Figure 1

Modulation of mitochondrial apoptosis in mitosis. (a) Central to mitochondrial apoptosis is the permeabilization of mitochondrial outer membrane by Bax and/or Bak multimers, leading to Cytochrome c release in the cytoplasm and subsequent activation of Caspase-9. This process is on one hand inhibited in mitosis by CDK1 (by direct phosphorylation of Caspase-2/8/9) and on the other hand promoted by inhibition of ‘Bax/Bak inhibitors’, that is, Bcl-2, Bcl-xL and Mcl-1. This latter phenomenon can occur either by direct inactivation of Bcl-2 and Bcl-xL by phosphorylation or by phosphorylation-dependent degradation of Mcl-1. Such degradation can have CDK1 and/or CKII/JNK/p38 as priming kinases and the APC/C-Cdc20 and/or SCF-FBW7 as phosphorylation-dependent Ubiquitin ligases, respectively. (b) Aurora A (and/or possibly Aurora B) kinase can reversibly phosphorylate Bim in mitosis and this modification is counteracted by the action of PP2A phosphatase. Phosphorylated Bim at Ser94/98 is selectively bound by SCF-βTrCP1, polyubiquitinated and degraded via the proteasome. Although the role of Bim in mitotic death remains to be fully understood, its regulation at the level of protein stability reveals how Aurora inhibitors might be used to promote cell death in mitosis