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

Aneuploidy Animals CRADD Signaling Adaptor Protein / physiology Caspase 2 / physiology Centrosome Cyclin-Dependent Kinase Inhibitor p21 / physiology Cytokinesis Death Domain Receptor Signaling Adaptor Proteins / physiology E2F Transcription Factors / physiology Female Hepatocytes / cytology Humans Liver Regeneration Male Mice Mice, Knockout Polyploidy Tumor Suppressor Protein p53 / physiology

PIDDosome caspases liver development p53 polyploidy regeneration

Journal

Developmental cell

ISSN: 1878-1551

Titre abrégé: Dev Cell

Pays: United States

ID NLM: 101120028

Informations de publication

Date de publication:
10 02 2020

Historique:

received: 16 05 2019

revised: 27 10 2019

accepted: 24 12 2019

pubmed: 28 1 2020

medline: 5 8 2020

entrez: 28 1 2020

Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1016/j.devcel.2019.12.016 PMID: 31983631

pubmed: 31983631

pii: S1534-5807(19)31039-1

doi: 10.1016/j.devcel.2019.12.016

pii:

doi:

Substances chimiques

CRADD Signaling Adaptor Protein 0

Cdkn1a protein, mouse 0

Cradd protein, mouse 0

Cyclin-Dependent Kinase Inhibitor p21 0

Death Domain Receptor Signaling Adaptor Proteins 0

E2F Transcription Factors 0

Pidd1 protein, mouse 0

Trp53 protein, mouse 0

Tumor Suppressor Protein p53 0

Casp2 protein, mouse EC 3.4.22.-

Caspase 2 EC 3.4.22.-

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

Pagination

335-349.e7

Informations de copyright

Déclaration de conflit d'intérêts

Declaration of Interests The authors declare no competing interests.