A p38-dependent pathway regulates Delta Np63 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 modi. cations, 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 Delta Np63 alpha. Here, we describe a novel mechanism through which Delta Np63 functions in order to prevent the survival and propagation of ultraviolet (UV)-damaged keratinocytes. We found that UVB stimulation induces the rapid phosphorylation of DNp63, which precedes DNp63 transcriptional downregulation and protein degradation, which is mediated by the p38 MAPK. Phosphorylated Delta Np63 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.