Differential regulation of the REGγ-proteasome pathway by p53/TGF-β signalling and mutant p53 in cancer cells

Nat Commun. 2013;4:2667. doi: 10.1038/ncomms3667.

Abstract

Proteasome activity is frequently enhanced in cancer to accelerate metastasis and tumorigenesis. REGγ, a proteasome activator known to promote p53/p21/p16 degradation, is often overexpressed in cancer cells. Here we show that p53/TGF-β signalling inhibits the REGγ-20S proteasome pathway by repressing REGγ expression. Smad3 and p53 interact on the REGγ promoter via the p53RE/SBE region. Conversely, mutant p53 binds to the REGγ promoter and recruits p300. Importantly, mutant p53 prevents Smad3/N-CoR complex formation on the REGγ promoter, which enhances the activity of the REGγ-20S proteasome pathway and contributes to mutant p53 gain of function. Depletion of REGγ alters the cellular response to p53/TGF-β signalling in drug resistance, proliferation, cell cycle progression and proteasome activity. Moreover, p53 mutations show a positive correlation with REGγ expression in cancer samples. These findings suggest that targeting REGγ-20S proteasome for cancer therapy may be applicable to human tumours with abnormal p53/Smad protein status. Furthermore, this study demonstrates a link between p53/TGF-β signalling and the REGγ-20S proteasome pathway, and provides insight into the REGγ/p53 feedback loop.

Publication types

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

MeSH terms

  • Animals
  • Autoantigens / genetics*
  • Autoantigens / metabolism
  • Cell Cycle
  • Cell Line, Tumor
  • E1A-Associated p300 Protein / genetics
  • E1A-Associated p300 Protein / metabolism
  • Escherichia coli / genetics
  • Escherichia coli / metabolism
  • Feedback, Physiological
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Mice
  • Mutation
  • Nuclear Receptor Co-Repressor 1 / genetics
  • Nuclear Receptor Co-Repressor 1 / metabolism
  • Promoter Regions, Genetic
  • Proteasome Endopeptidase Complex / genetics*
  • Proteasome Endopeptidase Complex / metabolism
  • Proteolysis
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Signal Transduction*
  • Smad3 Protein / genetics
  • Smad3 Protein / metabolism
  • Transforming Growth Factor beta / genetics*
  • Transforming Growth Factor beta / metabolism
  • Tumor Suppressor Protein p53 / genetics*
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Autoantigens
  • Ki antigen
  • NCOR1 protein, human
  • Nuclear Receptor Co-Repressor 1
  • Recombinant Fusion Proteins
  • Smad3 Protein
  • Smad3 protein, mouse
  • Transforming Growth Factor beta
  • Tumor Suppressor Protein p53
  • E1A-Associated p300 Protein
  • EP300 protein, human
  • Proteasome Endopeptidase Complex