The PIDDosome activates p53 in response to supernumerary centrosomes
| Autor: | 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 |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
p53
Transcriptional Activation Death Domain Receptor Signaling Adaptor Proteins Cell division Cells Organogenesis Centrosome Cytokinesis failure A549 Cells Animals CRADD Signaling Adaptor Protein Caspase 2 Cell Cycle Checkpoints Cells Cultured Cytokinesis Genes p53 Humans Liver Mice Multiprotein Complexes Genetics Developmental Biology Cultured Cell Cycle Genes Tumor Suppressor Protein p53 Research Paper |
| Zdroj: | Genes & development |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|