E2F-Family Members Engage the PIDDosome to Limit Hepatocyte Ploidy in Liver Development and Regeneration
| Autor: | Sladky, Valentina C., Knapp, Katja, Soratroi, Claudia, Heppke, Julia, Eichin, Felix, Rocamora-Reverte, Lourdes, Szabo, Tamas G., Bongiovanni, Laura, Westendorp, Bart, Moreno, Eva, van Liere, Elsbeth A., Bakker, Bjorn, Spierings, Diana C.J., Wardenaar, René, Pereyra, David, Starlinger, Patrick, Schultze, Simon, Trauner, Michael, Stojakovic, Tatjana, Scharnagl, Hubert, Fava, Luca L., Foijer, Floris, de Bruin, Alain, Villunger, Andreas |
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| Přispěvatelé: | Damage and Repair in Cancer Development and Cancer Treatment (DARE), Stem Cell Aging Leukemia and Lymphoma (SALL), Restoring Organ Function by Means of Regenerative Medicine (REGENERATE), Pathobiologie, dPB RMSC, Dep Biomolecular Health Sciences |
| Rok vydání: | 2019 |
| Předmět: |
p53
Cyclin-Dependent Kinase Inhibitor p21 Male Death Domain Receptor Signaling Adaptor Proteins caspases liver development PIDDosome polyploidy regeneration Polyploidy Mice Animals Humans Cytokinesis Centrosome Mice Knockout Caspase 2 CRADD Signaling Adaptor Protein Aneuploidy E2F Transcription Factors Liver Regeneration Hepatocytes Female Tumor Suppressor Protein p53 |
| Zdroj: | Developmental Cell Developmental Cell, 52(3), 335-349. CELL PRESS |
| ISSN: | 1878-1551 1534-5807 |
| Popis: | E2F transcription factors control the cytokinesis machinery and thereby ploidy in hepatocytes. If or how these proteins limit proliferation of polyploid cells with extra centrosomes remains unknown. Here, we show that the PIDDosome, a signaling platform essential for caspase-2-activation, limits hepatocyte ploidy and is instructed by the E2F network to control p53 in the developing as well as regenerating liver. Casp2 and Pidd1 act as direct transcriptional targets of E2F1 and its antagonists, E2F7 and E2F8, that together co-regulate PIDDosome expression during juvenile liver growth and regeneration. Of note, whereas hepatocyte aneuploidy correlates with the basal ploidy state, the degree of aneuploidy itself is not limited by PIDDosome-dependent p53 activation. Finally, we provide evidence that the same signaling network is engaged to control ploidy in the human liver after resection. Our study defines the PIDDosome as a primary target to manipulate hepatocyte ploidy and proliferation rates in the regenerating liver. Sladky et al. report a key role for the PIDDosome in regulating p53 activation to limit hepatocyte polyploidy during juvenile liver growth and regeneration. Expression of essential PIDDosome components is controlled by a E2F-family regulated circuitry. The study defines the PIDDosome as a putative target to enhance liver regeneration. |
| Databáze: | OpenAIRE |
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