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CELLULAR AND MOLECULAR

p53 Suppression of Arsenite-Induced Mitotic Catastrophe Is Mediated by p21^CIP1/WAF1

Department of Pharmacology and Toxicology, Center for Genetics and Molecular Medicine, James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky (B.F.T., S.C.M., H.L.M., J.C.S.); and Department of Environmental Medicine, University of Rochester, Rochester, New York (G.M.L., M.J.M.)

Arsenic trioxide, an acute promyelocytic leukemia chemotherapeutic, may be an efficacious treatment for other cancers. Understanding the mechanism as well as genetic and molecular characteristics associated with sensitivity to arsenite-induced cell death is key to providing effective chemotherapeutic usage of arsenite. Arsenite sensitivity correlates with deficient p53 pathways in multiple cell lines. The role of p53 in preventing arsenite-induced mitotic arrest-associated apoptosis (MAAA), a form of mitotic catastrophe, was examined in TR9-7 cells, a model cell line with p53 exogenously regulated in a tetracycline-off expression system. Arsenite activated G₁ and G₂ cell cycle checkpoints independently of p53, but mitotic catastrophe occurred preferentially in p53^(-) cells. Cyclin B/CDC2(CDK1) stabilization and caspase-3 activation persisted in arsenite-treated p53^(-) cells consistent with MAAA/mitotic catastrophe. N-Benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone, a pan-caspase inhibitor, completely abolished arsenite-induced MAAA/mitotic catastrophe and greatly increased the mitotic index. WEE1 and p21^CIP1/WAF1 inhibit cyclin B/CDC2 by CDC2 tyrosine-15 phosphorylation and direct binding, respectively. CDC2-Y15-P was transiently elevated in arsenite-treated p53⁽⁺⁾ cells but persisted in p53^(-) cells. Arsenite induced p53-S15-P and p21^CIP1/WAF1 only in p53⁽⁺⁾ cells. P21^CIP1/WAF1-siRNA-treated p53⁽⁺⁾ cells were similar to p53^(-) cells in mitotic index and cell cycle protein levels. p53-inducible proteins GADD45 and 14-3-3 are capable of inhibiting cyclin B/CDC2 but did not play a p53-dependent role in mitotic escape in TR9-7 cells. The data indicate that p53 mediates cyclin B/CDC2 inactivation and mitotic release directly via p21^CIP1/WAF1 induction.

Address correspondence to: Dr. J. Christopher States, Department of Pharmacology and Toxicology, University of Louisville, 570 South Preston Street, Suite 221, Louisville, KY 40202. E-mail: jcstates{at}louisville.edu