title: Endothelin-1 is a transcriptional target of p53 in epidermal keratinocytes and regulates ultraviolet-induced melanocyte homeostasis.
abstract: Keratinocytes contribute to melanocyte activity by influencing their microenvironment, in part, through secretion of paracrine factors. Here, we discovered that p53 directly regulates Edn1 expression in epidermal keratinocytes and controls UV-induced melanocyte homeostasis. Selective ablation of endothelin-1 (EDN1) in murine epidermis (EDN1(ep-/-) ) does not alter melanocyte homeostasis in newborn skin but decreases dermal melanocytes in adult skin. Results showed that keratinocytic EDN1 in a non-cell autonomous manner controls melanocyte proliferation, migration, DNA damage, and apoptosis after ultraviolet B (UVB) irradiation. Expression of other keratinocyte-derived paracrine factors did not compensate for the loss of EDN1. Topical treatment with EDN1 receptor (EDNRB) antagonist BQ788 abrogated UV-induced melanocyte activation and recapitulated the phenotype seen in EDN1(ep-/-)  mice. Altogether, the present studies establish an essential role of EDN1 in epidermal keratinocytes to mediate UV-induced melanocyte homeostasis in vivo.
authors.affiliation: Department of Pharmaceutical Sciences, Oregon State University, Corvallis, OR, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Hyter
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Coleman
authors.forename: Gitali
authors.initials: G
authors.lastname: Ganguli-Indra
authors.forename: Gary F
authors.initials: GF
authors.lastname: Merrill
authors.forename: Steven
authors.initials: S
authors.lastname: Ma
authors.forename: Masashi
authors.initials: M
authors.lastname: Yanagisawa
authors.forename: Arup K
authors.initials: AK
authors.lastname: Indra
mesh_terms: D000375:Aging; D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D049109:Cell Proliferation / Q000528:radiation effects; D004249:DNA Damage; D004260:DNA Repair / Q000528:radiation effects; D019332:Endothelin-1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000078404:Epidermal Cells; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000528:radiation effects; D006706:Homeostasis / Q000528:radiation effects*; D007150:Immunohistochemistry; D015603:Keratinocytes / Q000166:cytology / Q000201:enzymology / Q000528:radiation effects*; D020935:MAP Kinase Signaling System / Q000528:radiation effects; D008544:Melanocytes / Q000166:cytology / Q000201:enzymology / Q000528:radiation effects*; D051379:Mice; D009928:Organ Specificity / Q000528:radiation effects; D010641:Phenotype; D011493:Protein Kinase C / Q000378:metabolism; D044023:Receptor, Endothelin B / Q000378:metabolism; D014158:Transcription, Genetic / Q000528:radiation effects*; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000378:metabolism*; D014466:Ultraviolet Rays
chemical_list: D019332:Endothelin-1; D044023:Receptor, Endothelin B; D016159:Tumor Suppressor Protein p53; D011493:Protein Kinase C