Cargando…

The PIDDosome activates p53 in response to supernumerary centrosomes

Centrosomes, the main microtubule-organizing centers in animal cells, are replicated exactly once during the cell division cycle to form the poles of the mitotic spindle. Supernumerary centrosomes can lead to aberrant cell division and have been causally linked to chromosomal instability and cancer....

Descripción completa

Detalles Bibliográficos
Autores principales: Fava, Luca L., Schuler, Fabian, Sladky, Valentina, Haschka, Manuel D., Soratroi, Claudia, Eiterer, Lisa, Demetz, Egon, Weiss, Guenter, Geley, Stephan, Nigg, Erich A., Villunger, Andreas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5287111/
https://www.ncbi.nlm.nih.gov/pubmed/28130345
http://dx.doi.org/10.1101/gad.289728.116
Descripción
Sumario:Centrosomes, the main microtubule-organizing centers in animal cells, are replicated exactly once during the cell division cycle to form the poles of the mitotic spindle. Supernumerary centrosomes can lead to aberrant cell division and have been causally linked to chromosomal instability and cancer. Here, we report that an increase in the number of mature centrosomes, generated by disrupting cytokinesis or forcing centrosome overduplication, triggers the activation of the PIDDosome multiprotein complex, leading to Caspase-2-mediated MDM2 cleavage, p53 stabilization, and p21-dependent cell cycle arrest. This pathway also restrains the extent of developmentally scheduled polyploidization by regulating p53 levels in hepatocytes during liver organogenesis. Taken together, the PIDDosome acts as a first barrier, engaging p53 to halt the proliferation of cells carrying more than one mature centrosome to maintain genome integrity.