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, M., Moretti, F., Lanza, M., Marinari, B., Sartorelli, V., Guerrini, L., et al. (2005). A p38-dependent pathway regulates DeltaNp63 DNA binding to p53-dependent promoters in UV-induced apoptosis of keratinocytes. ONCOGENE, 24(46), 6970-6975 [10.1038/sj.onc.1208835].
A p38-dependent pathway regulates DeltaNp63 DNA binding to p53-dependent promoters in UV-induced apoptosis of keratinocytes
Marinari, B;Chimenti, S;Costanzo, A
2005-10-20
Abstract
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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
