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Vol. 62, Issue 3, 680-688, September 2002
Department of Experimental Therapeutics, the University of Texas
M. D. Anderson Cancer Center, Houston, Texas
Human myeloid leukemia ML-1 cells responded to cytostatic
concentrations of fludarabine nucleoside (F-ara-A) by instituting an
arrest in S-phase that involved the inhibition of cyclin-dependent kinase 2 (Cdk2). This seemed to be mediated by 1) persistent
phosphorylation on the Tyr15 residue of Cdk2 and 2) an
increased association of Cdk2 with p21. S-phase arrest was also
associated with an increase in Chk1 kinase activity. Concomitantly, the
activity of Cdc25A phosphatase was decreased. Immunoprecipitation
studies demonstrated complexes of Cdk2, Cdc25A, and Chk1. The addition
of the Chk1 kinase inhibitor 7-hydroxystaurosporine (UCN-01) to
F-ara-A-arrested S-phase cells resulted in a rapid decrease in the
fraction of cells with an S-phase DNA content and a corresponding
increase in the fraction of apoptotic cells. Under these conditions,
the kinase activity of Chk1 was reduced, Cdc25A phosphatase activity
was increased, the level of Tyr15 phosphorylation of Cdk2
was reduced, and the kinase activity associated with immunoprecipitates
of Cdk2 and cyclin A was reactivated. UCN-01 also had no effect on the
association of p21 with Cdk2. Lastly, cells incubated with UCN-01
before F-ara-A addition did not arrest in S-phase. Thus, the DNA damage
induced by F-ara-A initiated a hierarchical regulatory cascade through
Chk1 and Cdc25A that resulted in Cdk2 inhibition, affecting an S-phase
checkpoint that was dysregulated by UCN-01. These results suggest a
mechanism by which UCN-01 enhances the cytotoxicity of agents that
cause an S-phase arrest.
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