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) (1). In this context, errors frequently lead to aneuploidy, polyploidy and cancer (1). Adding to these well-known roles of this protein, this paper now shows for the first time that Survivin is required for cancer cells to enter mitosis, and that, in its absence, HeLa cells accumulate at early prophase, or prior to reported before (2, 3). This early prophase blockage is demonstrated by the presence of an intact nuclear lamina and low Cdk1 activity (4). Importantly, escaping the arrest induced by Survivin abrogation 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. Also, the recombinant Survivin protein can induce the activation of the Cdk1 kinase via the Cdc25 phosphatase in vitro . Moreover, Survivin directly interacts with the Cdc25B isoform, both in vitro and in vivo , and in its absence, an inactive cytosolic Cdc25B-Cdk1-Cyclin B1 complex accumulates. Finally, in agreement with a role for Survivin in the early activation of Cdk1, the early prophase accumulation induced in HeLa cells by Survivin abrogation could be bypassed by a gain-of-function Cdc25B mutant, which drove cells back into mitosis.