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. REG gamma, a proteasome activator known to promote p53/p21/p16 degradation, is often overexpressed in cancer cells. Here we show that p53/TGF-beta signalling inhibits the REG gamma-20S proteasome pathway by repressing REG gamma expression. Smad3 and p53 interact on the REG gamma promoter via the p53RE/SBE region. Conversely, mutant p53 binds to the REG gamma promoter and recruits p300. Importantly, mutant p53 prevents Smad3/N-CoR complex formation on the REG gamma promoter, which enhances the activity of the REG gamma-20S proteasome pathway and contributes to mutant p53 gain of function. Depletion of REG gamma alters the cellular response to p53/TGF-beta signalling in drug resistance, proliferation, cell cycle progression and proteasome activity. Moreover, p53 mutations show a positive correlation with REG gamma expression in cancer samples. These findings suggest that targeting REG gamma-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-beta signalling and the REG gamma-20S proteasome pathway, and provides insight into the REG gamma/p53 feedback loop.