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 DeltaNp63alpha, the predominant isoform of p63 in epithelia, positively regulates beta-Catenin through inhibition of GSK3beta. Results reported in this communication show that, upon transient overexpression, DeltaNp63alpha 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, DeltaNp63alpha 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 DeltaNp63alpha 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.
Drewelus
Isabella
I
Department of Molecular Oncology, Göttingen Center of Molecular Biosciences (GZMB), Ernst Caspari Haus, University of Göttingen, Göttingen, Germany.
Göpfert
Constanze
C
Hippel
Cathrin
C
Dickmanns
Antje
A
Damianitsch
Katharina
K
Pieler
Tomas
T
Dobbelstein
Matthias
M
D000818:Animals; D019521:Body Patterning; D004625:Embryo, Nonmammalian / Q000378:metabolism; D055785:Gene Knockdown Techniques; D017930:Genes, Reporter; D006801:Humans; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000378:metabolism; D008954:Models, Biological; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors; D014158:Transcription, Genetic; D015533:Transcriptional Activation / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D051153:Wnt Proteins / Q000378:metabolism*; D014981:Xenopus / Q000196:embryology / Q000378:metabolism*; D029867:Xenopus Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism
C497573:LEF1 protein, human; D051821:Lymphoid Enhancer-Binding Factor 1; D010750:Phosphoproteins; D034741:RNA, Small Interfering; C488640:TP63 protein, Xenopus; C115051:TP63 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D051153:Wnt Proteins; D029867:Xenopus Proteins; D051176:beta Catenin