Molecular pathways that limit the proliferation of cells with numerical centrosome aberrations. Distinct molecular pathways mediate cell cycle arrest or cell death in response to centrosome loss (left) or centrosome amplification (right). While stabilization of p53, a key mediator of cell cycle arrest and cell death, occurs in both conditions, upstream signaling pathways that regulate p53 differ in the condition of centrosome loss and amplification. (Left) Centrosome loss activates the USP28-53BP1-p53 mediated, mitotic surveillance pathway that is also activated by prolonged mitosis. [USP28, ubiquitin-specific protease 28 that interacts with 53BP1 (83); 53BP1, a p53 binding protein 1 (84)]. (Right) Centrosome amplification, on the other hand, activates the LATS2-mediated Hippo pathway or PIDDosome-mediated pathway. In the LATS2-mediated Hippo pathway, LATS2 binds and inhibits MDM2, an E3 ubiquitin ligase for degradation of p53, thus stabilizing p53 (85). In the PIDDosome-mediated pathway, PIDDosome is a protein complex composed of PIDD1 (protein with a death domain induced by p53), RAIDD (adaptor protein with a caspase-recruitment domain and death domain), and caspase-2 (86). The centriolar distal appendage protein ANKRD26 recruits PIDD1 to the distal appendage of mature centrioles, initiating the PIDDosome activation and the subsequent caspase-2 activation (enlarged box region). Consequently, activated caspase-2 or LATS2 suppresses the p53 inhibitor MDM2, leading to p53 stabilization (85, 87).
