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p53-dependent Chk1 phosphorylation is required for maintenance of prolonged G arrest

Radiation Research, ISSN: 0033-7587, Vol: 168, Issue: 6, Page: 706-715
2007
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Article Description

Targeting checkpoint kinases has been shown to have a potential chemosensitizing effect in cancer treatment. However, inhibitors of such kinases preferentially abrogate the DNA damage-induced G checkpoint in p53 as opposed to p53 cells. The mechanisms by which p53 (TP53) can prevent abrogation of the G checkpoint are unclear. Using normal human diploid p53 and p53 fibroblasts as model systems, we have compared the effects of three checkpoint inhibitors, caffeine, staurosporine and UCN-01, on γ-radiation-induced G arrest. The G arrest in p53 cells was abrogated by caffeine, but not by staurosporine and UCN-01, whereas the G arrest in p53 cells was sensitive to all three inhibitors. Chk2 (CHEK1) phosphorylation was maintained in the presence of all three inhibitors in both p53 and p53 cells. Chk1 phosphorylation was maintained only in the presence of staurosporine and UCN-01 in p53 cells. In the presence of caffeine Chk1 phosphorylation was inhibited regardless of p53 status. The pathway of Chk1 phosphorylation → Cdc25A degradation → inhibition of cyclin B1/Cdk1 activity → G arrest is accordingly resistant to staurosporine and UCN-01 in p53 cells. Moreover, sustained phosphorylation of Chk1 in the presence of staurosporine and UCN-01 is strongly related to phosphorylation of p53. The present study suggests the unique role of Chk1 in preventing abrogation of the G checkpoint in p53 cells. © 2007 by Radiation Research Society.

Bibliographic Details

Wang, Xiao Qi; Stanbridge, Eric J; Lao, Xiaoyan; Cai, Qi; Fan, Sheung Tat; Redpath, J Leslie

Radiation Research Society

Physics and Astronomy; Biochemistry, Genetics and Molecular Biology; Medicine

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