title: Modulation of beta-catenin-mediated TCF-signalling in prostate cancer cell lines by wild-type and mutant p53.
abstract: BACKGROUND
  Deregulation of the canonical Wnt/beta-catenin-pathway is known to play an important role in the progression of various tumour cell types including prostate cancer (PCa). Recently, the tumour-suppressor p53 was shown to down-regulate beta-catenin-signalling in colon cancer. As p53 is frequently mutated in late stage PCa we investigated the effect of wild-type p53 (p53wt) as well as p53-mutants on beta-catenin-signalling in PCa-cell lines.
  
  
  METHODS
  The effects of p53wt and p53-mutants on Wnt/beta-catenin-signalling were studied using reporter gene assays. Expression of beta-catenin levels was monitored by Western blotting.
  
  
  RESULTS
  Overexpression of p53wt as well as p53(249Ser) (a structural mutant) and p53(273His) (a DNA-contact-mutant) almost completely inhibited beta-catenin-mediated transcriptional activity of the T-cell factor (TCF) whereas p53(175His), a structural mutant, and a p53-mutant with a C-terminal deletion in the tetramerization domain (Deltap53) were unable to do so. Co-transfection experiments with p53wt and a dominant negative p53-mutant reversed the down-regulation of TCF-signalling, while Deltap53 was unable to interfere with p53wt-function. Down-regulation of TCF-signalling by p53wt and p53(273His) was accompanied by a reduction in beta-catenin protein level.
  
  
  CONCLUSIONS
  p53wt, p53(273His)- and p53(249Ser)-mutants are able to down-regulate beta-catenin-signalling in PCa-cells probably via degradation of beta-catenin. The degradation of beta-catenin in PCa by p53 is not linked to transcriptional activity of p53. So far the mechanism how p53 interferes with beta-catenin-signalling is unknown. For the first time we provide experimental evidence that the C-terminus of p53 plays an important role in the down-regulation of beta-catenin-mediated TCF-signalling in PCa-cell lines possibly via p53 transrepressional function.
authors.affiliation: Klinik und Poliklinik für Urologie und Kinderurologie, Medizinische Hochschule Hannover, Hannover, Germany.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Prowald
authors.forename: Marcus V
authors.initials: MV
authors.lastname: Cronauer
authors.forename: Christoph
authors.initials: C
authors.lastname: von Klot
authors.forename: Tyark
authors.initials: T
authors.lastname: Eilers
authors.forename: Ludwig
authors.initials: L
authors.lastname: Rinnab
authors.forename: Thomas
authors.initials: T
authors.lastname: Herrmann
authors.forename: Klaus-Dieter
authors.initials: KD
authors.lastname: Spindler
authors.forename: Mathias
authors.initials: M
authors.lastname: Montenarh
authors.forename: Udo
authors.initials: U
authors.lastname: Jonas
authors.forename: Martin
authors.initials: M
authors.lastname: Burchardt
mesh_terms: D015153:Blotting, Western; D045744:Cell Line, Tumor; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D016158:Genes, p53; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008297:Male; D009154:Mutation; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D051820:TCF Transcription Factors / Q000235:genetics / Q000378:metabolism*; D058118:Transcription Factor 7-Like 2 Protein; D015533:Transcriptional Activation; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism*; D051176:beta Catenin / Q000819:agonists / Q000378:metabolism*
chemical_list: D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; C495901:TP53 protein, human; D058118:Transcription Factor 7-Like 2 Protein; D016159:Tumor Suppressor Protein p53; D051176:beta Catenin; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3