論文 - 詳細
| RRC ID | 5820 |
|---|---|
| 著者 | Nakayama Y, Igarashi A, Kikuchi I, Obata Y, Fukumoto Y, Yamaguchi N. |
| タイトル | Bleomycin-induced over-replication involves sustained inhibition of mitotic entry through the ATM/ATR pathway. |
| ジャーナル | Exp Cell Res |
| Abstract |
Polyploid cells result in aneuploidy through aberrant chromosome segregation, possibly leading to tumorigenesis. Although polyploid cells are induced through over-replication by a variety of agents, including DNA-damaging drugs, the mechanisms that induce polyploidy have been hitherto unknown. Here, we show that treatment with bleomycin, a glycopeptide anticancer drug, induces over-replication at low cytotoxic doses. During bleomycin-induced over-replication, mitotic entry is inhibited through tyrosine phosphorylation of CDK1 along the ATM/ATR pathway in the early phase of treatment. Bleomycin-induced over-replication is inhibited by the inhibitors of the ATM/ATR pathway through abrogation of bleomycin-induced G2 arrest, and the ATM/ATR inhibitors promote cell death instead of over-replication. Following the phosphorylation of CDK1, the level of cyclin B1 is decreased in the late phase of treatment. Time-lapse imaging of clone cells that express a live cell marker of endogenous cyclin B1 revealed that cyclin B1 is degraded in G2-arrested cells upon bleomycin treatment. Our findings lead to a model of how the ATM/ATR pathway acts as a molecular switch for regulating cell fates, flipping between cell death via progress into mitosis, and over-replication via sustained G2 arrest upon DNA damage, where cyclin B1 degradation is an important factor for inducing over-replication. |
| 巻・号 | 315(15) |
| ページ | 2515-28 |
| 公開日 | 2009-9-10 |
| DOI | 10.1016/j.yexcr.2009.06.007 |
| PII | S0014-4827(09)00264-X |
| PMID | 19527713 |
| MeSH | Animals Antibiotics, Antineoplastic / pharmacology* Ataxia Telangiectasia Mutated Proteins Bleomycin / pharmacology* CDC2 Protein Kinase / metabolism Cell Cycle / drug effects Cell Cycle / physiology Cell Cycle Proteins / genetics Cell Cycle Proteins / metabolism* Cyclin B / metabolism Cyclin B1 DNA Replication / drug effects* DNA-Binding Proteins / genetics DNA-Binding Proteins / metabolism* Doxorubicin / pharmacology HeLa Cells Humans Mitosis / drug effects* Protein Serine-Threonine Kinases / genetics Protein Serine-Threonine Kinases / metabolism* RNA Interference Recombinant Fusion Proteins / genetics Recombinant Fusion Proteins / metabolism Signal Transduction / physiology Tumor Suppressor Proteins / genetics Tumor Suppressor Proteins / metabolism* |
| IF | 3.383 |
| 引用数 | 37 |
| WOS 分野 | ONCOLOGY CELL BIOLOGY |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 各媒体での言及数の合計 | 0 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| 遺伝子材料 | pENTR4-H1 (RDB04395) |