Role of mitotic motors, dynein and kinesin, in the induction of abnormal centrosome integrity and multipolar spindles in cultured V79 cells exposed to dimethylarsinic acid.
The role of microtubule-based motors in the induction of abnormal centrosome integrity by dimethylarsinic acid (DMAA) was investigated with the use of monastrol, a specific inhibitor of mitotic kinesin, and vanadate, an inhibitor of dynein ATPase. Cytoplasmic dynein co-localized with multiple foci of gamma-tubulin in mitotic cells arrested by DMAA. Disruption of microtubules caused dispersion of dynein while multiple foci of gamma-tubulin were coalesced to a single dot. Vanadate also caused dispersion of dynein, which had been co-localized with multiple foci of gamma-tubulin by DMAA, without affecting spindle organization. However, the dispersion of dynein did not prohibit the induction of abnormal centrosome integrity by DMAA. Inhibition of mitotic kinesin by monastrol resulted in monoastral cells with non-migrated centrosomes in the cell center. Monastrol, when applied to mitotic cells with abnormal centrosome integrity, rapidly reduced the incidence of cells with the centrosome abnormality. Moreover, monastrol completely inhibited reorganization of abnormal centrosomes that had been coalesced to a single dot by microtubule disruption. These results suggest that abnormal centrosome integrity caused by DMAA is not simply due to dispersion of fragments of microtubule-organizing centers, but is dependent on the action of kinesin. In addition, the results suggest that kinesin plays a role not only in the induction of mitotic centrosome abnormality, but also in maintenance.
Ochi
Takafumi
T
Department of Toxicology and Environmental Health, Faculty of Pharmaceutical Sciences, Teikyo University, Sagamiko, Kanagawa 199-0195, Japan. tkfmochi@pharm.teikyo-u.ac.jp
D000818:Animals; D002101:Cacodylic Acid / Q000494:pharmacology*; D002478:Cells, Cultured; D018385:Centrosome / Q000187:drug effects*; D006224:Cricetinae; D003412:Cricetulus; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism; D004398:Dyneins / Q000187:drug effects / Q000378:metabolism*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D016547:Kinesins / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008870:Microtubules / Q000187:drug effects / Q000648:ultrastructure; D011743:Pyrimidines / Q000494:pharmacology; D008941:Spindle Apparatus / Q000187:drug effects / Q000502:physiology*; D013871:Thiones / Q000494:pharmacology; D014404:Tubulin / Q000378:metabolism; D014638:Vanadates / Q000494:pharmacology
D011743:Pyrimidines; D013871:Thiones; D014404:Tubulin; D014638:Vanadates; C400223:monastrol; D002101:Cacodylic Acid; D004398:Dyneins; D016547:Kinesins