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

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.
Mesh Terms:
Animals, Autoantigens, Cell Cycle, Cell Line, Tumor, E1A-Associated p300 Protein, Escherichia coli, Feedback, Physiological, Gene Expression Regulation, Neoplastic, Humans, Mice, Mutation, Nuclear Receptor Co-Repressor 1, Promoter Regions, Genetic, Proteasome Endopeptidase Complex, Proteolysis, Recombinant Fusion Proteins, Signal Transduction, Smad3 Protein, Transforming Growth Factor beta, Tumor Suppressor Protein p53
Nat Commun
Date: Oct. 26, 2013
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