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Antizyme, a mediator of ubiquitin-independent proteasomal degradation and its inhibitor localize to centrosomes and modulate centriole amplification

Oncogene volume 27, pages 604–613 (2008)Cite this article

Abstract

The potential tumor suppressor antizyme and its endogenous inhibitor (antizyme inhibitor, AZI) have been implicated in the ubiquitin-independent proteasomal degradation of proteins involved in cell proliferation as well as in the regulation of polyamine levels. We show here that both antizyme and AZI concentrate at centrosomes and that antizyme preferentially associates with the maternal centriole. Interestingly, alterations in the levels of these proteins have opposing effects on centrosomes. Depletion of antizyme in various cell lines and primary cells leads to centrosome overduplication, whereas overexpression of antizyme reduces numerical centrosome abnormalities. Conversely, silencing of the antizyme inhibitor, AZI, results in a decrease of numerical centrosome abnormalities, whereas overexpression of AZI leads to centrosome overduplication. We further show that the numerical centrosome abnormalities are due to daughter centriole amplification. In summary, our results demonstrate that alterations in the antizyme/AZI balance cause numerical centrosomal defects and suggest a role for ubiquitin-independent proteasomal degradation in centrosome duplication.

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Acknowledgements

We thank Senya Matsufuji (Jikei University) and John Mitchell (Northern Illinois University) for their generous gifts of mouse monoclonal AZI antibody and rabbit polyclonal antizyme 1 antibody. We also thank Sri Diah and Sonia Kim for designing the siRNAs against rodent antizyme 1 and AZI. Special thanks to Amy Baldwin for providing the HFK cells. This work was supported by Grants no. CA37393 and CA066980 from the USPHS. The authors declare that they have no commercial affiliations/conflicts of interests with regard to this study.

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Authors and Affiliations

  1. Program in Vascular Biology, Children's Hospital Boston, Boston, MA, USA

    U Mangold & B R Zetter

  2. Department of Surgery, Harvard Medical School, Boston, MA, USA

    U Mangold & B R Zetter

  3. Department of Medicine, Channing Laboratory, Brigham and Women's Hospital, Boston, MA, USA

    H Hayakawa & K Münger

  4. Department of Cell Biology, Harvard Medical School, Boston, MA, USA

    M Coughlin

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  1. U Mangold
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  2. H Hayakawa
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  3. M Coughlin
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  4. K Münger
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  5. B R Zetter
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Correspondence to B R Zetter.

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

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Mangold, U., Hayakawa, H., Coughlin, M. et al. Antizyme, a mediator of ubiquitin-independent proteasomal degradation and its inhibitor localize to centrosomes and modulate centriole amplification. Oncogene 27, 604–613 (2008). https://doi.org/10.1038/sj.onc.1210685

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