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Trivalent dimethylarsenic compound induces histone H3 phosphorylation and abnormal localization of Aurora B kinase in
Toshihide Suzuki1, Koichi Miyazaki, Kayoko Kita
1Laboratory of Toxicology, Faculty of Pharmaceutical Sciences, Teikyo University, 1091-1 Sagamiko-cho, Sagamihara, Kanagawa 229-0195, Japan. toshi-su@pharm.teikyo-u.ac.jp
Abstract:
Trivalent dimethylarsinous acid [DMA(III)] has been shown to induce mitotic abnormalities, such as centrosome abnormality, multipolar spindles, multipolar division, and aneuploidy, in several cell lines. In order to elucidate the mechanisms underlying these mitotic abnormalities, we investigated DMA(III)-mediated changes in histone H3 phosphorylation and localization of Aurora B kinase, which is a key molecule in cell mitosis. DMA(III) caused the phosphorylation of histone H3 (ser10) and was distributed predominantly in mitotic cells, especially in prometaphase cells. By contrast, most of the phospho-histone H3 was found to be localized in interphase cells after treatment with inorganic arsenite [iAs(III)], suggesting the involvement of a different pathway in phosphorylation. DMA(III) activated Aurora B kinase and slightly activated ERK MAP kinase. Phosphorylation of histone H3 by DMA(III) was effectively reduced by ZM447439 (Aurora kinase inhibitor) and slightly reduced by U0126 (MEK inhibitor). By contrast, iAs(III)-dependent histone H3 phosphorylation was markedly reduced by U0126. Aurora B kinase is generally localized in the midbody during telophase and plays an important role in cytokinesis. However, in some cells treated with DMA(III), Aurora B was not localized in the midbody of telophase cells. These findings suggested that DMA(III) induced a spindle abnormality, thereby activating the spindle assembly checkpoint (SAC) through the Aurora B kinase pathway. In addition, cytokinesis was not completed because of the abnormal localization of Aurora B kinase by DMA(III), thereby resulting in the generation of multinucleated cells. These results provide insight into the mechanism of arsenic tumorigenesis.
Insights
Trivalent dimethylarsinous acid [DMA(III)] causes mitotic abnormalities by altering histone H3 phosphorylation and Aurora B kinase localization, leading to spindle defects and multinucleated cells, offering insights into arsenic-induced cancer. This research highlights DMA(III) as a potent inducer of cell division errors.
Area of Science:
- Cell Biology
- Molecular Toxicology
- Cancer Research
Background:
- Trivalent dimethylarsinous acid [DMA(III)] is known to induce mitotic abnormalities, including centrosome issues, multipolar spindles, and aneuploidy.
- Understanding the molecular mechanisms behind these abnormalities is crucial for elucidating arsenic's role in tumorigenesis.
Purpose of the Study:
- To investigate the mechanisms by which DMA(III) induces mitotic abnormalities, focusing on histone H3 phosphorylation and Aurora B kinase localization.
- To differentiate the effects of DMA(III) from inorganic arsenite [iAs(III)] on these cellular processes.
Main Methods:
- Treatment of cell lines with DMA(III) and iAs(III).
- Analysis of histone H3 phosphorylation (ser10) and Aurora B kinase localization during mitosis.
- Pharmacological inhibition of Aurora kinase and MEK to assess pathway involvement.
- Assessment of cytokinesis and cell multinucleation.
Main Results:
- DMA(III) induced histone H3 phosphorylation predominantly in mitotic cells, involving Aurora B kinase and ERK MAP kinase activation.
- In contrast, iAs(III) primarily caused histone H3 phosphorylation in interphase cells, with MEK pathway involvement.
- Abnormal Aurora B kinase localization in telophase cells treated with DMA(III) disrupted cytokinesis, leading to multinucleated cells.
- DMA(III) activated the spindle assembly checkpoint (SAC) via the Aurora B kinase pathway, contributing to mitotic errors.
Conclusions:
- DMA(III) induces mitotic abnormalities through specific alterations in histone H3 phosphorylation and Aurora B kinase localization.
- The disruption of cytokinesis by DMA(III) leads to multinucleation, a potential mechanism in arsenic-induced carcinogenesis.
- Distinct pathways are involved in histone H3 phosphorylation induced by DMA(III) and iAs(III).
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