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MAD2ΔC induces aneuploidy and promotes anchorage-independent growth in human prostate epithelial cells

Oncogene volume 27, pages 347–357 (2008)Cite this article

Abstract

The mitotic arrest deficient 2 (MAD2) is suggested to play a key role in a functional mitotic checkpoint because of its inhibitory effect on anaphase-promoting complex/cyclosome (APC/C) during mitosis. The binding of MAD2 to mitotic checkpoint regulators MAD1 and Cdc20 is thought to be crucial for its function and loss of which leads to functional inactivation of the MAD2 protein. However, little is known about the biological significance of this MAD2 mutant in human cells. In this study, we stably transfected a C-terminal-deleted MAD2 gene (MAD2ΔC) into a human prostate epithelial cell line, Hpr-1 and studied its effect on chromosomal instability, cell proliferation, mitotic checkpoint control and soft agar colony-forming ability. We found that MAD2ΔC was able to induce aneuploidy through promoting chromosomal duplication, which was a result of an impaired mitotic checkpoint and cytokinesis, suggesting a crucial role of MAD2-mediated mitotic checkpoint in chromosome stability in human cells. In addition, the MAD2ΔC-transfected cells displayed anchorage-independent growth in soft agar after challenged by 7,12-dimethylbenz[A]anthracene (DMBA), demonstrating a cancer-promoting effect of a defective mitotic checkpoint in human cells. Furthermore, the DMBA-induced transformation was accompanied by a complete loss of DNA damage-induced p53 response and activation of the MAPK pathway in MAD2ΔC cells. These results indicate that a defective mitotic checkpoint alone is not a direct cause of tumorigenesis, but it may predispose human cells to carcinogen-induced malignant transformation. The evidence presented here provides a link between MAD2 inactivation and malignant transformation of epithelial cells.

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Acknowledgements

We thank Dr Deng Wen for his technical support on SKY analysis. This work was supported by Association for International Cancer Research (AICR), UK, to X Wang.

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  1. Department of Anatomy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong

    K W To-Ho, H W Cheung, M-T Ling, Y C Wong & X Wang

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Correspondence to Y C Wong or X Wang.

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To-Ho, K., Cheung, H., Ling, MT. et al. MAD2ΔC induces aneuploidy and promotes anchorage-independent growth in human prostate epithelial cells. Oncogene 27, 347–357 (2008). https://doi.org/10.1038/sj.onc.1210633

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