The Caspase-2-PIDDosome activates p53 in response to cytokinesis failure

March 11th 2016
Versione stampabile

Venue: Edificio Povo 2, via Sommarive nr. 9, Povo (Tn) - Room B103
 At 2:00 p.m.

  • Luca Fava​ -  Division of Developmental Immunology, Innsbruck Medical University, Innsbruck, Austria

Caspase-2 has been implicated in several essential cellular processes, most notably in the DNA damage response (DDR) and the maintenance of genome integrity. Strikingly, however, murine models devoid of Caspase-2 or of members of its postulated activation platform, the PIDDosome, failed to reveal the phenotypes expected by a defective DDR, highlighting the fact that the physiological function of Caspase-2 is poorly understood. Here we perturbed the faithfulness of cell division and thereby identified cytokinesis failure as a genuine trigger for PIDDosome assembly and Caspase-2 activation. The PIDDosome did not promote apoptosis but induced Caspase-2-mediated cleavage of MDM2, resulting into p53 stabilization and p21 transactivation. PIDDosome deficiency prevented activation of p53/p21 upon cytokinesis failure, enhanced the proliferative capacity of polyploid cells, thereby enhancing excessive polyploidization in vitro and in vivo. Taken together, we show that the PIDDosome restrains the proliferative capacity of polyploidy cells via p53.