The role of inhibitory phosphorylation of CDC2 following DNA replication block and radiation-induced damage in human cells

A Blasina, ES Paegle and CH McGowan

Department of Molecular Biology, Scripps Research Institute, La Jolla, California 92037, USA.

It has been suggested that the survival response of p53 defective tumor cells to agents that inhibit DNA replication or damage DNA may be largely dependent on cell cycle checkpoints that regulate the onset of mitosis. In human cells, the mitosis-inducing kinase CDC2/cyclin B is inhibited by phosphorylation of threonine-14 and tyrosine-15, but the roles of these phosphorylations in enforcing checkpoints is not known. We have investigated the situation in a human cervical carcinoma cell line (HeLa cells) and found that low level expression of a mutant nonphosphorylatable form of CDC2 abrogates regulation of the endogenous CDC2/cyclin B. Disruption of this pathway is toxic and renders cells highly sensitive to killing by DNA damage or by inhibition of DNA replication. These findings establish the importance of inhibitory phosphorylation of CDC2 in the survival mechanism used by human cells when exposed to some of the most common forms of anticancer therapy.

Volume 8, Issue 6, pp. 1013-1023, 06/01/1997
Copyright © 1997 by The American Society for Cell Biology

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