Disruption of spindle checkpoint function ahead of facilitation of cell proliferation by repeated administration of hepatocarcinogens in rats
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- Kimura Masayuki
- Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology Pathogenetic Veterinary Science, United Graduate School of Veterinary Sciences, Gifu University
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- Mizukami Sayaka
- Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology Pathogenetic Veterinary Science, United Graduate School of Veterinary Sciences, Gifu University
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- Watanabe Yousuke
- Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology Pathogenetic Veterinary Science, United Graduate School of Veterinary Sciences, Gifu University
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- Hasegawa-Baba Yasuko
- Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology
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- Onda Nobuhiko
- Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology
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- Yoshida Toshinori
- Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology
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- Shibutani Makoto
- Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology
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We aimed to clarify the hepatocarcinogen-specific disruption of cell cycle checkpoint functions and its time course after repeated administration of hepatocarcinogens. Thus, rats were repeatedly administered with hepatocarcinogens (methapyrilene, carbadox and thioacetamide), a marginal hepatocarcinogen (leucomalachite green), hepatocarcinogenic promoters (oxfendazole and β-naphthoflavone) or non-carcinogenic hepatotoxicants (promethazine and acetaminophen) for 7, 28 or 90 days, and the temporal changes in cell proliferation, expression of G1/S and spindle checkpoint-related molecules, and apoptosis were examined using immunohistochemistry and/or real-time RT-PCR analysis. Hepatocarcinogens facilitating cell proliferation at day 28 of administration also facilitated cell proliferation and apoptosis at day 90. Hepatocarcinogen- or hepatocarcinogenic promoter-specific cellular responses were not detected by immunohistochemical single molecule analysis even after 90 days. Expression of Cdkn1a, Mad2l1, Chek1 and Rbl2 mRNA also lacked specificity to hepatocarcinogens or hepatocarcinogenic promoters. In contrast, all hepatocarcinogens and the marginally hepatocarcinogenic leucomalachite green induced Mdm2 upregulation or increase in the number of phosphorylated MDM2+ cells from day 28, irrespective of the lack of cell proliferation facilitation by some compounds. However, different Tp53 expression levels suggest different mechanisms of induction or activation of MDM2 among hepatocarcinogens. On the other hand, hepatocarcinogenic methapyrilene and carbadox downregulated the number of both ubiquitin D+ cells and proliferating cells remaining in M phase at day 28 and/or day 90, irrespective of the lack of cell proliferation facilitation in the latter. These results suggest that hepatocarcinogens disrupt spindle checkpoint function after 28 or 90 days of administration, which may be induced ahead of cell proliferation facilitation.
収録刊行物
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- The Journal of Toxicological Sciences
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The Journal of Toxicological Sciences 40 (6), 855-871, 2015
一般社団法人 日本毒性学会
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詳細情報 詳細情報について
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- CRID
- 1390282679880097664
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- NII論文ID
- 130005108874
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- NII書誌ID
- AN00002808
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- ISSN
- 18803989
- 03881350
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- NDL書誌ID
- 026971385
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- PubMed
- 26558467
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- 本文言語コード
- en
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- データソース種別
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- JaLC
- NDL
- Crossref
- PubMed
- CiNii Articles
- KAKEN
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- 抄録ライセンスフラグ
- 使用不可