Induction of karyotype instability in a murine tumor cell line by quercetin, 2‐amino‐1‐methyl‐6 phenylimidazo[4,5‐ <i>b</i>]pyridine, and okadaic acid, as revealed by transmission distortion of the inactive X chromosome

Kuwabara, Katsuhiro; Odani, Sumiko; Takahashi, Yoshiaki; Arakawa, Masaaki; Takagi, Nobuo; Nagao, Minako; Kominami, Ryo

doi:10.1002/mc.2940140411

Cited by 7 publications

(6 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, aneugens generally induce polyploidy in vitro (Matsuoka et al, 1999;Kirsch-Volders et al, 2002) and we observed that OA increased the number of PN after 24 h exposure in a dose-dependent manner. Moreover, an increase in karyotype instability was previously shown in cells treated with OA (Afshari et al, 1993;Kuwabara et al, 1995).…”

Section: Discussionmentioning

confidence: 76%

Aneugenic potential of okadaic acid revealed by the micronucleus assay combined with the FISH technique in CHO-K1 cells

Hégarat¹

2003

Mutagenesis

View full text Add to dashboard Cite

Okadaic acid (OA) is a major toxin involved in diarrhetic shellfish poisoning in humans and has been shown to be both a potent tumor promoter in rodent skin and stomach and an inhibitor of serine/threonine protein phosphatases, specifically PP1 and PP2A. The research on the genotoxic potential of OA amounts to only a few studies, which give conflicting results. In order to evaluate the ability of OA to induce DNA damage, the cytokinesis-block micronucleus assay was performed in the CHO-K1 cell line. A statistically significant induction of micronuclei without strong cytotoxicity was obtained after a 24 h treatment with 20 (approximately 5-fold) and 30 nM (approximately 10-fold) OA. Then, in order to discriminate between a clastogenic or aneugenic effect of OA, the micronucleus assay was carried out in combination with fluorescence in situ hybridization (FISH) using a (TTAGGG)(n) DNA probe for centromere detection. FISH analysis showed that OA mainly induced centromere-positive micronuclei (68.9% induction with 20 nM OA and 77.0% with 30 nM). Therefore, OA can be considered aneugenic. Using the same assay, biotransformation of OA was studied after a 4 h treatment with and without metabolic activation. The results show that reactive metabolites of OA were generated with a significant increase in genotoxic potential. The relationship between the different components involved in the mitotic process and OA inhibition of protein phosphatase is also discussed.

show abstract

Section: Discussionmentioning

confidence: 76%

Aneugenic potential of okadaic acid revealed by the micronucleus assay combined with the FISH technique in CHO-K1 cells

Hégarat¹

2003

Mutagenesis

View full text Add to dashboard Cite

show abstract

“…However, we have found that OA induces various genomic alterations in cultured cells, such as mutations endowing diphtheria-toxin resistance (4), sister chromatid exchange in the presence of bromodeoxyuridine (5), and loss of exogenous transforming oncogenes (6). OA also induces karyotype instability (7) and gene amplification under certain circumstances (8). Although the molecular mechanisms underlying the genotoxic activity of OA have not been fully elucidated as yet, all the observed genetic alterations point to the induction of recombination events rather than introduction of point mutations.…”

mentioning

confidence: 99%

Induction of minisatellite mutation in NIH 3T3 cells by treatment with the tumor promoter okadaic acid

Nakagama

Kaneko

Shima

et al. 1997

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

Self Cite

View full text Add to dashboard Cite

Okadaic acid (OA) is a strong tumor promoter of mouse skin carcinogenesis and also a potent inhibitor of serine͞threonine protein phosphatases. OA induces various genetic alterations in cultured cells, such as diphtheriatoxin-resistance mutations, sister chromatid exchange, exclusion of exogenous transforming oncogenes, and gene amplification. The present study revealed that it caused minisatellite mutation (MSM) at a high frequency in NIH 3T3 cells, although no microsatellite mutation was found. Nine of 31 clones (29%) exhibited MSM after 6 days of OA treatment, as opposed to only 1 of 30 clones (3%) without OA exposure. Moreover, NIH 3T3 cells treated with OA acquired tumorigenicity in nude mice, giving rise to 7 tumors within 25 weeks in 20 sites where 3 ؋ 10 6 cells were injected. In contrast, the same numbers of untreated cells gave rise to only one tumor, and the tumor grew much slower. All of three OA-induced tumors examined manifested the MSM. The findings thus point to a molecular mechanism by which OA could function as a tumor promoter, and also the biological relevance of the induction of MSM in the tumorigenic process by OA.

show abstract

“…Accordingly, somatic recombination or whole loss of these two chromosomes is frequently observed in a variety of tumor cells, even in normal somatic cells [9,10]. This suggests that the two chromosomes can serve as an ef®cient indicator of genomic or chromosomal instability.…”

Section: Introductionmentioning

confidence: 99%

Accumulation of aberrant Y chromosomes in ?-ray-induced thymic lymphomas lacking p53

et al. 1999

Self Cite

View full text Add to dashboard Cite

Male F(1) hybrids between MSM mice carrying a deficient p53 allele and BALB/c mice were irradiated with gamma-rays, and 80 thymic lymphomas were obtained, 46 of which developed in mice carrying the deficient p53 allele. Because the Y chromosome contributes little to cellular function, the stability of the Y chromosome in the tumors was assessed by polymerase chain reaction by examining three genes: Smcy and Sry on the short arm and Sts in the pseudoautosomal region of the long arm of the Y chromosome. Twenty-one lymphomas had lost one or two genes, probably as a result of mitotic recombination or interstitial deletion, whereas no lymphomas had lost all three genes. The p53 status of the lymphomas was determined by genotyping and allelic loss analysis; 34 had retained two wild-type p53 alleles, suggesting normal function; 34 had lost both alleles, indicating loss of function; and the other 12 had at least one wild-type p53 allele, so their p53 status was unclear. Compilation of these data revealed that changes in the Y chromosome were detected in only two of the 34 lymphomas retaining functional p53 but in 18 of the 34 lymphomas lacking p53 function, suggesting that p53 deficiency leads to an increase in the accumulation of radiation-induced aberrant chromosomes. This is consistent with our previous result from analysis of the inactive X chromosome. In contrast, a decrease in the fidelity of mitotic transmission in p53-deficient lymphomas was not noted for the Y chromosome.

show abstract

Induction of karyotype instability in a murine tumor cell line by quercetin, 2‐amino‐1‐methyl‐6 phenylimidazo[4,5‐ b]pyridine, and okadaic acid, as revealed by transmission distortion of the inactive X chromosome

Cited by 7 publications

References 35 publications

Aneugenic potential of okadaic acid revealed by the micronucleus assay combined with the FISH technique in CHO-K1 cells

Aneugenic potential of okadaic acid revealed by the micronucleus assay combined with the FISH technique in CHO-K1 cells

Induction of minisatellite mutation in NIH 3T3 cells by treatment with the tumor promoter okadaic acid

Accumulation of aberrant Y chromosomes in ?-ray-induced thymic lymphomas lacking p53

Contact Info

Product

Resources

About