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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....

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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
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author 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
author_facet 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
author_sort Fava, Luca L.
collection PubMed
description 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.
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spelling pubmed-52871112017-02-14 The PIDDosome activates p53 in response to supernumerary centrosomes 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 Genes Dev Research Paper 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. Cold Spring Harbor Laboratory Press 2017-01-01 /pmc/articles/PMC5287111/ /pubmed/28130345 http://dx.doi.org/10.1101/gad.289728.116 Text en © 2017 Fava et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by/4.0/ This article, published in Genes & Development, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/.
spellingShingle Research Paper
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
The PIDDosome activates p53 in response to supernumerary centrosomes
title The PIDDosome activates p53 in response to supernumerary centrosomes
title_full The PIDDosome activates p53 in response to supernumerary centrosomes
title_fullStr The PIDDosome activates p53 in response to supernumerary centrosomes
title_full_unstemmed The PIDDosome activates p53 in response to supernumerary centrosomes
title_short The PIDDosome activates p53 in response to supernumerary centrosomes
title_sort piddosome activates p53 in response to supernumerary centrosomes
topic Research Paper
url 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
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