title: Differential regulation of the REGγ-proteasome pathway by p53/TGF-β signalling and mutant p53 in cancer cells.
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.
authors.affiliation: 1] Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China [2] Guangxi Collaborative Innovation Center for Biomedicine and Drug Discovery, Guangxi Medical University, Nanning 530021, China [3] Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA [4].
authors.forename: Amjad
authors.initials: A
authors.lastname: Ali
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Wang
authors.forename: Junjiang
authors.initials: J
authors.lastname: Fu
authors.forename: Lei
authors.initials: L
authors.lastname: Ji
authors.forename: Jiang
authors.initials: J
authors.lastname: Liu
authors.forename: Lei
authors.initials: L
authors.lastname: Li
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.forename: Jiwu
authors.initials: J
authors.lastname: Chen
authors.forename: Carlos
authors.initials: C
authors.lastname: Caulin
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Myers
authors.forename: Pei
authors.initials: P
authors.lastname: Zhang
authors.forename: Jianru
authors.initials: J
authors.lastname: Xiao
authors.forename: Bianhong
authors.initials: B
authors.lastname: Zhang
authors.forename: Xiaotao
authors.initials: X
authors.lastname: Li
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000235:genetics* / Q000378:metabolism; D002453:Cell Cycle; D045744:Cell Line, Tumor; D050881:E1A-Associated p300 Protein / Q000235:genetics / Q000378:metabolism; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D025461:Feedback, Physiological; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D009154:Mutation; D056971:Nuclear Receptor Co-Repressor 1 / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D046988:Proteasome Endopeptidase Complex / Q000235:genetics* / Q000378:metabolism; D059748:Proteolysis; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: D001324:Autoantigens; C099558:Ki antigen; C539127:NCOR1 protein, human; D056971:Nuclear Receptor Co-Repressor 1; D011993:Recombinant Fusion Proteins; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D016212:Transforming Growth Factor beta; D016159:Tumor Suppressor Protein p53; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human; D046988:Proteasome Endopeptidase Complex