Validation of MdmX as a therapeutic target for reactivating p53 in tumors
- Daniel Garcia1,
- Matthew R. Warr2,
- Carla P. Martins1,3,
- Lamorna Brown Swigart1,
- Emmanuelle Passegué2 and
- Gerard I. Evan1,4,5
- 1Department of Pathology, the UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, California 94143, USA;
- 2The Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Department of Medicine, Division of Hematology/Oncology, University of California at San Francisco, San Francisco, California 94143, USA
Abstract
MdmX, also known as Mdm4, is a critical negative regulator of p53, and its overexpression serves to block p53 tumor suppressor function in many cancers. Consequently, inhibiting MdmX has emerged as an attractive approach to restoring p53 function in those cancers that retain functional p53. However, the consequences of acute systemic MdmX inhibition in normal adult tissues remain unknown. To determine directly the effects of systemic MdmX inhibition in normal tissues and in tumors, we crossed mdmX−/− mice into the p53ERTAM knockin background. In place of wild-type p53, p53ERTAM knockin mice express a variant of p53, p53ERTAM, that is completely dependent on 4-hydroxy-tamoxifen for its activity. MdmX inhibition was then modeled by restoring p53 function in these MdmX-deficient mice. We show that MdmX is continuously required to buffer p53 activity in adult normal tissues and their stem cells. Importantly, the effects of transient p53 restoration in the absence of MdmX are nonlethal and reversible, unlike transient p53 restoration in the absence of Mdm2, which is ineluctably lethal. We also show that the therapeutic impact of restoring p53 in a tumor model is enhanced in the absence of MdmX, affording a significant extension of life span over p53 restoration in the presence of MdmX. Hence, systemic inhibition of MdmX is both a feasible therapeutic strategy for restoring p53 function in tumors that retain wild-type p53 and likely to be significantly safer than inhibition of Mdm2.
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Footnotes
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↵5 Corresponding author.
E-mail gevan{at}cc.ucsf.edu.
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Supplemental material is available for this article.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.16722111.
- Received March 30, 2011.
- Accepted July 6, 2011.
- Copyright © 2011 by Cold Spring Harbor Laboratory Press