scholarly journals Hepatocytes Polyploidization and Cell Cycle Control in Liver Physiopathology

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Géraldine Gentric ◽  
Chantal Desdouets ◽  
Séverine Celton-Morizur
Keyword(s):  
Insulin Signalling ◽  
Cell Cycle Control ◽  
Liver Parenchyma ◽  
Postnatal Growth ◽  
Replication Capacity ◽  
Liver Growth ◽  
Diploid Complement ◽  
Mammalian Tissues ◽  
Functional Consequences

Most cells in mammalian tissues usually contain a diploid complement of chromosomes. However, numerous studies have demonstrated a major role of “diploid-polyploid conversion” during physiopathological processes in several tissues. In the liver parenchyma, progressive polyploidization of hepatocytes takes place during postnatal growth. Indeed, at the suckling-weaning transition, cytokinesis failure events induce the genesis of binucleated tetraploid liver cells. Insulin signalling, through regulation of the PI3K/Akt signalling pathway, is essential in the establishment of liver tetraploidization by controlling cytoskeletal organisation and consequently mitosis progression. Liver cell polyploidy is generally considered to indicate terminal differentiation and senescence, and both lead to a progressive loss of cell pluripotency associated to a markedly decreased replication capacity. Although adult liver is a quiescent organ, it retains a capacity to proliferate and to modulate its ploidy in response to various stimuli or aggression (partial hepatectomy, metabolic overload (i.e., high copper and iron hepatic levels), oxidative stress, toxic insult, and chronic hepatitis etc.). Here we review the mechanisms and functional consequences of hepatocytes polyploidization during normal and pathological liver growth.

scholarly journals The Clp1/Cdc14 phosphatase contributes to the robustness of cytokinesis by association with anillin-related Mid1

2008 ◽  
Vol 181 (1) ◽  
pp. 79-88 ◽  
Author(s):  
Dawn M. Clifford ◽  
Benjamin A. Wolfe ◽  
Rachel H. Roberts-Galbraith ◽  
W. Hayes McDonald ◽  
John R. Yates ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Schizosaccharomyces Pombe ◽  
Fission Yeast ◽  
Cell Cycle Control ◽  
Physical Property ◽  
Cyclin Dependent Kinase ◽  
Contractile Ring ◽  
Protein Mobility ◽  
Functional Consequences

Cdc14 phosphatases antagonize cyclin-dependent kinase–directed phosphorylation events and are involved in several facets of cell cycle control. We investigate the role of the fission yeast Cdc14 homologue Clp1/Flp1 in cytokinesis. We find that Clp1/Flp1 is tethered at the contractile ring (CR) through its association with anillin-related Mid1. Fluorescent recovery after photobleaching analyses indicate that Mid1, unlike other tested CR components, is anchored at the cell midzone, and this physical property is likely to account for its scaffolding role. By generating a mutation in mid1 that selectively disrupts Clp1/Flp1 tethering, we reveal the specific functional consequences of Clp1/Flp1 activity at the CR, including dephosphorylation of the essential CR component Cdc15, reductions in CR protein mobility, and CR resistance to mild perturbation. Our evidence indicates that Clp1/Flp1 must interact with the Mid1 scaffold to ensure the fidelity of Schizosaccharomyces pombe cytokinesis.

scholarly journals Isoform-Specific Roles of Mutant p63 in Human Diseases

Cancers ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 536
Author(s):  
Christian Osterburg ◽  
Susanne Osterburg ◽  
Huiqing Zhou ◽  
Caterina Missero ◽  
Volker Dötsch
Keyword(s):  
Cleft Lip ◽  
Ectodermal Dysplasia ◽  
Skin Development ◽  
Disease Mechanisms ◽  
Skin Fragility ◽  
Cleft Lip Palate ◽  
Life Threatening ◽  
Functional Consequences ◽  
Development And Differentiation

The p63 gene encodes a master regulator of epidermal commitment, development, and differentiation. Heterozygous mutations in the DNA binding domain cause Ectrodactyly, Ectodermal Dysplasia, characterized by limb deformation, cleft lip/palate, and ectodermal dysplasia while mutations in in the C-terminal domain of the α-isoform cause Ankyloblepharon-Ectodermal defects-Cleft lip/palate (AEC) syndrome, a life-threatening disorder characterized by skin fragility, severe, long-lasting skin erosions, and cleft lip/palate. The molecular disease mechanisms of these syndromes have recently become elucidated and have enhanced our understanding of the role of p63 in epidermal development. Here we review the molecular cause and functional consequences of these p63-mutations for skin development and discuss the consequences of p63 mutations for female fertility.

scholarly journals Prediction of Functional Consequences of Missense Mutations in ANO4 Gene

2021 ◽  
Vol 22 (5) ◽  
pp. 2732
Author(s):  
Nadine Reichhart ◽  
Vladimir M. Milenkovic ◽  
Christian H. Wetzel ◽  
Olaf Strauß
Keyword(s):  
Transmembrane Protein ◽  
Functional Characterization ◽  
Missense Mutations ◽  
Mutant Proteins ◽  
Functional Consequences ◽  
New Perspective ◽  
The Stability ◽  
Dynamics Simulations ◽  
And Function

The anoctamin (TMEM16) family of transmembrane protein consists of ten members in vertebrates, which act as Ca2+-dependent ion channels and/or Ca2+-dependent scramblases. ANO4 which is primarily expressed in the CNS and certain endocrine glands, has been associated with various neuronal disorders. Therefore, we focused our study on prioritizing missense mutations that are assumed to alter the structure and stability of ANO4 protein. We employed a wide array of evolution and structure based in silico prediction methods to identify potentially deleterious missense mutations in the ANO4 gene. Identified pathogenic mutations were then mapped to the modeled human ANO4 structure and the effects of missense mutations were studied on the atomic level using molecular dynamics simulations. Our data show that the G80A and A500T mutations significantly alter the stability of the mutant proteins, thus providing new perspective on the role of missense mutations in ANO4 gene. Results obtained in this study may help to identify disease associated mutations which affect ANO4 protein structure and function and might facilitate future functional characterization of ANO4.

The role of MCM proteins in the cell cycle control of genome duplication

BioEssays ◽  
1996 ◽  
Vol 18 (3) ◽  
pp. 183-190 ◽  
Author(s):  
Stephen E. Kearsey ◽  
Domenico Maiorano ◽  
Eddie C. Holmes ◽  
Ivan T. Todorov
Keyword(s):  
Cell Cycle ◽  
Genome Duplication ◽  
Cell Cycle Control ◽  
Mcm Proteins

scholarly journals Computational modelling of mitotic exit in budding yeast: the role of separase and Cdc14 endocycles

2011 ◽  
Vol 8 (61) ◽  
pp. 1128-1141 ◽  
Author(s):  
P. K. Vinod ◽  
Paula Freire ◽  
Ahmed Rattani ◽  
Andrea Ciliberto ◽  
Frank Uhlmann ◽  
...  
Keyword(s):  
Regulatory Networks ◽  
Budding Yeast ◽  
Cell Cycle Control ◽  
Computational Modelling ◽  
Eukaryotic Cell ◽  
Mitotic Exit ◽  
Intuitive Reasoning ◽  
Systematic Analysis ◽  
Systems View

The operating principles of complex regulatory networks are best understood with the help of mathematical modelling rather than by intuitive reasoning. Hereby, we study the dynamics of the mitotic exit (ME) control system in budding yeast by further developing the Queralt's model. A comprehensive systems view of the network regulating ME is provided based on classical experiments in the literature. In this picture, Cdc20–APC is a critical node controlling both cyclin (Clb2 and Clb5) and phosphatase (Cdc14) branches of the regulatory network. On the basis of experimental situations ranging from single to quintuple mutants, the kinetic parameters of the network are estimated. Numerical analysis of the model quantifies the dependence of ME control on the proteolytic and non-proteolytic functions of separase. We show that the requirement of the non-proteolytic function of separase for ME depends on cyclin-dependent kinase activity. The model is also used for the systematic analysis of the recently discovered Cdc14 endocycles. The significance of Cdc14 endocycles in eukaryotic cell cycle control is discussed as well.

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