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Experimental Therapeutics |
-Radiation-induced G2-M Checkpoint Independently of p53 by Targeting Both of the Checkpoint Kinases, Chk2 and Chk1
Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892-4255
UCN-01 (7-hydroxystaurosporine) is a cell-cycle checkpoint abrogator that sensitizes cells to ionizing radiation (IR) and chemotherapeutic agents. It has been shown previously that UCN-01 abrogates DNA-damage-induced G2 checkpoint most selectively in p53-defective cells, by primarily targeting Chk1. Here we show that UCN-01 prevented IR-induced p53 up-regulation and p53 phosphorylation on serine 20, a site previously identified for Chk2 (or/and Chk1) kinase. We found that in human colon carcinoma HCT116 cells, IR treatment enhanced Chk2 kinase activity, whereas Chk1 activity remained unchanged, which suggested that UCN-01 may interrupt IR-induced p53 response by inhibiting Chk2 kinase. This conclusion is supported by in vitro kinase assays, showing that UCN–01 inhibits Chk2 immunoprecipitated from HCT116 cells (IC50, 
10 nM). In addition, UCN-01 efficiently abrogated both the initiation and maintenance of IR-induced G2 arrest in HCT116 cells and their isogenic p53 (-/-) derivative, indicating that G2 checkpoint abrogation by UCN-01 is p53 independent. In the p53 (-/-) cells, there was no p21Waf1/Cip1 induction nor UCN-01-induced apoptosis. Taken together, these observations indicate that UCN-01 can modulate both Chk1 and Chk2 in intact cells and enhance IR-induced apoptosis in p53-deficient, and consequently p21-deficient, cells.
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