Survivin Mediates Mitotic Onset in HeLa Cells Through Activation of the Cdk1-Cdc25B Axis

The Survivin protein has roles in repairing incorrect microtubule-kinetochore attachments at prometaphase, and the faithful execution of cytokinesis, both as part of the chromosomal passenger complex (CPC). In its absence, mitotic errors often occur that lead to chromosome missegregation, a cause of aneuploidy, polyploidy and ultimately cancer. Adding to these well-known roles of Survivin, this paper now shows for the first time that this protein is required for cancer cells to enter mitosis, and that, in its absence, HeLa cells accumulate at early prophase, or prior to prometaphase as reported before. This early prophase blockage is demonstrated by the inability of Survivin-depleted cells to disassemble their nuclear lamina and their low Cdk1 activity. Importantly, escaping the arrest induced by the Survivin double mutant SUR D70A/D71A leads to multiple mitotic defects, or mitotic catastrophe, and eventually cell death. Mechanistically, Cdk1 does not localize at the centrosome in the absence of Survivin, pointing at this latter protein contributing to the activation of the mitotic kinase via Cdc25B. Furthermore, absence of Survivin leads to an inactive cytosolic Cdc25B-Cdk1-Cyclin B1 complex, which seems to indicate a role for Survivin in bridging this complex and its centrosomal activator/s. Interestingly, the drop in Cdc25B activity caused by interference with the Survivin’s function could be rescued when Survivin-depleted HeLa cell lysates were incubated with the recombinant Survivin protein. Also, a role for Survivin in the Cdc25B-mediated activation of Cdk1, and concomitant prophase to prometaphase transition could be confirmed by expression of a gain-of-function Cdc25B mutant, which overrode the G2/prophase blockage caused by Survivin depletion.