Spontaneous Polyploidization Results in Apoptosis in a Meth-A Tumor Cell Line.

Fujikawa-Yamamoto, Kohzaburo; Zong, Zhi-ping; Murakami, Manabu; Odashima, Shizuo; Ikeda, Teruaki; Yoshitake, Yoshino

doi:10.1247/csf.22.399

Cited by 23 publications

(14 citation statements)

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“…In these cells the loss of spindle checkpoint control leads to the uncoupling of cytokinesis and replication resulting in 8 N or even 16 N DNA contents. Most often the increase in ploidy is accompanied by the enlargement of the cells and the development of micronuclei (Fujikawa-Yamamoto et al, 1997). To investigate the possibility that the kinase inhibitor leads to similar postmitotic e ects, we investigated the nuclear morphology of MethAtsp53 cells using combined bright®eld-¯uorescence images of Considering the generation of micronuclei over the time (Figure 3b), it is obvious that NOC induces micronucleation to a greater extent (up to 88%) than the kinase inhibitor IC261 (up to 37%), at least at the used concentration of 0.6 mM.…”

Section: Effects Of Ic261 On Cell Cycle Distribution and Cell Survivamentioning

confidence: 99%

IC261, a specific inhibitor of the protein kinases casein kinase 1-delta and -epsilon, triggers the mitotic checkpoint and induces p53-dependent postmitotic effects

et al. 2000

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The p53-targeted kinases casein kinase 1d (CK1d) and casein kinase 1e (CK1e) have been proposed to be involved in regulating DNA repair and chromosomal segregation. Recently, we showed that CK1d localizes to the spindle apparatus and the centrosomes in cells with mitotic failure caused by DNA-damage prior to mitotic entry. We provide here evidence that 3-[(2,4,6-trimethoxyphenyl)methylidenyl]-indolin-2-one (IC261), a novel inhibitor of CK1d and CK1e, triggers the mitotic checkpoint control. At low micromolar concentrations IC261 inhibits cytokinesis causing a transient mitotic arrest. Cells containing active p53 arrest in the postmitotic G1 phase by blockage of entry into the S phase. Cells with non-functional p53 undergo postmitotic replication developing an 8N DNA content. The increase of DNA content is accompanied by a high amount of micronucleated and apoptotic cells. Immun¯uorescence images show that at low concentrations IC261 leads to centrosome ampli®cation causing multipolar mitosis. Our data are consistent with a role for CK1d and CK1e isoforms in regulating key aspects of cell division, possibly through the regulation of centrosome or spindle function during mitosis. Oncogene (2000) 19, 5303 ± 5313.

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Section: Effects Of Ic261 On Cell Cycle Distribution and Cell Survivamentioning

confidence: 99%

IC261, a specific inhibitor of the protein kinases casein kinase 1-delta and -epsilon, triggers the mitotic checkpoint and induces p53-dependent postmitotic effects

et al. 2000

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“…A single-cell MALDI-TOF mass spectrometry has the advantage of extracting a target cell from the surrounding cells and of making it possible to analyze the intracellular molecule dynamics. In the future, we expect that this method will be a powerful approach to analyze wound healing by fibroblasts, eosinophils and mast cells cocultivation systems, 16,17 and the polyploidization of a cell in intact tissue, 18,19 like the heterogeneous cell samples. Fig.…”

Section: Resultsmentioning

confidence: 99%

Development of the Single-Cell MALDI-TOF (Matrix-Assisted Laser Desorption/Ionization Time-of-Flight) Mass-Spectroscopic Assay

et al. 2003

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“…Meth-A cells always include a small population of large cells that are produced from diploid cells by spontaneous polyploidization and are eventually removed by apoptosis (Fujikawa-Yamamoto et al 1997). Meth-A cells may be particularly susceptible to polyploid transformation.…”

Section: Discussionmentioning

confidence: 99%

“…Graves and McMillan (1984) reported that tetraploid DON and BI Chinese hamster cells were karyotypically stable but the octaploid cells were not. In spite of these long-term studies, the mechanism of DNA content reduction is not yet known.Meth-A cells always include a small population of large cells that are produced from diploid cells by spontaneous polyploidization and are eventually removed by apoptosis (Fujikawa-Yamamoto et al 1997). Meth-A cells may be particularly susceptible to polyploid transformation.…”

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DNA Loss and Related Alterations in Long-term Cultures of Diploid, Tetraploid and Octaploid Meth-A Cells

2005

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SummaryThe DNA content of polyploid cells sometimes decreases during subculturing. The mechanism of DNA reduction is not yet known. Precise measurements of DNA decay and related alterations in polyploid cells will be required to understand the mechanism. Diploid, tetraploid and octaploid Meth-A cells were continuously cultured for 244 d and the cellular DNA content was measured from the DNA histograms. The DNA content decays gradually with day t as expressed by f(t)ϭI p exp{ϪG(t)}, where I p is the initial ploidy, G(t)ϭat/{exp(Ϫbt)ϩct}, and a, b and c are the following parameters: aϭ0.026, bϭ0.01 and cϭ0.0175 (for tetraploid cells) or cϭ0.01 (for octaploid cells). The DNA content of diploid Meth-A cells was constant within the experimental errors. The DNA loss of polyploid cells was confirmed by a decrease in chromosome number. The cellular morphology changed in diploid and octaploid Meth-A cells, but not in tetraploid cells, suggesting that DNA loss and morphology alteration are independent. The doubling time shortened with culture time in the tetraploid and octaploid cells. The findings suggested that chromosomes are not independent in polyploid cells. The DNA content of mammalian diploid cells is well preserved during subculturing; however, that of polyploid cells is not. The DNA content of polyploid cells sometimes decreases gradually, and occasionally it decreases abruptly by half. A few studies of DNA degradation in polyploid cells have been reported. Moor, et al. (1968) concluded that near triploid is the terminal ploidy of neartetraploid Ehrlich's ascites tumor cells based on 3 years of observation. Harris (1971) showed that the chromosome number was constant in diploid cells but decreased with subculturing in tetraploid and octaploid pig kidney cells. Graves and McMillan (1984) reported that tetraploid DON and BI Chinese hamster cells were karyotypically stable but the octaploid cells were not. In spite of these long-term studies, the mechanism of DNA content reduction is not yet known.Meth-A cells always include a small population of large cells that are produced from diploid cells by spontaneous polyploidization and are eventually removed by apoptosis (Fujikawa-Yamamoto et al. 1997). Meth-A cells may be particularly susceptible to polyploid transformation. Tetraploid Meth-A cell lines have been reproducibly established from diploid Meth-A cells highly polyploidized by demecolcine (Fujikawa-Yamamoto et al. 2001). Octaploid Meth-A cells were also produced from tetraploid cells highly polyploidized by demecolcine (Fujikawa-Yamamoto et al. 2003). The diploid, tetraploid and octaploid Meth-A cells showed marked differences in the expression of cell surface hydrocarbon chains, suggesting that the ploidy transformation is accompanied by functional alterations (Fujikawa-Yamamoto and Sakuma 2003). The diploid, tetraploid and octaploid Meth-A cell lines may provide a cell system for investigating polyploid cells.

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Spontaneous Polyploidization Results in Apoptosis in a Meth-A Tumor Cell Line.

Cited by 23 publications

References 13 publications

IC261, a specific inhibitor of the protein kinases casein kinase 1-delta and -epsilon, triggers the mitotic checkpoint and induces p53-dependent postmitotic effects

IC261, a specific inhibitor of the protein kinases casein kinase 1-delta and -epsilon, triggers the mitotic checkpoint and induces p53-dependent postmitotic effects

Development of the Single-Cell MALDI-TOF (Matrix-Assisted Laser Desorption/Ionization Time-of-Flight) Mass-Spectroscopic Assay

DNA Loss and Related Alterations in Long-term Cultures of Diploid, Tetraploid and Octaploid Meth-A Cells

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