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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....
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cold Spring Harbor Laboratory Press
2017
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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. |
format | Online Article Text |
id | pubmed-5287111 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Cold Spring Harbor Laboratory Press |
record_format | MEDLINE/PubMed |
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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