p53 accumulation following cytokinesis failure in the absence of caspase-2

Caspase-2 is the most conserved member of the caspase family, but its physiological function(s) remains a matter of some debate [ 1 ]. Recent work suggests that caspase-2 deficiency in mice makes animals more susceptible to tumorigenesis in various models leading to the concept that caspase-2 is a tumor suppressor [ 1 , 2 , 3 ]. One of the key characteristics of caspase-2 knockout (KO) MEFs in culture and cells from caspase-2-deficient tumors is a high degree of chromosomal instability (CIN), suggesting that caspase-2 prevents accumulation of aneuploid cells and CIN [ 1 , 2 , 3 , 4 ]. Real time imaging of KO cells following prolonged spindle-assembly checkpoint arrest suggests that caspase-2 is required for the deletion of cells carrying mitotic aberrations and this requires the catalytic function of caspase-2 [ 5 ]. Another model that may explain increased CIN is suggested by Fava et al. [ 6 ]. Their data suggest that supernumerary centrosomes trigger PIDDosome (a caspase-2 activating platform containing Pidd and Raidd)-dependent caspase-2 activation, which then cleaves MDM2, resulting in p53 stabilization and p21-dependent cell cycle arrest [ 6 ]. Thus PIDDosome-mediated caspase-2 activation is predicted to be required to restrain polyploidization, preventing CIN, and therefore cancer. The main caveat with such a model is that, unlike Casp2 KO animals, Pidd and Raidd KO mice are not susceptible to enhanced tumourigenesis indicating that PIDDosome is not responsible for the tumor suppressor function of caspase-2 [ 7 , 8 ].