Liver tetraploidization is controlled by a new process of incomplete cytokinesis

Margall-Ducos, Germain; Celton-Morizur, Séverine; Couton, Dominique; Brégerie, Olivier; Desdouets, Chantal

doi:10.1242/jcs.016907

Cited by 153 publications

(178 citation statements)

References 44 publications

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“…Mitotic defects have been detected upon ILK depletion in Drosophila S2 cells (Bettencourt-Dias et al, 2004), mouse hepatocytes (Gkretsi et al, 2007) and human glioblastoma cells (Koul et al, 2005;Edwards et al, 2008). It is interesting that, although the cellular phenotypes were not reported in detail in these studies, all of these systems contain supernumerary centrosomes (Weber et al, 1998;Guidotti et al, 2003;Margall-Ducos et al, 2007;Kwon et al, 2008). ILK has also been shown to localize to centrosomes and regulate mitotic microtubule organization, likely through its influences on Aurora-A/ch-TOG/ TACC3 complex formation .…”

Section: Introductionmentioning

confidence: 93%

A critical role of integrin-linked kinase, ch-TOG and TACC3 in centrosome clustering in cancer cells

et al. 2010

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Many cancer cells contain more than two centrosomes, which imposes a potential for multipolar mitoses, leading to cell death. To circumvent this, cancer cells develop mechanisms to cluster supernumerary centrosomes to form bipolar spindles, enabling successful mitosis. Disruption of centrosome clustering thus provides a selective means of killing supernumerary centrosome-harboring cancer cells. Although the mechanisms of centrosome clustering are poorly understood, recent genetic analyses have identified requirements for both actin and tubulin regulating proteins. In this study, we demonstrate that the integrin-linked kinase (ILK), a protein critically involved in actin and mitotic microtubule organization, is required for centrosome clustering. Inhibition of ILK expression or activity inhibits centrosome clustering in several breast and prostate cancer cell lines that have centrosome amplification. Furthermore, cancer cells with supernumerary centrosomes are significantly more sensitive to ILK inhibition than cells with two centrosomes, demonstrating that inhibiting ILK offers a selective means of targeting cancer cells. Live cell analysis shows ILK perturbation leads cancer cells to undergo multipolar anaphases, mitotic arrest and cell death in mitosis. We also show that ILK performs its centrosome clustering activity in a focal adhesion-independent, but centrosome-dependent, manner through the microtubule regulating proteins TACC3 and ch-TOG. In addition, we identify a specific TACC3 phosphorylation site that is required for centrosome clustering and demonstrate that ILK regulates this phosphorylation in an Aurora-A-dependent manner.

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Section: Introductionmentioning

confidence: 93%

A critical role of integrin-linked kinase, ch-TOG and TACC3 in centrosome clustering in cancer cells

et al. 2010

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“…However, evidence obtained in vivo shows that at least some tissues can handle the accumulation of extra chromosomes and centrosomes. This is the case for mammalian polyploid hepatocytes, which are generated by incomplete cytokinesis and appear post-natally in healthy livers (Faggioli et al, 2011;Guidotti et al, 2003;Margall-Ducos et al, 2007) and in Drosophila glia required to maintain the integrity of the blood-brain barrier (Unhavaithaya and OrrWeaver, 2012). In a healthy organism, it is possible that only some cell types have the capacity to accumulate extra centrosomes and chromosomes, and it will be important to identify the mechanisms that allow or prevent such accumulation.…”

Section: Nkmentioning

confidence: 99%

“…Importantly, however, we should also take into consideration the fact that centrosome amplification is not a unique feature of cancer cells. Certain cells in our body contain extra centrosomes, either transiently or permanently (Faggioli et al, 2011;Margall-Ducos et al, 2007), suggesting that in a healthy organism, centrosome amplification is tolerated and even required to promote genetic variability (Duncan et al, 2010;Kingsbury et al, 2005;Yang et al, 2003).…”

Section: Consequences Of Centrosome Amplificationmentioning

confidence: 99%

Never tear us apart – the importance of centrosome clustering

Marthiens

Piel

Basto

2012

Journal of Cell Science

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SummaryThe presence of more than two centrosomes (centrosome amplification) at the onset of mitosis has long been associated with multipolar spindle formation, and with the generation of genetic instability. However, in recent years, several studies have shown that a process termed 'centrosome clustering' actively contributes to bipolar division by promoting the gathering of extra centrosomes in two main poles. In this Commentary, we describe the main proteins that are involved in centriole duplication and discuss how centrosome amplification can be generated both in vitro and in vivo. We then summarize what is currently known about the processes that contribute to bipolar spindle formation when extra centrosomes are present, and which forces contribute to this process. Finally, we discuss how extra centrosomes might contribute to tumorigenesis, giving emphasis to the role of centrosome amplification in promoting genetic instability.

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“…Although the process of liver polyploidization has been documented extensively (6)(7)(8), this phenomenon remains poorly understood. During postnatal development, a scheduled division program characterized by incomplete cytokinesis results in the genesis of binuclear tetraploid hepatocytes (2x2n), which subsequently play a pivotal role in liver polyploidization (3,(9)(10)(11). Remarkably, during postnatal development and adult life, hepatocytes are able to increase their DNA content but also reduce it through a process call "ploidy reversal" (2,12).…”

Section: Introductionmentioning

confidence: 99%

Oxidative stress promotes pathologic polyploidization in nonalcoholic fatty liver disease

Gentric¹,

Maillet²,

Paradis³

et al. 2015

J. Clin. Invest.

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Liver tetraploidization is controlled by a new process of incomplete cytokinesis

Abstract: SummaryLiver tetraploidization is controlled by a new process of incomplete cytokinesis

Cited by 153 publications

References 44 publications

A critical role of integrin-linked kinase, ch-TOG and TACC3 in centrosome clustering in cancer cells

A critical role of integrin-linked kinase, ch-TOG and TACC3 in centrosome clustering in cancer cells

Never tear us apart – the importance of centrosome clustering

Oxidative stress promotes pathologic polyploidization in nonalcoholic fatty liver disease

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