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1.
Dev Cell ; 52(3): 335-349.e7, 2020 02 10.
Article in English | MEDLINE | ID: mdl-31983631

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.


Subject(s)
Caspase 2/physiology , Death Domain Receptor Signaling Adaptor Proteins/physiology , E2F Transcription Factors/physiology , Hepatocytes/cytology , Liver Regeneration , Polyploidy , Tumor Suppressor Protein p53/physiology , Aneuploidy , Animals , CRADD Signaling Adaptor Protein/physiology , Centrosome , Cyclin-Dependent Kinase Inhibitor p21/physiology , Cytokinesis , Female , Hepatocytes/metabolism , Humans , Male , Mice , Mice, Knockout
2.
J Cell Sci ; 130(22): 3779-3787, 2017 Nov 15.
Article in English | MEDLINE | ID: mdl-29142064

ABSTRACT

The PIDDosome is often used as the alias for a multi-protein complex that includes the p53-induced death domain protein 1 (PIDD1), the bipartite linker protein CRADD (also known as RAIDD) and the pro-form of an endopeptidase belonging to the caspase family, i.e. caspase-2. Yet, PIDD1 variants can also interact with a number of other proteins that include RIPK1 (also known as RIP1) and IKBKG (also known as NEMO), PCNA and RFC5, as well as nucleolar components such as NPM1 or NCL. This promiscuity in protein binding is facilitated mainly by autoprocessing of the full-length protein into various fragments that contain different structural domains. As a result, multiple responses can be mediated by protein complexes that contain a PIDD1 domain. This suggests that PIDD1 acts as an integrator for multiple types of stress that need instant attention. Examples are various types of DNA lesion but also the presence of extra centrosomes that can foster aneuploidy and, ultimately, promote DNA damage. Here, we review the role of PIDD1 in response to DNA damage and also highlight novel functions of PIDD1, such as in centrosome surveillance and scheduled polyploidisation as part of a cellular differentiation program during organogenesis.


Subject(s)
Centrosome/physiology , Death Domain Receptor Signaling Adaptor Proteins/physiology , Animals , Apoptosis , CRADD Signaling Adaptor Protein/physiology , Caspase 2/physiology , Cell Differentiation , DNA Damage , Humans , Multiprotein Complexes/physiology , Nucleophosmin , Polyploidy
3.
Trends Cell Biol ; 20(3): 150-9, 2010 Mar.
Article in English | MEDLINE | ID: mdl-20061149

ABSTRACT

Caspase-2, the most conserved member of the caspase family, has long been recognized as an important protein in the regulation of apoptosis. However, due to a lack of phenotype in caspase-2 knock-out mice, its precise role has been questioned. Recently, several publications have described new mechanisms regulating caspase-2 activation, including its role within an activating complex named the PIDDosome, linking caspase-2 function to p53. Consistent with this, evidence is accumulating for potential roles of caspase-2 in non-apoptotic processes, including cell cycle regulation and DNA repair. In addition, a tumor-suppressor function has been suggested for caspase-2. Here we discuss how different PIDDosome complexes could be involved in mechanisms regulating the switch between the various functions of caspase-2.


Subject(s)
Apoptosis/physiology , Caspase 2/physiology , Cell Cycle Proteins/physiology , Cell Cycle/physiology , Animals , CRADD Signaling Adaptor Protein/physiology , Carrier Proteins/physiology , Cell Cycle/drug effects , DNA Damage , DNA Repair/physiology , Death Domain Receptor Signaling Adaptor Proteins , Enzyme Activation , Humans , Mice , Mice, Knockout , Phosphorylation , Tumor Suppressor Protein p53/physiology , Tumor Suppressor Proteins/physiology
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