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

Amjad Ali, Zhuo Wang, Junjiang Fu, Lei Ji, Jiang Liu, Lei Li, Hui Wang, Jiwu Chen, Carlos Caulin, Jeffrey N. Myers, Pei Zhang, Jianru Xiao (), Bianhong Zhang () and Xiaotao Li
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Amjad Ali: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University
Zhuo Wang: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University
Junjiang Fu: Key Laboratory of Epigenetics and Oncology, The Research Center for Preclinical Medicine, Luzhou Medical College
Lei Ji: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University
Jiang Liu: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University
Lei Li: Changzheng Hospital, The Second Military Medical University
Hui Wang: Xinhua Hospital, School of Medicine, Shanghai Jiaotong University
Jiwu Chen: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University
Carlos Caulin: The University of Texas MD Anderson Cancer Center
Jeffrey N. Myers: The University of Texas MD Anderson Cancer Center
Pei Zhang: Second Chengdu Municipal Hospital
Jianru Xiao: Changzheng Hospital, The Second Military Medical University
Bianhong Zhang: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University
Xiaotao Li: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University

Nature Communications, 2013, vol. 4, issue 1, 1-16

Abstract: 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.

Date: 2013
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DOI: 10.1038/ncomms3667

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