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Published on: October 27, 2014
p63 antagonizes Wnt-induced transcription.
Isabella Drewelus1, Constanze Göpfert, Cathrin Hippel
1Department of Molecular Oncology, Göttingen Center of Molecular Biosciences (GZMB), Ernst Caspari Haus, University of Göttingen, Göttingen, Germany.
Cell Cycle (Georgetown, Tex.)
|January 29, 2010
Summary
The tumor suppressor p63 (TP73L) acts as a negative regulator of Wnt signaling by recruiting repressors. Its overexpression or knockdown activates Wnt-responsive genes, impacting cancer progression.
Area of Science:
- Molecular Biology
- Developmental Biology
- Cancer Biology
Background:
- p63 (TP73L) is crucial for epithelial development and shares functions with tissues exhibiting Wnt signaling.
- The DeltaNp63alpha isoform was hypothesized to activate beta-Catenin and Wnt signaling by inhibiting GSK3beta.
- Previous studies suggested a positive regulatory role for DeltaNp63alpha in Wnt signaling.
Purpose of the Study:
- To investigate the precise role of p63 in regulating Wnt signaling pathways.
- To reconcile conflicting observations regarding p63's effect on Wnt-responsive gene expression.
- To elucidate the mechanism by which p63 influences Wnt signaling in human cells and embryonic development.
Main Methods:
- Transient overexpression of DeltaNp63alpha in human cells.
- Wnt-inducible reporter gene assays.
- Secondary axis formation assays in Xenopus embryos.
- siRNA-mediated knockdown of endogenous p63.
- Analysis of beta-Catenin levels and phosphorylation.
- Co-immunoprecipitation to identify protein complexes involving DeltaNp63alpha and TCF/LEF factors.
Main Results:
- Overexpression of DeltaNp63alpha enhanced Wnt-inducible reporter gene activity and secondary axis formation.
- siRNA-mediated knockdown of p63 also increased Wnt-responsive gene expression.
- p63 knockdown did not alter beta-Catenin levels or phosphorylation.
- DeltaNp63alpha was found in a complex with TCF/LEF transcription factors.
- These findings suggest p63 acts as a negative regulator of Wnt signaling.
Conclusions:
- DeltaNp63alpha functions by recruiting transcriptional repressors to Wnt-responsive genes.
- Overexpression of p63 may sequester these repressors, leading to Wnt gene activation (squelching effect).
- The negative regulatory role of p63 in Wnt signaling aligns with its downregulation during tumor progression and the acquisition of mesenchymal phenotypes.
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