A p38-dependent pathway regulates DeltaNp63 DNA binding to p53-dependent promoters in UV-induced apoptosis of keratinocytes.
The p53 protein plays a pivotal role in determining the quality of the response to DNA damage through its transcriptional activity. Upon DNA damage, p53 is activated by post-translational modifications, binds its cognate sequences on the promoters of its target genes and stimulates transcription. In proliferating keratinocytes, the activity of p53 is blunted by its inhibitor DeltaNp63alpha. Here, we describe a novel mechanism through which DeltaNp63 functions in order to prevent the survival and propagation of ultraviolet (UV)-damaged keratinocytes. We found that UVB stimulation induces the rapid phosphorylation of DeltaNp63, which precedes DeltaNp63 transcriptional downregulation and protein degradation, which is mediated by the p38 MAPK. Phosphorylated DeltaNp63 has a lower affinity for p53REs and detaches from cell cycle arrest and apoptotic promoters, thus allowing the rapid activation of p53-dependent transcriptional apoptotic program.
Papoutsaki
Marina
M
Department of Dermatology, University of Rome, Tor Vergata, Viale Oxford 81, Rome 00133, Italy.
Moretti
Francesca
F
Lanza
Mauro
M
Marinari
Barbara
B
Sartorelli
Vittorio
V
Guerrini
Luisa
L
Chimenti
Sergio
S
Levrero
Massimo
M
Costanzo
Antonio
A
D017209:Apoptosis / Q000528:radiation effects*; D004247:DNA / Q000378:metabolism*; D004268:DNA-Binding Proteins; D016147:Genes, Tumor Suppressor; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism* / Q000528:radiation effects; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025521:Tumor Suppressor Proteins; D014466:Ultraviolet Rays; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D004268:DNA-Binding Proteins; D010750:Phosphoproteins; C115051:TP63 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D004247:DNA; D048051:p38 Mitogen-Activated Protein Kinases