title: The PIDDosome activates p53 in response to supernumerary centrosomes.
abstract: 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.
authors.affiliation: Division of Developmental Immunology, Biocenter, Medical University of Innsbruck, 6020 Innsbruck, Austria.
authors.forename: Luca L
authors.initials: LL
authors.lastname: Fava
authors.affiliation: Division of Developmental Immunology, Biocenter, Medical University of Innsbruck, 6020 Innsbruck, Austria.
authors.forename: Fabian
authors.initials: F
authors.lastname: Schuler
authors.affiliation: Division of Developmental Immunology, Biocenter, Medical University of Innsbruck, 6020 Innsbruck, Austria.
authors.forename: Valentina
authors.initials: V
authors.lastname: Sladky
authors.affiliation: Division of Developmental Immunology, Biocenter, Medical University of Innsbruck, 6020 Innsbruck, Austria.
authors.forename: Manuel D
authors.initials: MD
authors.lastname: Haschka
authors.affiliation: Division of Developmental Immunology, Biocenter, Medical University of Innsbruck, 6020 Innsbruck, Austria.
authors.forename: Claudia
authors.initials: C
authors.lastname: Soratroi
authors.affiliation: Division of Developmental Immunology, Biocenter, Medical University of Innsbruck, 6020 Innsbruck, Austria.
authors.forename: Lisa
authors.initials: L
authors.lastname: Eiterer
authors.affiliation: Department of Internal Medicine VI, Infectious Diseases, Immunology, Rheumatology, Pneumology, Medical University of Innsbruck, 6020 Innsbruck, Austria.
authors.forename: Egon
authors.initials: E
authors.lastname: Demetz
authors.affiliation: Department of Internal Medicine VI, Infectious Diseases, Immunology, Rheumatology, Pneumology, Medical University of Innsbruck, 6020 Innsbruck, Austria.
authors.forename: Guenter
authors.initials: G
authors.lastname: Weiss
authors.affiliation: Division of Molecular Pathophysiology, Biocenter, Medical University of Innsbruck, 6020 Innsbruck, Austria.
authors.forename: Stephan
authors.initials: S
authors.lastname: Geley
authors.affiliation: Biozentrum, University of Basel, 4056 Basel, Switzerland.
authors.forename: Erich A
authors.initials: EA
authors.lastname: Nigg
authors.affiliation: Division of Developmental Immunology, Biocenter, Medical University of Innsbruck, 6020 Innsbruck, Austria.|Tyrolean Cancer Research Institute, 6020 Innsbruck, Austria.
authors.forename: Andreas
authors.initials: A
authors.lastname: Villunger
mesh_terms: D000072283:A549 Cells; D000818:Animals; D053420:CRADD Signaling Adaptor Protein / Q000378:metabolism; D053143:Caspase 2 / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000235:genetics; D002478:Cells, Cultured; D018385:Centrosome / Q000473:pathology / Q000502:physiology*; D048749:Cytokinesis / Q000235:genetics; D053418:Death Domain Receptor Signaling Adaptor Proteins / Q000378:metabolism; D016158:Genes, p53 / Q000235:genetics*; D006801:Humans; D008099:Liver / Q000166:cytology / Q000196:embryology; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism*; D038081:Organogenesis / Q000235:genetics; D015533:Transcriptional Activation / Q000235:genetics*
chemical_list: D053420:CRADD Signaling Adaptor Protein; C484481:Cradd protein, mouse; D053418:Death Domain Receptor Signaling Adaptor Proteins; D046912:Multiprotein Complexes; C414729:Pidd1 protein, mouse; D053143:Caspase 2
keywords: cell division; centrosome; cytokinesis failure; p53