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Different effects of p14ARF on the levels of ubiquitinated p53 and Mdm2 in vivo

Oncogene volume 20, pages 4972–4983 (2001)Cite this article

Abstract

Mdm2 has been shown to promote its own ubiquitination and the ubiquitination of the p53 tumour suppressor by virtue of its E3 ubiquitin ligase activity. This modification targets Mdm2 and p53 for degradation by the proteasome. The p14ARF tumour suppressor has been shown to inhibit degradation of p53 mediated by Mdm2. Several models have been proposed to explain this effect of p14ARF. Here we have compared the effects of p14ARF overexpression on the in vivo ubiquitination of p53 and Mdm2. We report that the inhibition of the Mdm2-mediated degradation of p53 by p14ARF is associated with a decrease in the proportion of ubiquitinated p53. The levels of polyubiquitinated p53 decreased preferentially compared to monoubiquitinated species. p14ARF overexpression increased the levels of Mdm2 but it did not reduce the overall levels of ubiquitinated Mdm2 in vivo. This is unexpected because p14ARF has been reported to inhibit the ubiquitination of Mdm2 in vitro. In addition we show that like p14ARF, the proteasome inhibitor MG132 can promote the accumulation of Mdm2 in the nucleolus and that this can occur in the absence of p14ARF expression. We also show that the mutation of the nucleolar localization signal of Mdm2 does not impair the overall ubiquitination of Mdm2 but is necessary for the effective polyubiquitination of p53. These studies reveal important differences in the regulation of the stability of p53 and of Mdm2.

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Acknowledgements

We are grateful to Drs M Oren, K Vousden, C Sherr, A Levine and S Mittnacht for providing us with reagents. We also thank our colleagues in Dundee, E Warbrick and C Stephen for comments and critical review of the manuscript and C Midgley for providing the vector expressing the Mdm2 C464A mutant. D Xirodimas, S Laín and M Saville are recipients of postdoctoral fellowships from Cancer Research Campaign (UK) and Tenovus (Scotland). DP Lane is a Gibb fellow of the Cancer Research Campaign.

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  1. Department of Surgery and Molecular Oncology, Dundee Hospital and Medical School, Dundee DD1 9SY, Scotland, UK

    Dimitris Xirodimas, Mark K Saville, Charlotte Edling, David P Lane & Sonia Laín

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  1. Dimitris Xirodimas
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  2. Mark K Saville
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Correspondence to Sonia Laín.

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Xirodimas, D., Saville, M., Edling, C. et al. Different effects of p14ARF on the levels of ubiquitinated p53 and Mdm2 in vivo. Oncogene 20, 4972–4983 (2001). https://doi.org/10.1038/sj.onc.1204656

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