Regulation of cytokinesis and its clinical significance

Abstract

Dysregulation of the cell cycle leads to polyploid cells, which are classified into mononuclear or binuclear polyploid cells depending on the number of nuclei. Polyploidy is common in plants and in animals. Physiologically, polyploidy and binucleation are differentiation markers and also features of the aging process. In fact, although they provide multiple copies of genes required for survival, a negative correlation between growth capacity and polyploidy has been reported, and thus, suppression or reversal of this phenomenon may be a growth advantage. On the other hand, unscheduled polyploidization may cause genomic instability that might lead to neoplastic aneuploidy. The aim of this review is to analyze the mechanisms that lead to polyploidy, and particularly binucleation, and highlight the potential of ploidy as a marker of illness severity or the success of the adaptive response for an injury, with special emphasis in the liver under physiological and pathological conditions. Hepatocyte binucleation occurs in late fetal development and postnatal maturation, especially after weaning via phosphoinositide 3-kinase (PI3K)-protein kinase B (Akt). It also increases upon aging of the liver as well as in liver cirrhosis and cancer. Liver binucleation mainly indicates the severity of the damage. Furthermore, the eventual increase in hepatocyte binucleation points out compensatory proliferation associated with liver injury. Ploidy conveyor would also permit hepatocyte adaptation to xenobiotic or nutritional injury. In contrast, polyploidy is a feature of many human cancers, and it may predispose to genomic instability and generation of aneuploidization that play a major role in carcinogenesis. Finally, a better understanding of the polyploidization process is needed in order to approach clinical research but also, to get deeper knowledge of cell cycle control. The fascinating regulation of cell cycle in liver and the generation and reversal of ploidies will provide more clues for the mystery of liver regeneration.

Hepatocyte polyploidization and its association with pathophysiological processes

“…Thus, rapidly dividing diploid tumor cells are more easily mutated than the polyploid cells, resulting in increasing malignancy. 47, 48 HCC development is accompanied by decreased expression of miR-122. MiR-122, frequently the most specific miRNA in the liver, is considered necessary and sufficient for liver polyploidization, in addition to being an important tumor suppressor in hepatocellular carcinoma.…”

Cell-intrinsic and -extrinsic mechanisms promote cell-type-specific cytokinetic diversity

“…In animal cells, cytokinesis is driven by the equatorial constriction of an actomyosin contractile ring, composed of diaphanous family formin-nucleated F-actin and the motor myosin-II (for review see [ Cheffings et al, 2016 ; D'Avino et al, 2015 ; Green et al, 2012 ; Mandato et al, 2000 ; Mishima, 2016 ; Pollard, 2010 ]). Cytokinesis failure, which results in a binucleate tetraploid (polyploid) cell, can lead to human diseases including blood syndromes, neurological disorders, and cancer ( Bione et al, 1998 ; Moulding et al, 2007 ; Dieterich et al, 2009 ; Vinciguerra et al, 2010 ; Lacroix and Maddox, 2012 ; Iolascon et al, 2013 ; Liljeholm et al, 2013 ; Ferrer et al, 2014 ; Ganem et al, 2014 , 2007 ; Tormos et al, 2015 ). While it has long been assumed that all animal cells divide by a similar molecular mechanism, it is becoming increasingly clear that the functional regulation of cytokinesis has more diversity, or variation in mechanistic and regulatory pathways, than previously appreciated ( Herszterg et al, 2014 ; Guillot and Lecuit, 2013 ; Founounou et al, 2013 ; Herszterg et al, 2013 ; De Santis Puzzonia et al, 2016 ; Choudhary et al, 2013 ; Wheatley et al, 1997 ; Stopp et al, 2017 ).…”

“…In many animals (including humans), specific cell types or cell lineages within the organism are programmed to fail in cytokinesis and become bi- or multi-nucleate (e.g. osteoclasts in bone, megakaryocytes in blood, cardiomyocytes in the heart, hepatocytes in the liver) ( Lacroix and Maddox, 2012 ; Tormos et al, 2015 ; Zimmet and Ravid, 2000 ; Duncan, 2013 ; Takegahara et al, 2016 ). Thus, in some cell types, cytokinesis failure occurs normally during development and/or homeostasis and, in other cell types, cytokinesis failure can be pathogenic ( Lacroix and Maddox, 2012 ; Tormos et al, 2015 ; Zimmet and Ravid, 2000 ; Duncan, 2013 ; Takegahara et al, 2016 ), indicating a high degree of cellular variation in both the regulation of cytokinesis and the consequences of cytokinesis failure.…”

Cortical PAR polarity proteins promote robust cytokinesis during asymmetric cell division

“…Cytokinesis, the physical division of one cell into two, occurs trillions of times from fertilization to death, and division failures can have significant consequences, including miscarriage, neurological dysfunction, immunological defects, and cancer ( Lacroix and Maddox, 2012 ; Tormos et al, 2015 ). Cytokinesis is driven by the constriction of a contractile ring composed of formin-nucleated F-actin and the motor myosin-II, which is primarily positioned and controlled by the mitotic spindle ( Green et al, 2012 ).…”