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Laboratory of Molecular Pharmacology, Division of Cancer Treatment, Developmental Therapeutics Program, National Cancer Institute, NIH, Bethesda, Maryland 20892-4255
We have studied changes in cyclin A- and B1-dependent kinases during apoptosis induced in human promyelocytic leukemia (HL60) cells treated with the topolsomerase I inhibitor camptothecin. We found that cyclin B1/Cdc2 kinase activity transiently increases within 30 min after camptothecin treatment. This increase is followed by a rapid inactivation of the cyclin B1/Cdc2 kinase that is associated with Cdc2 tyrosine phosphorylation without any change in Cdc2 or cyclin B1 protein levels. The DNA polymerase inhibitor aphidicolin abrogates camptothecin-induced changes in cyclin B1/Cdc2 kinase activity, indicating that DNA replication-induced DNA damage is essential for both Cdc2 alterations and apoptosis activation. Apoptosis and the initial cyclin B1/Cdc2 kinase activation were amplified using synchronized S-phase cells, and cyclin A/cdk2 kinase did not change under these conditions. The same transient activation and subsequent inactivation of cyclin B1/Cdc2 kinase were observed after DNA damage by etoposide or bis-(2-chloroethyl)methylamine hydrochloride. These observations suggest that DNA damage promotes the transient and unscheduled stimulation of cyclin B1/Cdc2 kinase activity in HL60 cells prior to apoptosis.
1 To whom requests for reprints should be addressed, at Laboratory of Molecular Pharmacology, NCI, Bldg. 37, Rm. 5C25, NIH, Bethesda, MD 20892-4255.
Received 10/24/94. Accepted 12/ 1/94.
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