DNA topoisomerase II (topo II) is an essential nuclear enzyme required for chromatin condensation and chromosome segregation during mitosis. Forced overexpression of topo IIα was found to cause morphological changes in recipient cells associated with apoptosis. This induction of apoptosis required nuclear localization of topo IIα, yet was independent of the DNA cleavage-religation activity of the enzyme. Apoptosis mediated by topo IIα deregulation was blocked by overexpression of crmA, a specific inhibitor of certain caspases, but not by bcl-2. topo IIα-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 IIα levels through the cell cycle in that deregulation of topo IIα expression results in apoptotic cell death.
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.