Polyploidy control in hepatic health and disease

Sladky, Valentina C.; Eichin, Felix; Reiberger, Thomas; Villunger, Andreas

doi:10.1016/j.jhep.2021.06.030

Cited by 27 publications

(23 citation statements)

References 130 publications

(212 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The physiological role of the centrosome-PIDDosome-p53 axis has been explored in vivo in naturally polyploid tissues, which have acquired supernumerary centrosomes through different mechanisms [ 74 ]. For example, liver cells become polyploid through a process of incomplete cytokinesis, which is triggered around the time of weaning by changes in insulin signaling [ 75 , 76 ].…”

Section: Emerging Pathologicial and Physiolocial Roles Of Pidd1mentioning

confidence: 99%

PIDD1 in cell cycle control, sterile inflammation and cell death

Weiler

Szabó

Villunger

2022

Biochemical Society Transactions

Self Cite

View full text Add to dashboard Cite

The death fold domain-containing protein PIDD1 has recently attracted renewed attention as a regulator of the orphan cell death-related protease, Caspase-2. Caspase-2 can activate p53 to promote cell cycle arrest in response to centrosome aberrations, and its activation requires formation of the PIDDosome multi-protein complex containing multimers of PIDD1 and the adapter RAIDD/CRADD at its core. However, PIDD1 appears to be able to engage with multiple client proteins to promote an even broader range of biological responses, such as NF-κB activation, translesion DNA synthesis or cell death. PIDD1 shows features of inteins, a class of self-cleaving proteins, to create different polypeptides from a common precursor protein that allow it to serve these diverse functions. This review summarizes structural information and molecular features as well as recent experimental advances that highlight the potential pathophysiological roles of this unique death fold protein to highlight its drug-target potential.

show abstract

Section: Emerging Pathologicial and Physiolocial Roles Of Pidd1mentioning

confidence: 99%

PIDD1 in cell cycle control, sterile inflammation and cell death

Weiler

Szabó

Villunger

2022

Biochemical Society Transactions

Self Cite

View full text Add to dashboard Cite

show abstract

“…This may shift markedly in either direction under some physiological and pathological conditions including iron status [44] . The influence of different ploidy states in cells, thus variable gene copy numbers, on selected gene expressions in individual hepatocytes and contributions to expression of total cell populations in the liver following physiological, pharmacological or chemical stimulation in genetically modified animals, are far from understood and often ignored [45] , [46] .…”

Section: Discussionmentioning

confidence: 99%

Complex response to physiological and drug-induced hepatic heme demand in monoallelic ALAS1 mice

Vágány

Robinson

Chernova

et al. 2021

Molecular Genetics and Metabolism Reports

View full text Add to dashboard Cite

Regulation of 5-aminolevulinate synthase 1 (ALAS1) for nonerythroid heme is critical for respiration, cell signaling mechanisms and steroid/drug metabolism. ALAS1 is induced in some genetic disorders but unlike other genes in the heme pathway, a gene variant of ALAS1 associated with inherited disease has not been reported. BALB/c mice carrying a null ALAS1 allele caused by a βGEO insert were developed and used to determine the consequences of heme demand of a semi gene copy number. Homozygous disruption of ALAS1 (−/−) was lethal for embryo development post day 6.5 but expression in heterozygotes (+/−) was sufficient for the number of offspring and survival. In both wild type (WT +/+) and +/− mice expression of ALAS1 RNA was greatest in liver and harderian gland and much lower in kidney, lung, heart, brain and spleen. The effects of one WT ALAS1 allele in +/− mice on mRNA levels in liver and harderian gland were less marked compared to brain and other organs that were examined. Many other genes were up-regulated by heterozygosity in liver and brain but to a minimal extent. Hepatic heme oxygenase 1 (HMOX1) mRNA expression was significantly lower in +/− mice but not in brain. No elevated translation of WT allele ALAS1 mRNA was detected in +/− liver as a compensatory mechanism for the disabled allele. Fasting induced ALAS1 mRNA in both WT and +/− mice but only in +/− was this manifest as increased ALAS1 protein. The hepatic protoporphyria-inducing drug 4-ethyl-DDC caused induction of hepatic ALAS1 mRNA and protein levels in both WT and +/− mice but markedly less in the mice with only one intact allele. The findings illustrate the complex response of ALAS1 expression for heme demand but limited evidence that upregulation of a wild type allele can compensate for a null allele.

show abstract

“…Consistently, microcephaly-linked mutations in KIF14 and CIT are reported to increase the frequency of cytokinesis failure and the generation of polyploid progeny ( Bianchi et al 2017 ; Moawia et al 2017 ). Polyploidy can be tolerated in certain tissues such as the liver but has yet to be reported in patients or animal models of microcephaly ( Sladky et al 2021 ).…”

Section: The Molecular Genetics Of Primary Microcephalymentioning

confidence: 99%

Time is of the essence: the molecular mechanisms of primary microcephaly

Phan

Holland

2021

Genes Dev.

View full text Add to dashboard Cite

Primary microcephaly is a brain growth disorder characterized by a severe reduction of brain size and thinning of the cerebral cortex. Many primary microcephaly mutations occur in genes that encode centrosome proteins, highlighting an important role for centrosomes in cortical development. Centrosomes are microtubule organizing centers that participate in several processes, including controlling polarity, catalyzing spindle assembly in mitosis, and building primary cilia. Understanding which of these processes are altered and how these disruptions contribute to microcephaly pathogenesis is a central unresolved question. In this review, we revisit the different models that have been proposed to explain how centrosome dysfunction impairs cortical development. We review the evidence supporting a unified model in which centrosome defects reduce cell proliferation in the developing cortex by prolonging mitosis and activating a mitotic surveillance pathway. Finally, we also extend our discussion to centrosome-independent microcephaly mutations, such as those involved in DNA replication and repair.

show abstract

Polyploidy control in hepatic health and disease

Cited by 27 publications

References 130 publications

PIDD1 in cell cycle control, sterile inflammation and cell death

PIDD1 in cell cycle control, sterile inflammation and cell death

Complex response to physiological and drug-induced hepatic heme demand in monoallelic ALAS1 mice

Time is of the essence: the molecular mechanisms of primary microcephaly

Contact Info

Product

Resources

About