A brief staurosporine treatment of mitotic cells triggers premature exit from mitosis and polyploid cell formation.
At any point during the progression of many tumor types, cells can develop a hyperploid DNA content. Hyperploid tumors are significant 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 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 G(1), state wherein the cells 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 G(1)state, re-replicate their DNA without completing mitosis, and become octaploid.
Hall
L L
LL
Department of Biological Chemistry, School of Medicine, University of California, Davis 95616, USA.
Th'ng
J P
JP
Guo
X W
XW
Teplitz
R L
RL
Bradbury
E M
EM
D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism; D004273:DNA, Neoplasm / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D016193:G1 Phase / Q000187:drug effects; D006657:Histones / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000235:genetics* / Q000473:pathology*; D008677:Metaphase / Q000187:drug effects; D051379:Mice; D008938:Mitosis / Q000187:drug effects*; D015739:Nocodazole / Q000494:pharmacology; D010766:Phosphorylation; D011123:Polyploidy; D019311:Staurosporine; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000470:Alkaloids; D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D004791:Enzyme Inhibitors; D006657:Histones; D016203:CDC2 Protein Kinase; D019311:Staurosporine; D015739:Nocodazole