Modulation of β-catenin-mediated TCF-signalling in prostate cancer cell lines by wild-type and mutant p53

BACKGROUND Deregulation of the canonical Wnt/β‐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 β‐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 β‐catenin‐signalling in PCa‐cell lines. METHODS The effects of p53wt and p53‐mutants on Wnt/β‐catenin‐signalling were studied using reporter gene assays. Expression of β‐catenin levels was monitored by Western blotting. RESULTS Overexpression of p53wt as well as p53249Ser (a structural mutant) and p53273His (a DNA‐contact‐mutant) almost completely inhibited β‐catenin‐mediated transcriptional activity of the T‐cell factor (TCF) whereas p53175His, a structural mutant, and a p53‐mutant with a C‐terminal deletion in the tetramerization domain (Δp53) were unable to do so. Co‐transfection experiments with p53wt and a dominant negative p53‐mutant reversed the down‐regulation of TCF‐signalling, while Δp53 was unable to interfere with p53wt‐function. Down‐regulation of TCF‐signalling by p53wt and p53273His was accompanied by a reduction in β‐catenin protein level. CONCLUSIONS p53wt, p53273His‐ and p53249Ser‐mutants are able to down‐regulate β‐catenin‐signalling in PCa‐cells probably via degradation of β‐catenin. The degradation of β‐catenin in PCa by p53 is not linked to transcriptional activity of p53. So far the mechanism how p53 interferes with β‐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 β‐catenin‐mediated TCF‐signalling in PCa‐cell lines possibly via p53 transrepressional function. Prostate 67: 1751–1760, 2007. © 2007 Wiley‐Liss, Inc.