Identification of a novel Bax-Cdk1 signalling complex that links activation of the mitotic checkpoint to apoptosis.

In eucaryotes entry into and exit from mitosis is regulated, respectively, by the transient activation and inactivation of Cdk1. Taxol, an anti-microtubule anti-cancer drug, prevents microtubule-kinetochore attachments to induce Spindle Assembly Checkpoint (SAC, also known as the Mitotic Checkpoint)-activated mitotic arrest. SAC activation causes mitotic arrest by chronically activating Cdk1. One consequence of prolonged Cdk1 activation is cell death. However, the cytoplasmic signal(s) that link SAC activation to the initiation of cell death remain unknown. We show here that activated Cdk1 forms a complex with the pro-apoptotic proteins Bax and Bak during SAC-induced apoptosis. Bax and Bak-mediated delivery of activated Cdk1 to the mitochondrion is essential for the phosphorylation of the anti-apoptotic proteins Bcl-2 and Bcl-xL and the induction of cell death. The interaction between a key cell cycle control protein and key pro-apoptotic proteins identify the Cdk1-Bax and Cdk1-Bak complexes as the long-sought-after cytoplasmic signal that couple SAC activation to the induction of apoptotic cell death.