Journal Article

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

Wang, Hui, Ji, Lei, Fu, Junjiang, Zhang, Pei, Caulin, Carlos, Myers, Jeffrey N., Wang, Zhuo, Liu, Jiang, Xiao, Jianru, Chen, Jiwu, Ali, Amjad, Li, Xiaotao, Li, Lei, Zhang, Bianhong

2013

Overview

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. REGγ is a proteasome activator and is frequently overexpressed in cancer cells. Here Ali et al . demonstrate that p53/TGF-β signalling inhibits REGγ expression, whereas p53 mutations increase REGγ transcription, identifying a gain of function for mutant p53.

• Publisher: Nature Publishing Group UK,Nature Pub.lishing Group,Nature Pub. Group
• Subject: 13 / 13/109 / 13/2 / 13/51 / 13/89 / 631/67 / 631/80/474/2085 / 631/80/86 / 82 / 82/1 / 82/29 / 82/83 / Animals / Autoantigens - genetics / Autoantigens - metabolism / Biochemistry, biophysics & molecular biology / Biochimie, biophysique & biologie moléculaire / 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 / Humanities and Social Sciences / Humans / Life sciences / Mice / multidisciplinary / Mutation / Nuclear Receptor Co-Repressor 1 - genetics / Nuclear Receptor Co-Repressor 1 - metabolism / p53 / Promoter Regions, Genetic / Proteasome Endopeptidase Complex - genetics / Proteasome Endopeptidase Complex - metabolism / Proteolysis / Recombinant Fusion Proteins - genetics / Recombinant Fusion Proteins - metabolism / Reggamma / Science / Science (multidisciplinary) / Sciences du vivant / Signal Transduction / smad3 / 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