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 dev elop a hyperploid DNA content. Hyperploid tumors are significantly mor e aggressive, with a higher growth rate and a poor patient prognosis, Yeast genetics have implicated three important genes involved in DNA p loidy changes: cdc2, cyclin b, and a specific inhibitor of the p34(cdc 2)/cyclin B kinase, rum1. Mutations in these genes uncoupled the depen dence of mitosis on DNA replication in the fission yeast, Saccharomyce s pombe, It was proposed that the inactivation of the mitotic kinase c omplex, p34(cdc2)/cyclin B, induces a G(1) state wherein the cells re- replicate their DNA without an intervening mitosis. We show in this re port that treatment of only M phase-arrested mouse cells, with the pro tein kinase inhibitor staurosporine, induced polyploidy, Nocodazole-ar rested metaphase FT210 cells were pulsed with 100 ng/ml of staurospori ne for 1 h, This 1-h treatment results in the inhibition of the mitoti c p34(cdc2) kinase. The inhibition of the mitotic kinases leads to a r eduction in the histone H1 and H3 mitotic-associated phosphorylations, chromosome decondensation, and nuclear membrane reformation. When rel eased into normal growth medium, these cells are reset to a G(1) state , re-replicate their DNA without completing mitosis, and become octapl oid.