title: Endothelin-1 protects human melanocytes from UV-induced DNA damage by activating JNK and p38 signalling pathways.
abstract: Endothelin-1 is a paracrine factor with mitogenic, melanogenic and survival effects on cultured human melanocytes. We report that endothelin-1 signalling reduced the generation and enhanced the repair of ultraviolet radiation (UV)-induced DNA photoproducts, and inhibited apoptosis of human melanocytes, without increasing cAMP levels, melanin content or proliferation. Treatment with endothelin-1 activated the MAP kinases JNK and p38, as evidenced by phosphorylation of their target, activating transcription factor-2 (ATF-2). Endothelin-1 also enhanced the phosphorylation of JNK, p38 and ATF-2 by UV. The effects of endothelin-1 were dependent on increasing intracellular calcium mobilization by endothelin B receptor signalling. Activation of both JNK and p38 was required for reducing DNA photoproducts, but only JNK partially contributed to the survival effect of endothelin-1. ATF-2 activation depended mainly on JNK, yet was not sufficient for the effect of endothelin-1 on UV-induced DNA damage, suggesting the requirement for other JNK and p38 targets for this effect. Our results underscore the significance of endothelin-1 and endothelin B receptor signalling in reducing the genotoxic effects of UV via activating JNK and p38, hence restoring genomic stability of melanocytes.
authors.affiliation: Department of Dermatology, University of Cincinnati College of Medicine, Cincinnati, OH, USA; Cancer and Cell Biology, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
authors.forename: Anne M
authors.initials: AM
authors.lastname: von Koschembahr
authors.forename: Viki B
authors.initials: VB
authors.lastname: Swope
authors.forename: Renny J
authors.initials: RJ
authors.lastname: Starner
authors.forename: Zalfa A
authors.initials: ZA
authors.lastname: Abdel-Malek
mesh_terms: D020013:Calcium Signaling; D002478:Cells, Cultured; D004249:DNA Damage; D019332:Endothelin-1 / Q000378:metabolism*; D042822:Genomic Instability; D006801:Humans; D020935:MAP Kinase Signaling System; D008544:Melanocytes / Q000378:metabolism* / Q000528:radiation effects*; D011740:Pyrimidine Dimers / Q000378:metabolism; D044023:Receptor, Endothelin B / Q000378:metabolism; D014466:Ultraviolet Rays / Q000009:adverse effects
chemical_list: D019332:Endothelin-1; D011740:Pyrimidine Dimers; D044023:Receptor, Endothelin B
keywords: Endothelin-1; JNK; human melanocytes; p38; ultraviolet radiation