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.

Endothelin‐1 and α‐melanocortin have redundant effects on global genome repair in UV‐irradiated human melanocytes despite distinct signaling pathways

“…In the two different HM strains tested, neither α‐MSH nor End‐1 significantly reduced induction of CPD immediately after UV exposure (Figure a). Previously, we reported that End‐1 significantly reduced the induction of CPD in HM by UV (von Koschembahr et al, ). We attribute the difference in the response to End‐1 to donor variability.…”

“…This is also the case for α‐MSH, since the treatment of HM with α‐MSH only after UV exposure did not lead to increased CPD repair after 48 hr, despite increased p‐ATM within 3 hr post‐UV (Figure ). These results suggest that in addition to rapid post‐translational modifications, full execution of DDR in HM in response to α‐MSH and End‐1 requires upregulation of certain DDR genes by transcription factors such as p53, which we reported to be activated by α‐MSH (Kadekaro et al, ), and ATF2, which we previously found to be activated by End‐1 (von Koschembahr et al, ). We now present data showing increased total p53 levels and its downstream target p21 by End‐1 at 18 hr post‐UV, and of p‐ATF2 on Thr69/71 by α‐MSH, at 45 min after UV (Figure ), further supporting translational regulation of genes involved in the DDR of HM to UV by End‐1 and α‐MSH.…”

“…Enhancement of the DNA repair capacity of HM by the α‐MSH/MC1R axis has been confirmed by others (Bohm et al, ; D'Orazio et al, ; Jarrett, Wolf Horrell, Boulanger, & D’Orazio, ; Smith et al, ). Importantly, we reported that End‐1 promotes repair of DNA photoproducts in HM expressing LOF MC1R (von Koschembahr et al, ). We hereby present evidence that despite different signaling pathways of the MC1R and EDNRB, their activation by their respective physiological agonists α‐MSH and End‐1 regulates common targets in the DDR and global genome repair (GGR) subpathway of NER in HM.…”

Melanocyte UV resistance: Feelin' the endothelin

“…Although tremendous advances – most notably in immunotherapies and molecular targeting of the MAP kinase cascade – are being made in the treatment of advanced melanoma, the prognosis for the vast majority of patients with advanced disease remains dismal. The recent contribution by the Abdel‐Malek group is important because it informs us of how melanocytes cope with UV radiation and introduces a novel and potentially exploitable pathway for the prevention of melanoma. On the surface, it seems counter‐intuitive that the efficiency whereby melanocytes resist or repair UV damage would not be in a continuous ‘optimal’ state of UV‐readiness given their positioning in the skin.…”

“…Using primary human melanocytes, von Koschembahr and colleagues found that pretreating melanocytes with ET1 prior to UV exposure decreased levels of photodimers in melanocytes. Protection by ET1 was observed even immediately after UV exposure, suggesting that ET1 may somehow ‘prime’ melanocytes from accumulating UV photodamage, even before repair can occur.…”