UXT, a novel MDMX-binding protein, promotes glycolysis by mitigating p53-mediated restriction of NF-κB activity

Oncotarget. 2015 Jul 10;6(19):17584-93. doi: 10.18632/oncotarget.3770.

Abstract

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.

Keywords: MDMX; NF-κB; UXT; p53.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Cycle Proteins
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic / metabolism*
  • Flow Cytometry
  • Fluorescent Antibody Technique
  • Glycolysis
  • Heterografts
  • Humans
  • Immunoblotting
  • Mice
  • Mice, Inbred BALB C
  • Molecular Chaperones
  • NF-kappa B / metabolism*
  • Neoplasm Proteins / metabolism*
  • Nuclear Proteins / metabolism*
  • Proto-Oncogene Proteins / metabolism*
  • RNA, Small Interfering
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sarcoma / metabolism
  • Sarcoma / pathology
  • Transfection
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • Cell Cycle Proteins
  • MDM4 protein, human
  • Molecular Chaperones
  • NF-kappa B
  • Neoplasm Proteins
  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • RNA, Small Interfering
  • Tumor Suppressor Protein p53
  • UXT protein, human