Hyperploidy induced by drugs that inhibit formation of microtubule promotes chromosome instability

Nitta, Masayuki; Tsuiki, Hiromasa; Arima, Yoshimi; Harada, Kei; Nishizaki, Takahumi; Sasaki, Kousuke; Mimori, Tatsuyuki; Ushio, Yukitaka; Saya, Hideyuki

doi:10.1046/j.1356-9597.2001.00509.x

Cited by 23 publications

(19 citation statements)

References 46 publications

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“…SIRT2 prevents microtubule poison-induced hyperploid cell formation via a block of entry to chromosome condensation After the prolonged exposure to nocodazole, U251MG cells, which carry a p53 mutation (Alonso et al, 2003), undergo a transient arrest at mitosis and subsequently escape from mitotic arrest and then undergo DNA replication, but they do not complete chromosome segregation and cell division. This phenomenon is termed 'mitotic slippage' and represents a failure to maintain a mitotic arrested state (Di Leonardo et al, 1997;Nitta et al, 2002). As a result of mitotic slippage, U251MG cells undergo DNA re-replication and form hyperploid cells, which are considered to be a frequent precursor of aneuploidy during tumorigenesis (Shackney et al, 1989).…”

Section: Resultsmentioning

confidence: 99%

“…When considering the therapeutic context, it should be noted that in the U251MG cells, SIRT2 blocks entry to chromosome condensation and subsequent mitotic slippage, and in turn, the DNA re-replication that promotes CIN, including both numerical and structural chromosomal changes (Nitta et al, 2002). Particularly, the formation of hyperploid cells was at least partially prevented by exogenous expression of SIRT2 in U251MG cells, which harbor a p53 mutation.…”

Section: Discussionmentioning

confidence: 99%

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SIRT2, a tubulin deacetylase, acts to block the entry to chromosome condensation in response to mitotic stress

et al. 2006

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We previously identified SIRT2, an nicotinamide adenine dinucleotide (NAD)-dependent tubulin deacetylase, as a protein downregulated in gliomas and glioma cell lines, which are characterized by aneuploidy. Other studies reported SIRT2 to be involved in mitotic progression in the normal cell cycle. We herein investigated whether SIRT2 functions in the mitotic checkpoint in response to mitotic stress caused by microtubule poisons. By monitoring chromosome condensation, the exogenously expressed SIRT2 was found to block the entry to chromosome condensation and subsequent hyperploid cell formation in glioma cell lines with a persistence of the cyclin B/cdc2 activity in response to mitotic stress. SIRT2 is thus a novel mitotic checkpoint protein that functions in the early metaphase to prevent chromosomal instability (CIN), characteristics previously reported for the CHFR protein.We further found that histone deacetylation, but not the aberrant DNA methylation of SIRT2 5 0 untranslated region is involved in the downregulation of SIRT2. Although SIRT2 is normally exclusively located in the cytoplasm, the rapid accumulation of SIRT2 in the nucleus was observed after treatment with a nuclear export inhibitor, leptomycin B and ionizing radiation in normal human fibroblasts, suggesting that nucleo-cytoplasmic shuttling regulates the SIRT2 function. Collectively, our results suggest that the further study of SIRT2 may thus provide new insights into the relationships among CIN, epigenetic regulation and tumorigenesis. Oncogene (2007) 26, 945-957.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

SIRT2, a tubulin deacetylase, acts to block the entry to chromosome condensation in response to mitotic stress

et al. 2006

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“…As a working hypothesis, it is tempting to assume that one of the mechanisms that contribute to oncogenesis may be what we might call a 'cytogenetic catastrophe'. Aneuploidization could result from the asymmetric division of polyploid cells, generated from an illicit cell fusion, as it may occur in vivo (DeWitt and Knight, 2002;Terada et al, 2002;Wurmser and Gage, 2002;Vassilopoulos et al, 2003) or from endoreplication/endomitosis (Nitta et al, 2003). Indeed, polyploidy is frequently observed in neoplasia and constitutes a negative prognostic factor, while aneuploidy is a near-to-general characteristic of cancer (Slovak et al, 2000;Choma et al, 2001;Jallepalli and Lengaue, 2001;Shih et al, 2001;Lingle et al, 2002;Masuda and Takahashi, 2002a, b;Sen et al, 2002;Tort et al, 2003).…”

Section: Mitotic Catastrophe and The Apoptotic Machinerymentioning

confidence: 99%

Cell death by mitotic catastrophe: a molecular definition

et al. 2004

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“…A number of studies have demonstrated that the suppression of survivin results in cells with multipolar mitotic spindles that are either multinucleated or aneuploid (Li et al, 1999;Beltrami et al, 2004;Kappler et al, 2004). Some studies have also indicated that aneuploidy promotes chromosome instability (CIN) in glioma and cervical carcinoma cells (Nitta et al, 2002;Olaharski et al, 2006).…”

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confidence: 99%

Centrosome amplification induced by survivin suppression enhances both chromosome instability and radiosensitivity in glioma cells

et al. 2008

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Glioblastoma is characterised by invasive growth and a high degree of radioresistance. Survivin, a regulator of chromosome segregation, is highly expressed and known to induce radioresistance in human gliomas. In this study, we examined the effect of survivin suppression on radiosensitivity in malignant glioma cells, while focusing on centrosome aberration and chromosome instability (CIN). We suppressed survivin by small interfering RNA transfection, and examined the radiosensitivity using a clonogenic assay and a trypan blue exclusion assay in U251MG (p53 mutant) and D54MG (p53 wild type) cells. To assess the CIN status, we determined the number of centrosomes using an immunofluorescence analysis, and the centromeric copy number by fluorescence in situ hybridisation. As a result, the radiosensitisation differed regarding the p53 status as U251MG cells quickly developed extreme centrosome amplification ( ¼ CIN) and enhanced the radiosensitivity, while centrosome amplification and radiosensitivity increased more gradually in D54MG cells. TUNEL assay showed that survivin inhibition did not lead to apoptosis after irradiation. This cell death was accompanied by an increased degree of aneuploidy, suggesting mitotic cell death. Therefore, survivin inhibition may be an attractive therapeutic target to overcome the radioresistance while, in addition, proper attention to CIN (centrosome number) is considered important for improving radiosensitivity in human glioma.

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Hyperploidy induced by drugs that inhibit formation of microtubule promotes chromosome instability

Cited by 23 publications

References 46 publications

SIRT2, a tubulin deacetylase, acts to block the entry to chromosome condensation in response to mitotic stress

SIRT2, a tubulin deacetylase, acts to block the entry to chromosome condensation in response to mitotic stress

Cell death by mitotic catastrophe: a molecular definition

Centrosome amplification induced by survivin suppression enhances both chromosome instability and radiosensitivity in glioma cells

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