p63 antagonizes Wnt-induced transcription.
Cell Cycle
; 9(3): 580-87, 2010 Feb 01.
Article
de En
| MEDLINE
| ID: mdl-20107313
ABSTRACT
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.
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Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Phosphoprotéines
/
Transcription génétique
/
Xenopus
/
Transactivateurs
/
Protéines de Xénope
/
Protéines suppresseurs de tumeurs
/
Protéines de type Wingless
Type d'étude:
Prognostic_studies
Limites:
Animals
/
Humans
Langue:
En
Journal:
Cell Cycle
Année:
2010
Type de document:
Article
Pays d'affiliation:
Allemagne