The E3 ubiquitin ligase WWP1 regulates ΔNp63-dependent transcription through Lys63 linkages.
The transcription factor p63, a member of the p53 family, plays a crucial role in epithelial development and tumorigenesis through the regulation of epithelial progenitor cell proliferation, differentiation and apoptosis. Similarly to p53, p63 activity is regulated by post-translational modifications, including ubiquitylation. Here, we report that the WWP1 E3 ubiquitin ligase binds specifically to ΔNp63 isoform but it does not trigger ΔNp63 proteasome-dependent degradation. Accordingly, we found that WWP1-dependent ubiquitylation of ΔNp63 occurs through the formation of Lys63-linked poly-ubiquitin chains. Importantly, we found that WWP1 is able to increase ΔNp63-dependent transcription and depletion of WWP1 in human primary keratinocytes induces cell cycle arrest. All together these results indicate that WWP1 regulates ΔNp63 transcriptional activity, acting thus as a potential regulator of the proliferation and survival of epithelial-derived cells.
IDI IRCCS Biochemistry Laboratory, Department of Experimental Medicine and Biochemical Sciences, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy.
Angelo
A
Peschiaroli
Flavia
F
Scialpi
Francesca
F
Bernassola
El Said
el S
El Sherbini
Gerry
G
Melino
D002453:Cell Cycle; D002460:Cell Line; D049109:Cell Proliferation; D002470:Cell Survival; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D008239:Lysine / Q000235:genetics / Q000378:metabolism*; D025821:Polyubiquitin / Q000378:metabolism; D055550:Protein Stability; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors; D014158:Transcription, Genetic; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
C115051:TP63 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D025821:Polyubiquitin; C471642:WWP1 protein, human; D044767:Ubiquitin-Protein Ligases; D008239:Lysine