E2F-Family Members Engage the PIDDosome to Limit Hepatocyte Ploidy in Liver Development and Regeneration

Valentina C Sladky, Katja Knapp, Claudia Soratroi, Julia Heppke, Felix Eichin, Lourdes Rocamora-Reverte, Tamas G Szabo, Laura Bongiovanni, Bart Westendorp, Eva Moreno, Elsbeth A van Liere, Bjorn Bakker, Diana C J Spierings, René Wardenaar, David Pereyra, Patrick Starlinger, Simon Schultze, Michael Trauner, Tatjana Stojakovic, Hubert ScharnaglLuca L Fava, Floris Foijer, Alain de Bruin, Andreas Villunger

Research output: Contribution to journalArticleAcademicpeer-review

12 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)335-349
Number of pages15
JournalDevelopmental Cell
Volume52
Issue number3
Early online date13-Jan-2020
DOIs
Publication statusPublished - 10-Feb-2020

Cite this