Priority Research Papers:

Inhibition of Mdmx (Mdm4) in vivo induces anti-obesity effects

Ning Kon, Donglai Wang, Tongyuan Li, Le Jiang, Li Qiang and Wei Gu _

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Oncotarget. 2018; 9:7282-7297. https://doi.org/10.18632/oncotarget.23837

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Ning Kon1,*, Donglai Wang1,*, Tongyuan Li1, Le Jiang1, Li Qiang2,3,** and Wei Gu1,3

1 Institute for Cancer Genetics, College of Physicians and Surgeons of Columbia University, New York, New York, USA

2 Naomi Berrie Diabetes Center, Department of Medicine, College of Physicians and Surgeons of Columbia University, New York, New York, USA

3 Department of Pathology and Cell Biology, College of Physicians and Surgeons of Columbia University, New York, New York, USA

* These two authors contributed equally to this work

** This author is listed as a co-corresponding author

Correspondence to:

Wei Gu, email:

Keywords: p53; Mdmx; Mdm4; metabolism; adipose tissues

Received: September 26, 2017 Accepted: December 08, 2017 Published: January 02, 2018


Although cell-cycle arrest, senescence and apoptosis remain as major canonical activities of p53 in tumor suppression, the emerging role of p53 in metabolism has been a topic of great interest. Nevertheless, it is not completely understood how p53-mediated metabolic activities are regulated in vivo and whether this part of the activities has an independent role beyond tumor suppression. Mdmx (also called Mdm4), like Mdm2, acts as a major suppressor of p53 but the embryonic lethality of mdmx-null mice creates difficulties to evaluate its physiological significance in metabolism. Here, we report that the embryonic lethality caused by the deficiency of mdmx, in contrast to the case for mdm2, is fully rescued in the background of p533KR/3KR, an acetylation-defective mutant unable to induce cell-cycle arrest, senescence and apoptosis. p533KR/3KR/mdmx-/- mice are healthy but skinny without obvious developmental defects. p533KR/3KR/mdmx-/- mice are resistant to fat accumulation in adipose tissues upon high fat diet. Notably, the levels of p53 protein are only slightly increased and can be further induced upon DNA damage in p533KR/3KR/mdmx-/- mice, suggesting that Mdmx is only partially required for p53 degradation in vivo. Further analyses indicate that the anti-obesity phenotypes in p533KR/3KR/mdmx-/- mice are caused by activation of lipid oxidation and thermogenic programs in adipose tissues. These results demonstrate the specific effects of the p53/Mdmx axis in lipid metabolism and adipose tissue remodeling and reveal a surprising role of Mdmx inhibition in anti-obesity effects beyond, commonly expected, tumor suppression. Thus, our study has significant implications regarding Mdmx inhibitors in the treatment of obesity related diseases.

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