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J. Biol. Chem., Vol. 281, Issue 13, 8675-8685, March 31, 2006

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DNA Damage-induced Expression of p53 Suppresses Mitotic Checkpoint Kinase hMps1

THE LACK OF THIS SUPPRESSION IN p53^MUT CELLS CONTRIBUTES TO APOPTOSIS^*

Mandar R. Bhonde, Marie-Luise Hanski, Jan Budczies, Minh Cao, Bernd Gillissen^¶, Dhatchana Moorthy, Federico Simonetta^||, Hans Scherübl, Matthias Truss^**, Christian Hagemeier^**, Hans-Werner Mewes, Peter T. Daniel^¶, Martin Zeitz, and Christoph Hanski¹

From the Department of Gastroenterology, University Medical Center Charité, Campus Benjamin Franklin, 12200 Berlin, Germany, Institute for Bioinformatics, GSF-National Research Center for Environment and Health, 85764 Neuherberg, Germany, ^¶University Medical Center Charité, Campus Virchow Klinikum, 13353 Berlin, Germany, ^||Department of Internal Medicine, Division of Internal Medicine and Clinical Immunology, University of Genoa, 16132 Genoa, Italy, and ^**Children's Hospital, Laboratory for Molecular Biology, Charité-CCM, Humboldt University, 10117 Berlin, Germany

DNA damage induced by the topoisomerase I inhibitor irinotecan (CPT-11) triggers in p53^WT colorectal carcinoma cells a long term cell cycle arrest and in p53^MUT cells a transient arrest followed by apoptosis (Magrini, R., Bhonde, M. R., Hanski, M. L., Notter, M., Scherübl, H., Boland, C. R., Zeitz, M., and Hanski, C. (2002) Int. J. Cancer 101, 23-31; Bhonde, M. R., Hanski, M. L., Notter, M., Gillissen, B. F., Daniel, P. T., Zeitz, M., and Hanski, C. (2006) Oncogene 25, 165-175). The mechanism of the p53-independent apoptosis still remains largely unclear. Here we used five p53^WT and five p53^MUT established colon carcinoma cell lines to identify gene expression alterations associated with apoptosis in p53^MUT cells after treatment with SN-38, the irinotecan metabolite. After treatment, 16 mitosis-related genes were found to be expressed at least 2-fold stronger in the apoptosis-executing p53^MUT cells than in the cell cycle-arrested p53^WT cells by oligonucleotide microarray analysis. One of the genes whose strong post-treatment expression was associated with apoptosis was the mitotic checkpoint kinase hMps1 (human ortholog of the yeast monopolar spindle 1 kinase). hMps1 mRNA and protein expression were suppressed by the treatment-induced and by the exogenous adenovirus-coded p53 protein. The direct suppression of hMps1 on RNA level or inhibition of its activity by a dominant-negative hMps1 partly suppressed apoptosis. Together, these data indicate that the high expression of mitotic genes in p53^MUT cells after SN-38 treatment contributes to DNA damage-induced apoptosis, whereas their suppression in p53^WT cells acts as a safeguard mechanism preventing mitosis initiation and the subsequent apoptosis. hMps1 kinase is one of the mitotic checkpoint proteins whose expression after DNA damage in p53^MUT cells activates the checkpoint and contributes to apoptosis.

Received for publication, October 18, 2005 , and in revised form, January 4, 2006.

^* This work was supported by the NGFN1 Program of the Bundesministerium für Bildung und Forschung and the Sonnenfeld Stiftung and the Monika Kutzner Stiftung. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The online version of this article (available at http://www.jbc.org) contains Tables S1 and S2 and Figs. S1-S5.

¹ To whom correspondence should be addressed: Charité-Universitaetsmedizin Berlin, Campus Benjamin Franklin, Dept. of Gastroenterology, Hindenburgdamm 30, 12200 Berlin, Germany. Tel.: 49-30-8445-4522; Fax: 49-30-8445-4582; E-mail: christoph.hanski{at}charite.de.

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