期刊
CELL CYCLE
卷 8, 期 8, 页码 1196-1205出版社
TAYLOR & FRANCIS INC
DOI: 10.4161/cc.8.8.8203
关键词
CHK1; radiation; G(2)-M checkpoint; p53
类别
资金
- Association pour la Recherche sur le Cancer
- Ligue contre le Cancer
- Agence Nationale pour la Recherche
- Institut National du Cancer
- Canceropole Ile-de-France and European Union
Checkpoint kinase-1 (CHK1) is a key regulator of the DNA damage-elicited G(2)-M checkpoints. The aim of the present study was to investigate the effects of a selective CHK1 inhibitor, Chir124, on cell survival and cell cycle progression following ionizing radiation (IR). Treatment with Chir-124 resulted in reduced clonogenic survival and abrogated the IR-induced G(2)-M arrest in a panel of isogenic HCT116 cell lines after IR. This radiosensitizing effect was relatively similar between p53(-/-) and p53-sufficient wild type (WT) HCT116 cells. However, the number of mitotic cells (as measured by assessing the phosphorylation of mitotic proteins) increased dramatically in p53(-/-) HCT116 cells after concomitant Chir-124 exposure, compared to IR alone, while no such effect was observed in p53-sufficient WT HCT116 cells. In p53(-/-) cells, Chir-124 treatment induced a marked accumulation of polyploid cells that were characterized by micronucleation or multinucleation. p21(-/-) HCT116 cells displayed a similar pattern of response as p53(-/-) cells. Chir-124 was able to radiosensitize HCT116 cells that lack checkpoint kinase-2 (CHK2) or that were deficient for the spindle checkpoint protein Mad2. Finally, Chir-124 could radiosensitize tetraploid cell lines, which were relatively resistant against DNA damaging agents. Altogether these results suggest that Chir-124-mediated radiosensitization is profoundly influenced by the p53 and cell cycle checkpoint system.
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