Peroxisome proliferator-activated receptor-α is a functional target of p63 in adult human keratinocytes

p63 is a master switch in the complex network of signaling pathways controlling the establishment and maintenance of stratified epithelia. We provide evidence that peroxisome proliferator-activated receptor-alpha (PPAR alpha), a ligand-activated nuclear receptor that participates in the skin wound healing process, is a target of p63 in human keratinocytes. Silencing of p63 by RNA interference and transient transfections showed that p63 represses PPARa through a functional region of promoter B. Chromatin immunoprecipitation analyses indicate that p63 is bound to this region, in the absence of a recognizable p63-binding motif, suggesting that it acts through interactions with other transcription factors (TFs). Distinct PPAR alpha transcripts are differentially regulated by p63, indicating a bimodal action in promoter and/or transcription start specification. PPAR alpha repression is consistent with lack of expression in the interfollicular epidermis under physiological conditions. Furthermore, we show that PPAR alpha is a negative regulator of Delta Np63 alpha levels and that it also binds to a functional region of the Delta Np63 promoter that lacks PPRE motifs. Therefore, the reciprocal regulation is exerted either through binding to non-consensus sites or through interactions with other DNA-bound TFs. In conclusion, our data establish a link between two TFs intimately involved in the maintenance of skin homeostatic conditions.