Proliferation of aneuploid human cells is limited by a p53-dependent mechanism

Thompson, Sarah L.; Compton, Duane A.

doi:10.1083/jcb.200905057

Cited by 439 publications

(477 citation statements)

References 54 publications

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“…A similar finding was reported recently through a completely different approach than the one used here (29). Together with the suggestion that aneuploid cells are genetically unfit for proliferation (24,25), we propose that the cellular re- sponse to aneuploidy ranges from passive (unfitness) to active (activation of p53), depending on the severity of the aneuploidy (Fig.…”

Section: Discussionsupporting

confidence: 60%

The ATM–p53 pathway suppresses aneuploidy-induced tumorigenesis

Li¹,

Xiao²,

Baker

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

222

247

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The spindle assembly checkpoint (SAC) is essential for proper sister chromatid segregation. Defects in this checkpoint can lead to chromosome missegregation and aneuploidy. An increasing body of evidence suggests that aneuploidy can play a causal role in tumorigenesis. However, mutant mice that are prone to aneuploidy have only mild tumor phenotypes, suggesting that there are limiting factors in the aneuploidy-induced tumorigenesis. Here we provide evidence that p53 is such a limiting factor. We show that aneuploidy activates p53 and that loss of p53 drastically accelerates tumor development in two independent aneuploidy models. The p53 activation depends on the ataxia-telangiectasia mutated (ATM) gene product and increased levels of reactive oxygen species. Thus, the ATM-p53 pathway safeguards not only DNA damage but also aneuploidy.

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Section: Discussionsupporting

confidence: 60%

The ATM–p53 pathway suppresses aneuploidy-induced tumorigenesis

Li¹,

Xiao²,

Baker

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

222

247

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“…We next followed the fate of each chromatid of a single human chromosome during mitosis in HCT116 cells by using a LacO array integrated into a single chromosomal locus and detected by expression of LacI-GFP (16)(17)(18). The probability of witnessing a lagging chromatid from this specific chromosome using live cell imaging is expected to be quite rare (1/45 chromosomes tagged × 1 lagging chromosome observed in every 3 HCT116 cells recovering from monastrol-or nocodazole-induced mitotic delay = 1/135 cells would display an error in this specific chromosome; ref.…”

Section: Resultsmentioning

confidence: 99%

“…We have performed MCAK knockdown by using siRNA (16) and used the significant increase in lagging chromosomes in anaphase to confirm efficient knockdown in these experiments (Fig. S2).…”

Section: Resultsmentioning

confidence: 99%

Chromosome missegregation in human cells arises through specific types of kinetochore–microtubule attachment errors

Thompson

Compton

2011

Proc. Natl. Acad. Sci. U.S.A.

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247

225

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Most solid tumors are aneuploid, and many missegregate chromosomes at high rates in a phenomenon called chromosomal instability (CIN). CIN reflects the erosion of mitotic fidelity, and it correlates with poor patient prognosis and drug resistance. The most common mechanism causing CIN is the persistence of improper kinetochore-microtubule attachments called merotely. Chromosomes with merotelic kinetochores often manifest as lagging chromosomes in anaphase, suggesting that lagging chromosomes fail to segregate properly. However, it remains unknown whether the lagging chromosomes observed in anaphase segregate to the correct or incorrect daughter cell. To address this question, we tracked the segregation of a single human chromosome during cell division by using LacI-GFP to target an integrated LacO array. By scoring the distribution of each sister chromatid during mitosis, we show that a majority of lagging chromosomes in anaphase segregate to the correct daughter cell. Instead, sister chromatids that segregate erroneously frequently do so without obvious evidence of lagging during anaphase. This outcome is expected if sister kinetochores on a chromosome bind microtubules oriented toward the same spindle pole, and we find evidence for syntelic kinetochore attachments in cells after treatments that increase missegregation rates. Thus, lagging chromosomes in anaphase are symptomatic of defects in kinetochore-microtubule attachment dynamics that cause chromosome missegregation associated with CIN, but the laggards rarely missegregate.aneuploidy | syntely | MCAK | micronuclei | genome instability S olid tumors are frequently aneuploid and many missegregate chromosomes at high rates in a phenomenon called chromosomal instability (CIN; refs. 1 and 2). CIN is associated with poor patient prognosis, and various studies have shown that it correlates with advanced tumor stage including acquisition of metastatic potential and drug resistance (3-5). It has been proposed that by frequently changing the karyotype of tumor cells, that CIN provides an agent of change that drives the evolution of tumor cell phenotypes (3-8). The treatment difficulties encountered in advanced stage tumors underscores the importance of determining the mechanisms of CIN and how they contribute to tumor growth.Various mechanisms have been proposed to cause CIN including dysfunction of the spindle assembly checkpoint, defects in sister chromatid cohesion, and defects in the attachment of chromosomes to spindle microtubules (2). Recently, live cell imaging demonstrated that the most common cause of CIN is the persistence of errors in the attachment of spindle microtubules to chromosomes (9, 10). Microtubules bind to chromosomes at specialized structures called kinetochores. Each chromosome has a pair of kinetochores, and faithful chromosome segregation arises when single kinetochores bind microtubules oriented toward only one spindle pole resulting in the biorientation of chromosomes on the spindle. However, errors in the orientation of kinetochore-mic...

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“…A key molecular regulator of this phenomenon is p53, whose deficiency is permissive for the bypass of mitotic catastrophe and the creation and survival of tetraploid cells, a metastable intermediate between normal diploidy and oncogenic aneuploidy (Storchova and Pellman, 2004;Castedo et al, 2004Castedo et al, , 2006Ganem and Pellman, 2007;Thompson and Compton, 2010).…”

Section: Introductionmentioning

confidence: 99%

MOS, aneuploidy and the ploidy cycle of cancer cells

Ērenpreisa

Cragg

2010

Oncogene

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After DNA or spindle damage, p53-defective tumor cells undergo a complex cycle of reversible polyploidy. How this process occurs and more importantly, why, has recently become the focus of several research groups, prompting this review in which we discuss two related phenomena that accompany the reversible polyploidy of tumor cells: the induction of meiosis genes such as MOS and the decrease in genomic instability observed during the reversion from polyploidy to para-diploidy. The reversible polyploidy likely provides the means through which the balance between increased chromosome instability (CIN), driving genetic variation and decreased CIN, necessary for perpetuating these malignant clones, is maintained. These concepts are integrated with recent findings that many meiotic and self-renewal genes become activated during reversible polyploidy and lead us to the hypothesis that tumor cell immortality may be achieved through germline-like transmission.

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Proliferation of aneuploid human cells is limited by a p53-dependent mechanism

Abstract: After chromosome missegregation, the growth of nondiploid cells is inhibited thanks to a p53-dependent mechanism.

Cited by 439 publications

References 54 publications

The ATM–p53 pathway suppresses aneuploidy-induced tumorigenesis

The ATM–p53 pathway suppresses aneuploidy-induced tumorigenesis

Chromosome missegregation in human cells arises through specific types of kinetochore–microtubule attachment errors

MOS, aneuploidy and the ploidy cycle of cancer cells

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