/- and p27+/- mouse embryonic fibroblasts and p27-silenced human cells exhibited a significant increase in centrosome amplification after DNA damage. Moreover, abnormal mitotic cells with amplified centrosomes were frequently observed in p27-silenced cells. In response to DNA damage, the level of p27 gradually increased in normal cells independently of the ataxia telangiectasia mutated/p53 pathway, whereas Skp2, an F-box protein component of an SCF ubiquitin ligase complex that targets p27, was reduced. Additionally, p27 levels in MYCN-overexpressing cells were restored by treatment with Skp2 small interfering RNA, indicating that down-regulation of p27 by MYCN was due to high expression of Skp2. These results suggest that the accumulation of p27 after DNA damage is required for suppression of centrosome amplification, thereby preventing chromosomal instability.
Volume 66(8)
Pages 4020-9
Published 2006-4-15
DOI 10.1158/0008-5472.CAN-05-3250
PII 66/8/4020
PMID 16618721
MeSH Ataxia Telangiectasia Mutated Proteins Cell Cycle Proteins / metabolism Cell Line, Tumor Centrosome / physiology* Centrosome / radiation effects Cyclin-Dependent Kinase Inhibitor p27 / biosynthesis Cyclin-Dependent Kinase Inhibitor p27 / genetics Cyclin-Dependent Kinase Inhibitor p27 / metabolism* DNA Damage / physiology* DNA-Binding Proteins / metabolism Down-Regulation Gamma Rays Humans Mitosis / physiology Mitosis / radiation effects N-Myc Proto-Oncogene Protein Neuroblastoma / genetics Neuroblastoma / metabolism Neuroblastoma / pathology Nuclear Proteins / biosynthesis Nuclear Proteins / genetics Oncogene Proteins / biosynthesis Oncogene Proteins / genetics Protein-Serine-Threonine Kinases / metabolism RNA, Small Interfering / genetics S-Phase Kinase-Associated Proteins / metabolism Signal Transduction Transfection Tumor Suppressor Protein p53 / metabolism Tumor Suppressor Proteins / metabolism
IF 8.378
Times Cited 30
Human and Animal Cells 293 NB1RGB