Blocking CHK1 expression induces apoptosis and abrogates the G2 checkpoint mechanism

被引:46
作者
Luo, Y
Rockow-Magnone, SK
Kroeger, PE
Frost, L
Chen, ZH
Han, EKH
Ng, SC
Simmer, RL
Giranda, VL
机构
[1] Abbott Labs, Pharmaceut Prod Div, Dept 47S AP9A, Canc Res, Abbott Pk, IL 60064 USA
[2] Abbott Labs, Pharmaceut Prod Div, Dept 4MD AP10, Adv Technol, Abbott Pk, IL 60064 USA
[3] Abbott Labs, Pharmaceut Prod Div, Dept 4N6 AP9, Canc Res, Abbott Pk, IL 60064 USA
来源
NEOPLASIA | 2001年 / 3卷 / 05期
关键词
Chk1; antisense; ribozyme; checkpoint; chemotherapy sensitization;
D O I
10.1038/sj.neo.7900175
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Checkpoint kinase 1 (Chk1) is a checkpoint gene that is activated after DNA damage. It phosphorylates and inactivates the Cdc2 activating phosphatase Cdc25C. This in turn inactivates Cdc2, which leads to G2/M arrest. We report that blocking Chk1 expression by antisense or ribozymes in mammalian cells induces apoptosis and interferes with the G2/M arrest induced by adriamycin. The Chk1 inhibitor UCN-01 also blocks the G2 arrest after DNA damage and renders cells more susceptible to adriamycin. These results indicate that Chk1 is an essential gene for the checkpoint mechanism during normal cell proliferation as well as in the DNA damage response.
引用
收藏
页码:411 / 419
页数:9
相关论文
共 46 条
[11]   Requirement for Atr in phosphorylation of Chk1 and cell cycle regulation in response to DNA replication blocks and UV-damaged DNA in Xenopus egg extracts [J].
Guo, ZJ ;
Kumagai, A ;
Wang, SX ;
Dunphy, WG .
GENES & DEVELOPMENT, 2000, 14 (21) :2745-2756
[12]  
Jackson JR, 2000, CANCER RES, V60, P566
[13]  
Jarvis TC, 1996, RNA, V2, P419
[14]  
Kaneko, 1999, ONCOGENE, V18, P5246
[15]   Cell cycle-dependent and ATM-independent expression of human Chk1 kinase [J].
Kaneko, Y ;
Watanabe, N ;
Morisaki, H ;
Akita, H ;
Fujimoto, A ;
Tominaga, K ;
Terasawa, M ;
Tachibana, A ;
Ikeda, K ;
Nakanishi, M .
ONCOGENE, 1999, 18 (25) :3673-3681
[16]  
KASTAN MB, 1991, CANCER RES, V51, P6304
[17]   Positive regulation of Wee1 by Chk1 and 14-3-3 proteins [J].
Lee, J ;
Kumagai, A ;
Dunphy, WG .
MOLECULAR BIOLOGY OF THE CELL, 2001, 12 (03) :551-563
[18]   P53 MUTATIONS INCREASE RESISTANCE TO IONIZING-RADIATION [J].
LEE, JM ;
BERNSTEIN, A .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1993, 90 (12) :5742-5746
[19]  
Liu QH, 2000, GENE DEV, V14, P1448
[20]   Nuclear localization of Cdc25 is regulated by DNA damage and a 14-3-3 protein [J].
Lopez-Girona, A ;
Furnari, B ;
Mondesert, O ;
Russell, P .
NATURE, 1999, 397 (6715) :172-175