Chk1 regulates the S phase checkpoint by coupling the physiological turnover and ionizing radiation-induced accelerated proteolysis of Cdc25A

被引:449
作者
Sorensen, CS
Syluåsen, RG
Falck, J
Schroeder, T
Rönnstrand, L
Khanna, KK
Zhou, BB
Bartek, J
Lukas, J
机构
[1] Danish Canc Soc, Inst Canc Biol, DK-2100 Copenhagen O, Denmark
[2] Ludwig Inst Canc Res, Ctr Biomed, S-75124 Uppsala, Sweden
[3] PO Royal Brisbane Hosp, Queensland Inst Med Res, Brisbane, Qld 4029, Australia
[4] Inctye Genom Inc, Drug Discovery Biol, Newark, DE 19714 USA
关键词
D O I
10.1016/S1535-6108(03)00048-5
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Chk1 kinase coordinates cell cycle progression and preserves genome integrity. Here, we show that chemical or genetic ablation of human Chk1 triggered supraphysiological accumulation of the S phase-promoting Cdc25A phosphatase, prevented ionizing radiation (IR)-induced degradation of Cdc25A, and caused radioresistant DNA synthesis (RDS). The basal turnover of Cdc25A operating in unperturbed S phase required Chk1-dependent phosphorylation of serines 123, 178, 278, and 292. IR-induced acceleration of Cdc25A proteolysis correlated with increased phosphate incorporation into these residues generated by a combined action of Chk1 and Chk2 kinases. Finally, phosphorylation of Chk1 by ATM was required to fully accelerate the IR-induced degradation of Cdc25A. Our results provide evidence that the mammalian S phase checkpoint functions via amplification of physiologically operating, Chk1-dependent mechanisms.
引用
收藏
页码:247 / 258
页数:12
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