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Molecular and Cellular Biology, June 2005, p. 5040-5051, Vol. 25, No. 12
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.12.5040-5051.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

DNA Topoisomerase I Is a Cofactor for c-Jun in the Regulation of Epidermal Growth Factor Receptor Expression and Cancer Cell Proliferation

Antoine Mialon,^1,2, Matti Sankinen,^1,2, Henrik Söderström,^1,2 Teemu T. Junttila,^2,3,5 Tim Holmström,¹ Riku Koivusalo,³ Anastassios C. Papageorgiou,¹ Randall S. Johnson,⁶ Sakari Hietanen,^3,4 Klaus Elenius,^2,3 and Jukka Westermarck^1,2*

Centre for Biotechnology, University of Turku and Åbo Akademi University, 20520 Turku, Finland,¹ Department of Medical Biochemistry and Molecular Biology, University of Turku, 20520 Turku, Finland,² Medicity Research Laboratory, University of Turku, 20520 Turku, Finland,³ Department of Obstetrics and Gynecology, Turku University Hospital, 20520 Turku, Finland,⁴ Turku Graduate School of Biomedical Sciences, University of Turku, 20520 Turku, Finland,⁵ Molecular Biology Section, Division of Biological Sciences, School of Medicine, University of California, San Diego, La Jolla, California 92093⁶

Received 30 August 2004/ Returned for modification 22 February 2005/ Accepted 2 March 2005

DNA topoisomerase I (Topo I) is a molecular target for the anticancer agent topotecan in the treatment of small cell lung cancer and ovarian carcinomas. However, the molecular mechanisms by which topotecan treatment inhibits cancer cell proliferation are unclear. We describe here the identification of Topo I as a novel endogenous interaction partner for transcription factor c-Jun. Reciprocal coimmunoprecipitation analysis showed that Topo I and c-Jun interact in transformed human cells in a manner that is dependent on JNK activity. c-Jun target gene epidermal growth factor receptor (EGFR) was identified as a novel gene whose expression was specifically inhibited by topotecan. Moreover, Topo I overexpression supported c-Jun-mediated reporter gene activation and both genetic and chemical inhibition of c-Jun converted cells resistant to topotecan-elicited EGFR downregulation. Topotecan-elicited suppression of proliferation was rescued by exogenously expressed EGFR. Furthermore, we demonstrate the cooperation of the JNK-c-Jun pathway, Topo I, and EGFR in the positive regulation of HT-1080 cell proliferation. Together, these results have identified transcriptional coactivator Topo I as a first endogenous cofactor for c-Jun in the regulation of cell proliferation. In addition, the results of the present study strongly suggest that inhibition of EGFR expression is a novel mechanism by which topotecan inhibits cell proliferation in cancer therapy.

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* Corresponding author. Mailing address: Centre for Biotechnology, University of Turku and Åbo Akademi University, Tykistökatu 6B, 20520 Turku, Finland. Phone: 358-2-3338242. Fax: 358-2-3338000. E-mail: jukwes{at}utu.fi.

A.M. and M.S. contributed equally to this study.

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Molecular and Cellular Biology, June 2005, p. 5040-5051, Vol. 25, No. 12
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.12.5040-5051.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

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