Journal
NATURE COMMUNICATIONS
Volume 4, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms3667
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Funding
- National Basic Research Program [2009CB918402, 2011CB504200]
- National Institutes of Health [1R01CA131914]
- Norman Hackerman Advanced Research Program [1082318401, PN004949-0012-2009]
- Pilot/Feasibility Program of the Diabetes & Endocrinology Research Center at the Baylor College of Medicine [P30-DK079638]
- National Natural Science Foundation of China [81071657, 31100946, 81172049, 81272943]
- Science and Technology Commission of Shanghai Municipality [06DZ22923, 11DZ2260300, 10JC1404200]
- Fundamental Research Funds for the Central Universities [78210101, 78210139]
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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.
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