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Molecular and Cellular Biology, July 2003, p. 4929-4938, Vol. 23, No. 14
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.14.4929-4938.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Critical Role for a Central Part of Mdm2 in the Ubiquitylation of p53

Erik Meulmeester,1 Ruth Frenk,1 Robert Stad,1,{dagger} Petra de Graaf,1 Jean-Christophe Marine,2 Karen H. Vousden,3 and Aart G. Jochemsen1*

Department of Molecular and Cell Biology and Center for Biomedical Genetics, Leiden University Medical Center, 2300 RA Leiden, The Netherlands,1 ULB-IBMM, Laboratoire d'Embryologie Moléculaire, 6041 Gosselies, Belgium,2 Beatson Institute for Cancer Research, Bearsden, Glasgow G61 1BD, United Kingdom3

Received 4 December 2002/ Returned for modification 22 January 2003/ Accepted 9 April 2003

The stability of the p53 protein is regulated by Mdm2. By acting as an E3 ubiquitin ligase, Mdm2 directs the ubiquitylation of p53 and its subsequent degradation by the 26S proteasome. In contrast, the Mdmx protein, although structurally similar to Mdm2, cannot ubiquitylate or degrade p53 in vivo. To ascertain which domains determine this functional difference between Mdm2 and Mdmx and consequently are essential for p53 ubiquitylation and degradation, we generated Mdm2-Mdmx chimeric constructs. Here we show that, in addition to a fully functional Mdm2 RING finger, an internal domain of Mdm2 (residues 202 to 302) is essential for p53 ubiquitylation. Strikingly, the function of this domain can be fulfilled in trans, indicating that the RING domain and this internal region perform distinct activities in the ubiquitylation of p53.

* Corresponding author. Mailing address: Leiden University Medical Center, Department of Molecular and Cell Biology, P.O. Box 9503, 2300 RA Leiden, The Netherlands. Phone: 31 715276136. Fax: 31 71 5276284. E-mail: A.G.Jochemsen{at}lumc.nl.

{dagger} Present address: University of Amsterdam, Faculty of Sciences, 1090 GB Amsterdam, The Netherlands.

Molecular and Cellular Biology, July 2003, p. 4929-4938, Vol. 23, No. 14
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.14.4929-4938.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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