PKC epsilon Controls Mitotic Progression by Regulating Centrosome Migration and Mitotic Spindle Assembly

摘要

To form a proper mitotic spindle, centrosomes must be duplicated and driven poleward in a timely and controlled fashion. Improper timing of centrosome separation and errors in mitotic spindle assembly may lead to chromosome instability, a hallmark of cancer. Protein kinase Cepsilon (PKCe) has recently emerged as a regulator of several cell-cycle processes associated with the resolution of mitotic catenation during the metaphase-anaphase transition and in regulating the abscission checkpoint. However, an engagement of PKCe in earlier (pre) mitotic events has not been addressed. Here, we now establish that PKCe controls prophase-to-metaphase progression by coordinating centrosome migration and mitotic spindle assembly in transformed cells. This control is exerted through cytoplasmic dynein function. Importantly, it is also demonstrated that the PKCe dependency of mitotic spindle organization is correlated with the nonfunctionality of the TOPO2A-dependent G(2) checkpoint, a characteristic of many transformed cells. Thus, PKCe appears to become specifically engaged in a programme of controls that are required to support cell-cycle progression in transformed cells, advocating for PKCe as a potential cancer therapeutic target. (C) 2017 AACR.