Abstract
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.
Highlights
Tumor suppressor p53 is a transcription factor, exerting its regulations on gene transcription through direct binding to p53 responsive elements and recruiting cofactors to facilitate assembly of transcription machinery [1, 2]
It is established that the lethality of mdmx knockout mice is caused by p53-mediated growth arrest [19]; in addition, the lethality of mdmx knockout mice is rescued by a mutant p53 with reduced transcriptional signaling in cell cycle arrest and apoptotic responses [20]
Because of the critical roles of mdm2 and mdmx in negatively regulating p53, the ability to rescue the embryonic lethality of mdm2 and mdmx knockout mice becomes imperative to gauge the extent of loss of functions for p53, for p53 mutants with partial loss of functions [20, 22]
Summary
Tumor suppressor p53 is a transcription factor, exerting its regulations on gene transcription through direct binding to p53 responsive elements and recruiting cofactors to facilitate assembly of transcription machinery [1, 2]. P533KR/3KR mice do not show early-onset tumor formation, suggesting that additional www.impactjournals.com/oncotarget p53 dependent functions play important roles in tumor suppression [9] Ubiquitination is another important posttranslational modification of p53, which is mainly controlled by p53 E3 ligase Mdm, and Mdm2-related protein Mdmx [1016]. P53 is activated through dissociation with Mdmx mediated by phosphorylation of Mdmx under metabolic stress, highlighting the importance of mdmx in p53-dependent metabolic regulation [23] In light of these studies, and the absence of induction of apoptosis, senescence and cell cycle arrest in mutant p533KR/3KR mice, we reason that the combination of p53 3KR mutation and the absence of p53 negative regulator Mdmx may provide unique opportunities to uncover novel p53-regulated functions, in metabolic regulations, which would be otherwise masked by cell death and cell growth arrest in wild-type p53 mice. By abolishing p53-dependent apoptosis, senescence, and cell cycle arrest through p53 3KR mutations, we uncovered a catabolic function of p53 in adipose biology
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