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A Brief Staurosporine Treatment of Mitotic Cells Triggers Premature Exit from Mitosis and Polyploid Cell Formation¹

Department of Biological Chemistry, School of Medicine, University of California, Davis, California 95616 [L. L. H., X. W. G., R. L. T., E. M. B.]; Bloomfield Center for Research in Aging, Lady Davis Institute, Jewish General Hospital, Montreal, Quebec H3T 1E2, Canada [J. P. H. T.]; and Life Sciences Division, Los Alamos National Laboratories, Los Alamos, New Mexico 87545 [E. M. B.]

At any point during the progression of many tumor types, cells can develop a hyperploid DNA content. Hyperploid tumors are significantly more aggressive, with a higher growth rate and a poor patient prognosis. Yeast genetics have implicated three important genes involved in DNA ploidy changes: cdc2, cyclin b, and a specific inhibitor of the p34^cdc2/cyclin B kinase, rum1. Mutations in these genes uncoupled the dependence of mitosis on DNA replication in the fission yeast, Saccharomyces pombe. It was proposed that the inactivation of the mitotic kinase complex, p34^cdc2/cyclin B, induces a G₁ state wherein the cell re-replicate their DNA without an intervening mitosis. We show in this report that treatment of only M phase-arrested mouse cells, with the protein kinase inhibitor staurosporine, induced polyploidy. Nocodazole-arrested metaphase FT210 cells were pulsed with 100 ng/ml of staurosporine for 1 h. This 1-h treatment results in the inhibition of the mitotic p34^cdc2 kinase. The inhibition of the mitotic kinases leads to a reduction in the histone H1 and H3 mitotic-associated phosphorylations, chromosome decondensation, and nuclear membrane reformation. When released into normal growth medium, these cells are reset to a G₁ state, re-replicate their DNA without completing mitosis, and become octaploid.

¹ Supported by Grant GM45890 from the NIH USPHS, Grants F510 and ERWF510 (to E. M. B.) from the Department of Energy Program, and a grant from Lady Davis Foundation, Jewish General Hospital (to J. P. H. T.).

² To whom requests for reprints should be addressed, at Department of Biological Chemistry, School of Medicine, University of California, Davis, CA 95616. Fax: (916) 752-3516; E-mail: llhall@ucdavis.edu.

Received 11/13/95. Accepted 5/28/96.

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