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

Abstract

ABSTRACTThe Survivin protein has roles in repairing incorrect microtubule-kinetochore attachments at prometaphase and the faithful execution of cytokinesis, both as part of thechromosomalpassengercomplex(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). The early prophase blockage in cells lacking Survivin is demonstrated by the presence of an intact nuclear lamina and low Cdk1 activity (4). Interestingly, Survivin and Cdk1 form a complexin vivo. This interaction peaks at mitosis, and its molecular targeting indicates that Survivin is needed for Cdk1 to be active. In this regard, escaping the blockage induced by Survivin abrogation leads to multiple mitotic defects, ormitotic catastrophe, and eventually cell death. Mechanistically, recombinant Survivin can induce the activation of Cdk1 via Cdc25in vitro. Coincidentally, Cdk1 mislocalizes at the centrosome when Survivin is not expressed. Moreover, Survivin directly interacts with phosphatase Cdc25B, bothin vitroandin vivo, and in the absence of the former, an inactive cytosolic Cdc25B-Cdk1-Cyclin B1 complex accumulates, which coincides with the mitotic arrest induced by Survivin depletion. Finally, in agreement with a role for Survivin in the early activation of Cdk1, the G2/early prophase accumulation induced in HeLa cells by Survivin abrogation could be bypassed by a gain-of-function Cdc25B mutant, which drove cells into mitosis.