Defective chromosome segregation during mitosis is a major contributor to malignant transformation. Higher eukaryotes have developed a strategy to eliminate mitotic-incompetent cells, so called Mitotic Catastrophe. Mitotic Catastrophe is an oncosuppressive mechanism that senses mitotic failure and responds by driving a cell into an irreversible antiproliferative state of death or senescence. Failure of the Mitotic Catastrophe process allows the continued proliferation of defective cells, leading to aneuploidy and tumour onset. Thus, the induction of Mitotic Catastrophe constitutes an important therapeutic endpoint.

 Mitotic Catastrophe is driven by a complex, yet poorly understood, signalling cascade that involves extensive crosstalk between cell division and cell death pathways. Our lab is particularly interested in understanding the molecular signals that connect mitotic arrest and cell death and we are investigating the role of mitochondrial proteins in the cross-talk between these independent but equally important events.

 We use state-of-the-art proteomic and biochemical technologies to identify components of the mitotic machinery that regulate mitotic cell death. We have found that mitotic specific cyclin-dependent kinase 1 (Cdk1) directly phosphorylates the pro-apoptotic BH3-only Bcl-2 family member, Bim, an event that is mediated by a temporal interaction between cyclin B1 and Bim during mitosis (Mac Fhearraigh et al., 2011).  Thus, the hyperphosphorylation of Bim may be an important event that dictates cell fate following prolonged arrest.

 Targeting mitotic exit is also an important anti-cancer strategy. Cytokinesis represents the last stage of mitosis and involves the abscission of the intercellular bridge separating two daughter cells. Centrosome proteins are implicated in cytokinesis, yet, the identity and function of key regulators are only beginning to emerge. We have recently shown that the peptidyl prolyl isomerase, cyclophilin A,  is a novel centrosome protein that is essential for the timely completion of cytokinesis (Bannon et al., 2012). Thus, we have identified a druggable target whose function is indispensable for faithful cell division and we are currently investigating the potential of small molecule cyclophilin A inhibitors as novel anti-cytokinetic agents.                                                                                                                                                                

• Professor Gerard I. Evan  UCSF
• Professor D. Clive Williams   TCD
• Dr Daniela Zisterer  TCD
• Dr Jean-Francois Guichou, University of Montpellier, France
• Professor Alan Chavanieu, University of Montpellier, France