UXT, a novel MDMX-binding protein, promotes glycolysis by mitigating p53-mediated restriction of NF-κB activity
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Min Qi1,*, Suthakar Ganapathy2,*, Weiqi Zeng3, Jianglin Zhang3, John B. Little2, Zhi-Min Yuan2
1Department of Plastic Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, PR China
2Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA
3Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, PR China
*These authors have contributed equally to this work
Keywords: p53, NF-κB, MDMX, UXT
Received: February 17, 2015 Accepted: April 24, 2015 Published: May 07, 2015
The importance of stress-induced p53 activation has been extensively investigated and well established. How the basal activity of p53 prevents carcinogenesis, however, remains incompletely understood. We report the identification of a novel p53 inhibitor, UXT, which binds to MDMX and suppresses the basal activity of p53. Interestingly, human TCGA database indicates that the UXT gene is frequently amplified in human sarcoma where p53 mutation is rare. We thus used sarcoma as a model to show that UXT acts as an oncogene promoting cell proliferation in vitro and tumor progression in vivo. A screening of 10 major cellular pathways uncovered that UXT-mediated p53 inhibition results in an activation of NF-κB, leading to induction of glycolysis. While elevated glycolytic metabolism provides growth advantage it also renders UXT expressing sarcoma cells heightened sensitivity to glycolysis inhibition. Altogether, our data demonstrate a crucial role for the basal activity of p53 in restriction of NF-κB. By impeding such an activity of p53, UXT unleashes the oncogenic activity of NF-κB resulting in induction of glycolysis fueling carcinogenesis.
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