p63 antagonizes Wnt-induced transcription

The p53 homologue p63/TP73L is required for the proper development of squamous epithelia, mammary glands and limb buds, with some of these tissues also displaying strong canonical Wnt signalling activity. It was previously suggested that Delta Np63 alpha, the predominant isoform of p63 in epithelia, positively regulates beta-Catenin through inhibition of GSK3 beta. Results reported in this communication show that, upon transient overexpression, Delta Np63 alpha indeed promotes Wnt-inducible reporter gene activity in human cells, as well as secondary axis formation in Xenopus embryos. However, in apparent contradiction to these observations, siRNA-mediated knockdown of endogenous p63 equally enhanced the expression of Wnt-responsive genes. While p63 knockdown did not detectably affect beta-Catenin levels or phosphorylation, Delta Np63 alpha was found in a complex with members of the TCF/LEF family of Wnt-responsive transcription factors. On the basis of these findings, we propose that Delta Np63 alpha has a function in recruiting transcriptional repressors to Wnt-responsive genes. Overexpression of p63 may lead to sequestration of such repressors (squelching), resulting in a similar effect like siRNA-mediated removal of p63, i.e., activation of Wnt-responsive genes. The role of p63 as a negative Wnt-regulator thus matches with the frequently observed downregulation of p63 during tumor progression, when cancer cells adopt a more mesenchymal, invasive phenotype.