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.