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J Biol Chem, Vol. 275, Issue 20, 15363-15369, May 19, 2000

Distinct Chk2 Activation Pathways Are Triggered by Genistein and DNA-damaging Agents in Human Melanoma Cells*

Jean-Marie DarbonDagger §, Marie PenaryDagger , Nathalie EscalasDagger , Fabrice CasagrandeDagger , Françoise Goubin-GramaticaDagger , Caroline Baudouin||, and Bernard DucommunDagger

From the Dagger  Laboratoire de Biologie Cellulaire et Moléculaire du Contrôle de la Prolifération Cellulaire, UMR 5088 CNRS, Université Paul Sabatier, 118 Route de Narbonne, 31062 Toulouse Cedex and the || Institut de Recherche Pierre Fabre, Faculté de Médecine Rangueil, 133 Route de Narbonne, 31062 Toulouse, France

Genistein, a natural isoflavone found in soybeans, exerts a number of biological actions suggesting that it may have a role in cancer prevention. We have previously shown that it potently inhibits OCM-1 melanoma cell proliferation by inducing a G2 cell cycle arrest. Here we show that genistein exerts this effect by impairing the Cdc25C-dependent Tyr-15 dephosphorylation of Cdk1, as the overexpression of this phosphatase allows the cells to escape G2 arrest and enter an abnormal chromatin condensation stage. Caffeine totally overrides the genistein-induced G2 arrest, whereas the block caused by etoposide is not bypassed and that caused by adriamycin is only partially abolished. We also report that genistein activates the checkpoint kinase Chk2 as efficiently as the two genotoxic agents and that caffeine may counteract the activation of Chk2 by genistein but not by etoposide. In contrast, caffeine abolishes the accumulation of p53 caused by all the compounds. Wortmannin does not suppress the Chk2 activation in any situation, suggesting that the ataxia telangiectasia-mutated kinase is not involved in this regulation. Finally, unlike etoposide and adriamycin, genistein induces only a weak response in terms of DNA damage in OCM-1 cells. Taken together, these results suggest that the G2 checkpoints activated by genistein and the two genotoxic agents involve different pathways.

* This work was supported by INSERM, Université Paul Sabatier, Association pour la Recherche sur le Cancer, and Ligue Nationale Contre le Cancer.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ To whom correspondence should be addressed. Tel.: (33) 5 61 55 69 14; Fax: (33) 5 61 55 69 19; E-mail: darbon@cict.fr.

Recipient of fellowship from the Association pour la Recherche sur le Cancer.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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