Peroxisome proliferator-activated receptor-alpha 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 (PPARalpha), 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 PPARalpha 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 PPARalpha transcripts are differentially regulated by p63, indicating a bimodal action in promoter and/or transcription start specification. PPARalpha repression is consistent with lack of expression in the interfollicular epidermis under physiological conditions. Furthermore, we show that PPARalpha is a negative regulator of DeltaNp63alpha levels and that it also binds to a functional region of the DeltaNp63 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.
Pozzi
Silvia
S
Dipartimento di Scienze Biomolecolari e Biotecnologie, Universita' degli Studi di Milano, Milano, Italy.
Boergesen
Michael
M
Sinha
Satrajit
S
Mandrup
Susanne
S
Mantovani
Roberto
R
D002478:Cells, Cultured; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism*; D047493:PPAR alpha / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D012867:Skin / Q000166:cytology / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
D047493:PPAR alpha; C115051:TP63 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins