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Id-1 promotes chromosomal instability through modification of APC/C activity during mitosis in response to microtubule disruption

Oncogene volume 27, pages 4456–4466 (2008)Cite this article

Abstract

Id-1 (Inhibitor of DNA binding/differential-1) plays a positive role in tumorigenesis through regulation of multiple signaling pathways. Recently, it is suggested that upregulation of Id-1 in cancer cells promotes chromosomal instability. However, the underlying molecular mechanism is not known. In this study, we report a novel function of Id-1 in regulation of mitosis through physical interaction with Cdc20 (cell division cycle protein 20) and Cdh1 (Cdc20 homolog 1). During early mitosis, Id-1 interacts with Cdc20 and RASSF1A (Ras association domain family 1A), leading to enhanced APCCdc20 activity, which in turn promotes cyclin B1/securin degradation and premature mitosis. During late mitosis, Id-1 binds to Cdh1 and disrupts the interaction between Cdh1 and APC, resulting in suppression of APCCdh1 activity. On the other hand, overexpression of Cdh1 leads to Id-1 protein degradation, suggesting that Id-1 may also act as a substrate of APCCdh1. The negative effect of Id-1 on APCCdh1 results in suppression of APCCdh1-induced Aurora A and Cdc20 degradation, leading to failure in cytokinesis. As a result, overexpression of Id-1 in human prostate epithelial cells leads to polyploidy in response to microtubule disruption, and this effect is abolished when Id-1 expression is suppressed using antisense technology. These results demonstrate a novel function of Id-1 in promoting chromosomal instability through modification of APC/C activity during mitosis and provide a novel molecular mechanism accounted for the function of Id-1 as an oncogene.

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Acknowledgements

This research was funded by RGC (the Research Grant Council of Hong Kong) HKU7490/03M (YCW) and Association for International Cancer Research, UK (XW).

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Author notes

  1. K Di and X Zhang: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Anatomy, Cancer Biology Group, Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China

    X Wang, K Di, X Zhang, H Y Han, Y C Wong, S C L Leung & M-T Ling

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  1. X Wang
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  2. K Di
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Correspondence to X Wang or M-T Ling.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Wang, X., Di, K., Zhang, X. et al. Id-1 promotes chromosomal instability through modification of APC/C activity during mitosis in response to microtubule disruption. Oncogene 27, 4456–4466 (2008). https://doi.org/10.1038/onc.2008.87

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