When 2+2=5: The origins and fates of aneuploid and tetraploid cells

King, Randall W.

doi:10.1016/j.bbcan.2008.07.007

Cited by 65 publications

(66 citation statements)

References 92 publications

(149 reference statements)

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“…3 M-O). Multipolar spindles often result in multinucleated cells (28). Consistent with this idea, cells lacking WNK1 were frequently multinucleate (Fig.…”

Section: Depletion Of Wnk1 Causes Aberrant Mitotic Spindles and Defecsupporting

confidence: 73%

WNK1 is required for mitosis and abscission

Tu¹,

Bugde

Luby-Phelps

et al. 2011

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

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WNK [with no lysine (K)] protein kinases are found in all sequenced multicellular and many unicellular organisms. WNKs influence ion balance. Two WNK family members are associated with a single gene form of hypertension. RNA interference screens have implicated WNKs in survival and growth, and WNK1 is essential for viability of mice. We found that the majority of WNK1 is localized on cytoplasmic puncta in resting cells. During cell division, WNK1 localizes to mitotic spindles. Therefore, we analyzed mitotic phenotypes in WNK1 knockdown cells. A large percentage of WNK1 knockdown cells fail to complete cell division, displaying defects in mitotic spindles and also in abscission and cell survival. One of the bestcharacterized WNK1 targets is the protein kinase OSR1 (oxidative stress responsive 1). OSR1 regulates ion cotransporters, is activated in response to osmotic stress by WNK family members, and is largely associated with WNK1. In resting cells, the majority of OSR1, like WNK1, is on cytoplasmic puncta. OSR1 is also in nuclei. In contrast to WNK1, however, OSR1 does not concentrate around spindles during mitosis and does not show a WNK1-like localization pattern in mitotic cells. Knockdown of OSR1 has only a modest effect on cell survival and does not lead to spindle defects. We conclude that decreased cell survival associated with loss of WNK1 is attributable to defects in chromosome segregation and abscission and is independent of the effector kinase OSR1.cytokinesis | microtubules | serine-| proline-| alanine-rich kinase

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“…3 M-O). Multipolar spindles often result in multinucleated cells (28). Consistent with this idea, cells lacking WNK1 were frequently multinucleate (Fig.…”

Section: Depletion Of Wnk1 Causes Aberrant Mitotic Spindles and Defecsupporting

confidence: 73%

WNK1 is required for mitosis and abscission

Tu¹,

Bugde

Luby-Phelps

et al. 2011

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

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“…The presence of tetraploid metaphase spreads showing replicated mirror-image multicentrics in M2 has been described (Krishnaja and Sharma 2004). The potential causes of tetraploidization include cytokinesis failure, cell fusion and endoreduplication (King 2008). In our study, we confirmed the occurrence of tetraploidization and endoreduplication using molecular cytogenetic methods.…”

Section: Discussionsupporting

confidence: 76%

“…As many solid tumors have sub-tetraploid karyotypes and supernumerary centrosomes, it is likely that the initial step toward aneuploidy is tetraploidization (Storchova and Pellman 2004, King 2008, Storchova and Kuffer 2008, Davoli and de Lange 2011. The frequency of chromosomes with unstable abnormalities is known to decrease with post-irradiation time (Awa et al 1978, Buckton et al 1978, Bauchinger et al 1989, Lindholm et al 1998.…”

Section: Discussionmentioning

confidence: 99%

Induction and Persistence of Multicentric Chromosomes in Cultured Human Peripheral Blood Lymphocytes Following High-Dose Gamma Irradiation

Suto¹,

Hirai²,

Akiyama³

et al. 2012

CYTOLOGIA

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Summary Among radiation-induced chromosome aberrations, multicentric chromosomes, as represented by dicentric chromosomes (dicentrics), are regarded as sensitive and specific biomarkers for assessing radiation dose in the 0 to 5 Gy range. The objective of this study was to characterize chromosome aberrations induced in vitro by a higher dose of radiation. Peripheral blood lymphocytes were exposed to 15 Gy gamma rays at a dose rate of 0.5 Gy/min and harvested at 48, 50, 52, 54, 56 and 72 h. The first mitotic peak appeared at 52-54 h, showing about a 6 h mitotic delay as compared with nonirradiated control cultures. Cell-cycle analysis of parallel and simultaneous cultures by sister-chromatid differentiation staining suggests that metaphase cells examined in 48-56 h cultures were in the first mitosis after culture initiation. The mean dicentric equivalent counts ranged from 9.0 to 9.3 in consecutively harvested cultures with no significant differences among them. At 72 h, about 20% of dividing cells were tetraploid, persisting with faithfully replicated unstable chromosome aberrations. The non-random distribution of replicated chromosome pairs, deduced from multicolor fluorescence in situ hybridization analysis, led us to surmise that the predominant mechanism underlying the induction of tetraploid cells is endoreduplication. These findings suggest that a high-dose in vitro irradiation applied to peripheral blood lymphocytes may affect on the replication process, in addition to structural chromosome damage.

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“…27,28 However, if abnormal cells are eliminated efficiently, the cell population may be maintained in a stable manner, even when chromosomes missegregation was observed at high frequency. 29 The level of CIN cannot be determined by only scoring the presence of genetic alteration in cells fixed at a particular time point due to the dynamic process of genetic alterations. 7 Thus, a strategy based on the combination of fluorescence in situ hybridization (FISH) with long-term live cell imaging is an effective way to delineate the process and the consequence of the changes in karyotype stability.…”

Section: Resultsmentioning

confidence: 99%