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J Biol Chem, Vol. 275, Issue 18, 13948-13954, May 5, 2000

Modulation of Human DNA Topoisomerase IIalpha Function by Interaction with 14-3-3epsilon *

Ebba U. KurzDagger , Kelly B. LeaderDagger , David J. KrollDagger §, Michael Clark||, and Frank Gieseler||

From the Dagger  Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Health Sciences Center and § University of Colorado Cancer Center, Denver, Colorado 80262 and the || University Hospital, Klinik für Allgemeine Innere Medizin, Christian Albrechts University, 24105 Kiel, Germany

Human DNA topoisomerase IIalpha (topo II), a ubiquitous nuclear enzyme, is essential for normal and neoplastic cellular proliferation and survival. Several common anticancer drugs exert their cytotoxic effects through interaction with topo II. In experimental systems, altered topo II expression has been associated with the appearance of drug resistance. This mechanism, however, does not adequately account for clinical cases of resistance to topo II-directed drugs. Modulation by protein-protein interactions represents one mechanism of topo II regulation that has not been extensively defined. Our laboratory has identified 14-3-3epsilon as a topo II-interacting protein. In this study, glutathione S-transferase co-precipitation, affinity column chromatography, and immunoprecipitations confirm the authenticity of these interactions. Three assays evaluate the impact of 14-3-3epsilon on distinct topo II functional properties. Using both a modified alkaline comet assay and a DNA cleavage assay, we demonstrate that 14-3-3epsilon negatively affects the ability of the chemotherapeutic, etoposide, to trap topo II in cleavable complexes with DNA, thereby preventing DNA strand breaks. By electrophoretic mobility shift assay, this appears to be due to reduced DNA binding activity. The association of topo II with 14-3-3 proteins does not extend to all 14-3-3 isoforms. No protein interaction or disruption of topo II function was observed with 14-3-3sigma .

* This work was supported by National Institutes of Health Grant CA-76201 (to D. J. K.) and a grant from the Cancer League of Colorado (to E. U. K.).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: Dept. of Pharmaceutical Sciences, Box C238, University of Colorado Health Sciences Center, 4200 E. Ninth Ave., Denver, CO 80262-0238. Fax: 303-315-6281; E-mail: david.kroll@uchsc.edu.

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