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Induction of Apoptosis by Deregulated Expression of DNA Topoisomerase II¹

Departments of Pharmacology [J. P. M., G. J. G.], Medicine [G. J. G.], and Interdepartmental Division of Oncology [G. J. G.], University of Toronto, Toronto, Ontario, M5S 1A8 Canada

DNA topoisomerase II (topo II) is an essential nuclear enzyme required for chromatin condensation and chromosome segregation during mitosis. Forced overexpression of topo II was found to cause morphological changes in recipient cells associated with apoptosis. This induction of apoptosis required nuclear localization of topo II, yet was independent of the DNA cleavage-religation activity of the enzyme. Apoptosis mediated by topo II deregulation was blocked by overexpression of crmA, a specific inhibitor of certain caspases, but not by bcl-2. topo II-induced apoptosis was also blocked by overexpression of a dominant-acting mutant of stress-activated protein kinase kinase (SEK1/MKK4) but not by the overexpression of its normal counterpart. Furthermore, apoptosis was blocked by coexpression of a dominant-negative form of the cyclin-dependent kinase cdk2 but not by dominant-negative cdc2. These results provide a rationale for the tight regulation of topo II levels through the cell cycle in that deregulation of topo II expression results in apoptotic cell death.

¹ This work was supported by Grant NCI-7439 from the National Cancer Institute of Canada and Grant MT-13158 from the Medical Research Council of Canada. J. P. M. was supported by an Ontario Graduate Scholarship.

² Present address: Molecular Pharmacology and Therapeutics Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021.

³ To whom requests for reprints should be addressed, at Interdepartmental Division of Oncology, University of Toronto, Medical Sciences Building, Room 2113, I King's College Circle, Toronto, Ontario, M5S 1A8 Canada. Phone: (416) 978-3649; Fax: (416) 971-2462; E-mail: gerald.goldenberg@utoronto.ca.

Received 6/11/98. Accepted 9/ 1/98.

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