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Originally published In Press as doi:10.1074/jbc.M110295200 on November 29, 2001

J. Biol. Chem., Vol. 277, Issue 7, 5187-5193, February 15, 2002
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Prevalent Loss of Mitotic Spindle Checkpoint in Adult T-cell Leukemia Confers Resistance to Microtubule Inhibitors*

Takefumi Kasai, Yoichi Iwanaga, Hidekatsu Iha, and Kuan-Teh JeangDagger

From the Molecular Virology Section, Laboratory of Molecular Microbiology, NIAID, National Institutes of Health, Bethesda, Maryland 20892-0460

Human T-cell leukemia virus type I (HTLV-I) is the causative agent for adult T-cell leukemia (ATL). Molecularly, ATL cells have extensive aneugenic abnormalities that occur, at least in part, from cell cycle dysregulation by the HTLV-I-encoded Tax oncoprotein. Here, we compared six HTLV-I-transformed cells to Jurkat and primary peripheral blood mononuclear cells (PBMC) in their responses to treatment with microtubule inhibitors. We found that both Jurkat and PBMCs arrested efficiently in mitosis when treated with nocodazole. By contrast, all six HTLV-I cells failed to arrest comparably in mitosis, suggesting that ATL cells have a defect in the mitotic spindle assembly checkpoint. Mechanistically, we observed that in HTLV-I Tax-expressing cells human spindle assembly checkpoint factors hsMAD1 and hsMAD2 were mislocated from the nucleus to the cytoplasm. This altered localization of hsMAD1 and hsMAD2 correlated with loss of mitotic checkpoint function and chemoresistance to microtubule inhibitors.

* The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger To whom correspondence should be addressed: Molecular Virology Section, Laboratory of Molecular Microbiology, NIAID, National Institutes of Health, Bldg. 4, Rm. 306, 9000 Rockville Pike, Bethesda, MD 20892-0460. Tel.: 301-496-6680; Fax: 301-480-3686; E-mail: kj7e@nih.gov.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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