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