Figure 3.

Mitotic errors can trigger activation of p53. (A) Lagging chromosomes that become damaged in the cleavage furrow or in micronuclei can elicit the canonical DNA damage repair pathway that activates p53. In addition, aneuploidy can also cause increased reactive oxidative species that lead to activation of DNA damage signaling. (B) Cytokinesis failure has been proposed to activate p53 through two distinct pathways. (1) Activation of the Hippo pathway. The Hippo pathway kinase LATS2 is activated in a tetraploid cell, leading to the phosphorylation and cytoplasmic sequestration of the transcription factor YAP. In addition, LATS2 binds and inactivates MDM2, a negative regulator of p53 stability. Inhibiting MDM2 allows for the increased accumulation of p53, which up-regulates p21 to elicit a growth arrest. (2) Activation of PIDDosome signaling. Tetraploid cells activate the PIDDosome, a multiprotein complex comprised of PIDD and RAIDD that in turn activates Caspase-2 (CASP2). Caspase 2 cleaves and inactivates MDM2, allowing p53 stabilization.