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J. Biol. Chem., Vol. 282, Issue 45, 32603-32612, November 9, 2007

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MDM2 Chaperones the p53 Tumor Suppressor^*

Bartosz Wawrzynow, Alicja Zylicz, Maura Wallace^¶, Ted Hupp^¶, and Maciej Zylicz¹

From the International Institute of Molecular and Cell Biology in Warsaw, 02-109 Warsaw, Poland, The Nencki Institute of Experimental Biology, PAS, 02-093 Warsaw, Poland, and the ^¶University of Edinburgh, Division of Oncology, Cancer Research UK Cell Signalling Unit, Edinburgh EH4 2XU, Scotland, United Kingdom

The murine double minute (mdm2) gene encodes an E3 ubiquitin ligase that plays a key role in the degradation of p53 tumor suppressor protein. Nevertheless recent data highlight other p53-independent functions of MDM2. Given that MDM2 protein binds ATP, can interact with the Hsp90 chaperone, plays a role in the modulation of transcription factors and protection and activation of DNA polymerases, and is involved in ribosome assembly and nascent p53 protein biosynthesis, we have evaluated and found MDM2 protein to possess an intrinsic molecular chaperone activity. MDM2 can substitute for the Hsp90 molecular chaperone in promoting binding of p53 to the p21-derived promoter sequence. This reaction is driven by recycling of MDM2 from the p53 complex, triggered by binding of ATP to MDM2. The ATP binding mutant MDM2 protein (K454A) lacks the chaperone activity both in vivo and in vitro. Mdm2 cotransfected in the H1299 cell line with wild-type p53 stimulates efficient p53 folding in vivo but at the same time accelerates the degradation of p53. MDM2 in which one of the Zn²⁺ coordinating residues is mutated (C478S or C464A) blocks degradation but enhances folding of p53. This is the first demonstration that MDM2 possesses an intrinsic molecular chaperone activity, indicating that the ATP binding function of MDM2 can mediate its chaperone function toward the p53 tumor suppressor.

Received for publication, April 2, 2007 , and in revised form, September 4, 2007.

^* This work was supported by Ministry of Education and Science Grant PBZ-KBN-107/P04/2004 and European Commission 5th Framework Programme Project Centre of Excellence in Molecular Bio-Medicine Contract QLK6-CT-2002-90363. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental material, Figs. 1 and 2, and additional references.

¹ To whom correspondence should be addressed: International Institute of Molecular and Cell Biology in Warsaw, 4 Trojdena St., 02-109 Warsaw, Poland. Tel.: 48-22-5970740; Fax: 48-22-5970743; E-mail: mzylicz{at}iimcb.gov.pl.

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