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Partial downregulation of MAD1 causes spindle checkpoint inactivation and aneuploidy, but does not confer resistance towards taxol

Oncogene volume 24, pages 4301–4310 (2005)Cite this article

Abstract

The mitotic spindle assembly checkpoint ensures proper chromosome segregation during mitosis by inhibiting the onset of anaphase until all kinetochores are attached to the mitotic spindle and tension across the kinetochores is generated. Here, we report that the stable partial downregulation of the spindle checkpoint gene MAD1, which is observed in human cancer, leads to a functional inactivation of the spindle checkpoint resulting in gross aneuploidy. Interestingly, although Mad1 is thought to act as a kinetochore based activator of Mad2 during checkpoint activation, we show that normal levels of Mad2, but not of Mad1, are required for preventing premature sister chromatid separation and for maintaining the timing of an undisturbed mitosis, suggesting a Mad1 independent function of Mad2 that operates independent of its checkpoint function. Most significantly, a partial repression of either MAD1 or MAD2 confers resistance to nocodazole, a drug that inhibits microtubule attachment. In contrast, sensitivity to clinically relevant drugs like taxol or monastrol that inhibit the generation of tension across kinetochores is not modulated by partial downregulation of MAD1, suggesting a functional bifurcation of spindle checkpoint dependent apoptotic pathways.

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Acknowledgements

We thank Tim Yen for generously providing Mad1 antibodies, Bert Vogelstein, Loren Michel and Robert Benezra for providing HCT116 and derivative cell lines and Rene Bernards for the pSuper vector. We are grateful to Irmgard Hofmann for help with the generation of the knockdown cell lines and to Heike Krebber for helpful discussions and critically reading the manuscript. This work was supported by grants from the Deutsche Forschungsgemeinschaft, the Deutsche Krebshilfe and the PE Kempkes Stiftung.

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  1. Anne Kienitz and Celia Vogel: These authors contributed equally to this work

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  1. Institute for Molecular Biology and Tumor Research (IMT), Philipps University Marburg, Emil-Mannkopff-Strasse 2, D-35037, Marburg, Germany

    Anne Kienitz, Celia Vogel, Ivonne Morales, Rolf Müller & Holger Bastians

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  1. Anne Kienitz
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Correspondence to Holger Bastians.

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Kienitz, A., Vogel, C., Morales, I. et al. Partial downregulation of MAD1 causes spindle checkpoint inactivation and aneuploidy, but does not confer resistance towards taxol. Oncogene 24, 4301–4310 (2005). https://doi.org/10.1038/sj.onc.1208589

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