IC261, a specific inhibitor of the protein kinases casein kinase 1-delta and -epsilon, triggers the mitotic checkpoint and induces p53-dependent postmitotic effects

被引:105
作者
Behrend, L
Milne, DM
Stöter, M
Deppert, W
Campbell, LE
Meek, DW
Knippschild, U
机构
[1] Univ Hamburg, Heinrich Pette Inst Expt Virol & Immunol, D-20251 Hamburg, Germany
[2] Univ Dundee, Ninewells Hosp & Med Sch, Biomed Res Ctr, Dundee DD1 9SY, Scotland
基金
英国医学研究理事会;
关键词
casein kinase 1; mitotic checkpoint; chromosome segregation; centrosome amplification; micronucleation;
D O I
10.1038/sj.onc.1203939
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The p53-targeted kinases casein kinase 1 delta (CK1 delta) and casein kinase 1 epsilon (CK1 epsilon) have been proposed to be involved in regulating DNA repair and chromosomal segregation. Recently, we showed that CK1 delta localizes to the spindle apparatus and the centrosomes in cells with mitotic failure caused by DNA-damage prior to mitotic entry. We provide here evidence that 3-[(2,4,6-trimethoxyphenyl)methylidenyl]-indolin-2-one (IC261), a novel inhibitor of CK1 delta and CK1 epsilon, triggers the mitotic checkpoint control. At low micromolar concentrations IC261 inhibits cytokinesis causing a transient mitotic arrest. Cells containing active p53 arrest in the postmitotic G1 phase by blockage of entry into the S phase. Cells with non-functional p53 undergo postmitotic replication developing an 8N DNA content. The increase of DNA content is accompanied by a high amount of micronucleated and apoptotic cells. Immunfluorescence images show that at low concentrations IC261 leads to centrosome amplification causing multipolar mitosis. Our data are consistent with a role for CK1 delta and CK1 epsilon isoforms in regulating key aspects of cell division, possibly through the regulation of centrosome or spindle function during mitosis.
引用
收藏
页码:5303 / 5313
页数:11
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