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J. Biol. Chem., Vol. 281, Issue 44, 33030-33035, November 3, 2006

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MDMX Overexpression Prevents p53 Activation by the MDM2 Inhibitor Nutlin^*

Baoli Hu, Daniele M. Gilkes, Bilal Farooqi, Said M. Sebti, and Jiandong Chen¹

From the Molecular Oncology Program and Drug Discovery Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612

The p53 tumor suppressor plays a key role in maintaining genomic stability and protection against malignant transformation. MDM2 and MDMX are both p53-binding proteins that regulate p53 stability and activity. Recent development of the MDM2 inhibitor Nutlin 3 has greatly facilitated functional analysis of MDM2-p53 binding. We found that although MDMX is homologous to MDM2 and binds to the same region on p53 N terminus, Nutlin does not disrupt p53-MDMX interaction. The ability of Nutlin to activate p53 is compromised in tumor cells overexpressing MDMX. Combination of Nutlin with MDMX siRNA resulted in synergistic activation of p53 and growth arrest. These results suggest that MDMX is also a valid target for p53 activation in tumor cells. Development of novel compounds that are MDMX-specific or optimized for dual-inhibition of MDM2 and MDMX are necessary to achieve full activation of p53 in tumor cells.

Received for publication, June 7, 2006 , and in revised form, August 9, 2006.

^* This work was supported by grants from the American Cancer Society and the National Institutes of Health (to J. C.). 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: H. Lee Moffitt Cancer Center, MRC3057A, 12902 Magnolia Dr., Tampa, FL 33612. Tel.: 813-903-6822; Fax: 813-903-6817; E-mail: jchen{at}moffitt.usf.edu.

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