Caspases are conserved cysteine protease with defined roles in both apoptotic and non-apoptotic pathways, including inflammation and necroptosis. We have previously described additional roles for Caspase-2 in tumour suppression, DNA damage, oxidative stress response, metabolic regulation and ageing. Our recent findings have demonstrated an important role for caspase-2 in mitotic catastrophe, by preventing the survival of aberrant mitotic cells including aneuploid cells. We have shown this by live-cell imaging analysis and the clonogenic survival of giant, multi-nucleated and aneuploid Casp2-/- cells following pro-longed mitotic arrest and mitotic failure. Survival of these aberrant Casp2-/- cells is also observed in mouse models of oxidative stress and tumourigenesis and is associated with accelerated hepatocellular carcinoma in a diethylnitrosamine-induced liver cancer mouse model. In addition, Casp2-/- bone marrow from aged mice show increased aneuploidy, indicating a link with cellular ageing. The focus of our current work is determining how caspase-2 limits aneuploidy and whether this is associated with caspase-2 mediated regulation of oxidative stress and/or tumour suppression.
The increased aneuploidy in Casp2-/- cells is partly due to reduced activation of the canonical apoptosis pathway due to reduced cleavage of the caspase-2 substrate Bid. We have generated a caspase-2 catalytic mouse mutant (C320S) strain and have demonstrated that caspase-2 protease activity is required to limit aneuploidy and restrain aneuploidy tolerance. Interestingly, aside from its cell-death inducing activity, caspase-2 can cleave (and inactivate) Mdm2, which is important for inducing p53-mediated cell cycle arrest in aneuploid cells. We are currently investigating the mechanisms regulating caspase-2-mediated pathways that prevent aneuploidy. As part of this we have identified caspase-2 post-translational modifications, including novel phosphorylation and ubiquitination sites that may regulate its activation and function. These findings will be discussed and will highlight potential mechanisms that limit aneuploidy tolerance and tumourigenesis.