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J. Biol. Chem., Vol. 283, Issue 20, 13707-13713, May 16, 2008

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Phosphorylation of MDMX Mediated by Akt Leads to Stabilization and Induces 14-3-3 Binding^*

From the Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, Massachusetts 02115

The critical tumor suppressor p53 is mutated or functionally inactivated in nearly all cancers. We have shown previously that the MDM2-MDMX complex functions as an integral unit in targeting p53 for degradation. Here we identify the small protein 14-3-3 as a binding partner of MDMX, which binds at the C terminus (Ser³⁶⁷) in a phosphorylation-dependent manner. Importantly, we demonstrate that the serine/threonine kinase Akt mediates phosphorylation of MDMX at Ser³⁶⁷. This phosphorylation leads to stabilization of MDMX and consequent stabilization of MDM2. Previous studies have shown that Akt phosphorylates and stabilizes MDM2. Our data suggest that stabilization of MDMX by Akt may be an alternative mechanism by which Akt up-regulates MDM2 protein levels and exerts its oncogenic effects on p53 in tumor cells.

Received for publication, December 10, 2007 , and in revised form, March 20, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants R01CA85679–02 (to Z.-M. Y.) and T32ES07155 (to V. L.-P. and M. M. K.). 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.

¹ To whom correspondence should be addressed: 665 Huntington Ave., Bldg. 1-507, Boston, MA 02215. Fax: 617-432-0107; E-mail: zyuan{at}hsph.harvard.edu.

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