Abstract

Caspase-2, the most evolutionarily conserved member of the caspase family, has redundant function in cell death during development. Our recent work suggests that caspase-2 is a tumour suppressor as caspase-2 deficiency enhances tumourigenesis in several mouse models. Interestingly caspase-2-deficient tumours always show enhanced chromosomal instability (CIN) and aneuploidy. Increased CIN and aneuploidy are also characteristics of caspase-2-deficient mouse embryonic fibroblasts in culture as well as human tumour cells with CASP2 gene knockout. We further found that caspase-2 is required for apoptotic deletion of cells carrying mitotic defects. Thus apoptotic activity of caspase-2 is necessary for deleting cells with CIN to limit aneuploidy and we propose that this is linked to the tumour suppressor function of caspase-2. Other recent studies have suggested that in response of cytokinesis failure caspase-2-mediates cleavage of Mdm2 that results in p53 stabilization and cell cycle arrest, thus preventing polyploidy. It is therefore possible that caspase-2 is involved in two checkpoints, one leading to apoptosis of cells with CIN and the other, cell cycle arrest following cytokinesis failure. We are now investigating how caspase-2 senses mitotic errors and becomes activated and how is such activation regulated.