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Inactivation of the p53-homologue p73 by the mdm2-oncoprotein

Oncogene volume 18, pages 2101–2106 (1999)Cite this article

Abstract

The p73β protein shares structural and functional similarities with the tumor suppressor gene product p53. Both proteins activate transcription from p53-responsive promoters. p53's activity is antagonized by the mdm2 protein (also termed hdm2 in human cells). Complex formation between p53 and mdm2 results in p53's transcriptional inactivation and destabilization. Here we show that overexpression of mdm2 reduces p73β's ability to activate transcription, too. The mdm2 protein forms a specific complex with p73β in vitro with an efficiency comparable to p53-binding. Further, both p73β and p53 relocalize a transport-defective mutant of mdm2 from the cytoplasm to the nucleus, arguing that complex formation occurs in vivo as well. Mutational analysis suggests that the interaction between p73β and mdm2 follows structural principles analogous to the p53-mdm2-complex. Whereas p53 is destabilized in the presence of mdm2, the amount of intracellular p73β was not detectably reduced by mdm2. The carboxyterminal RING finger domain of mdm2 was found to be required to reduce the intracellular abundance of p53, but it was dispensable for transcriptionally inactivating either p53 or p73β. Our results suggest that the autoregulatory feedback loop between p53 and mdm2 also controls p73's activity, but that mdm2-mediated protein degradation is unique to p53.

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Acknowledgements

We thank HD Klenk and R Arnold for their generous support. D Caput, J Chen and WG Kaelin for plasmids. M Eilers and E Slater for helpful discussion. This work was supported by the German Research Foundation, the German Cancer Research Center (Stipendium für Infektionsbiologie to MD), the Hoechst Foundation (scholarship to SW), and the Fazit foundation (scholarship to CK).

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Authors and Affiliations

  1. Institut für Virologie, Zentrum für Mikrobiologie und Hygiene, Philipps-Universität Marburg, Robert Koch Str. 17, Marburg, 35037, Germany

    Matthias Dobbelstein, Sandra Wienzek & Claudia König

  2. Abteilung Gastroenterologie und Stoffwechsel, Zentrum für Innere Medizin, Fachbereich Medizin der Philipps-Universität Marburg, Baldingerstraße, 35045, Marburg, Germany

    Judith Roth

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  1. Matthias Dobbelstein
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Dobbelstein, M., Wienzek, S., König, C. et al. Inactivation of the p53-homologue p73 by the mdm2-oncoprotein. Oncogene 18, 2101–2106 (1999). https://doi.org/10.1038/sj.onc.1202512

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