title: PBRM1 (BAF180) protein is functionally regulated by p53-induced protein degradation in renal cell carcinomas.
abstract: About 40% of clear-cell renal cell carcinomas (ccRCC) harbour mutations in Polybromo-1 (PBRM1), encoding the BAF180 subunit of a SWI/SNF chromatin remodelling complex. This qualifies PBRM1 as a major cancer gene in ccRCC. The PBRM1 protein alters chromatin structure and its known functions include transcriptional regulation by controlling the accessibility of DNA and influencing p53 transcriptional activity. Since little is known about the regulation of PBRM1, we studied possible mechanisms and interaction partners involved in the regulation of PBRM1 expression. Activation of p53 in RCC cells resulted in a marked decrease of PBRM1 protein levels. This effect was abolished by siRNA-mediated down-regulation of p53, and transcriptional activity was not crucial for p53-dependent PBRM1 regulation. Pulse-chase experiments determined post-translational protein degradation to be the underlying mechanism for p53-dependent PBRM1 regulation, which was accordingly inhibited by proteasome inhibitors. The effects of p53 activation on PBRM1 expression were confirmed in RCC tissue ex vivo. Our results demonstrate that PBRM1 is a target of p53-induced proteasomal protein degradation and provide further evidence for the influence of PBRM1 on p53 function in RCC tumour cells. Considering the paramount role of p53 in carcinogenesis and the presumptive impact of PBRM1 in RCC development, this novel regulation mechanism might be therapeutically exploited in the future.
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Germany.|Molecular Tumour Pathology, German Cancer Research Centre (DKFZ), Heidelberg, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Macher-Goeppinger
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Germany.|Molecular Tumour Pathology, German Cancer Research Centre (DKFZ), Heidelberg, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Keith
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Germany.|Molecular Tumour Pathology, German Cancer Research Centre (DKFZ), Heidelberg, Germany.
authors.forename: Katrin E
authors.initials: KE
authors.lastname: Tagscherer
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Singer
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Germany.
authors.forename: Juliane
authors.initials: J
authors.lastname: Winkler
authors.affiliation: Cellular Senescence, German Cancer Research Centre (DKFZ), DKFZ-ZMBH Alliance, Heidelberg, Germany.
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Hofmann
authors.affiliation: Department of Urology, University Hospital Heidelberg, Germany.
authors.forename: Sascha
authors.initials: S
authors.lastname: Pahernik
authors.affiliation: Molecular Uro-oncology, Department of Urology, University Hospital Heidelberg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Duensing
authors.affiliation: Department of Urology, University Hospital Heidelberg, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Hohenfellner
authors.affiliation: Department of Applied Tumour Biology, Institute of Pathology, University Hospital Heidelberg, Germany.
authors.forename: Juergen
authors.initials: J
authors.lastname: Kopitz
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Schirmacher
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Germany.|Molecular Tumour Pathology, German Cancer Research Centre (DKFZ), Heidelberg, Germany.
authors.forename: Wilfried
authors.initials: W
authors.lastname: Roth
mesh_terms: D002292:Carcinoma, Renal Cell / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D007680:Kidney Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D009687:Nuclear Proteins / Q000096:biosynthesis*; D016133:Polymerase Chain Reaction; D016016:Proportional Hazards Models; D034741:RNA, Small Interfering; D046888:Tissue Array Analysis; D014157:Transcription Factors / Q000096:biosynthesis*; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C102195:PBRM1 protein, human; D034741:RNA, Small Interfering; C495901:TP53 protein, human; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53
keywords: PBRM1; TP53; kidney; protein degradation; renal cell carcinoma