Apoptotic pathways targeted by α‐MSH in human melanocytes

Abstract

It is well established that treatment of human epidermal melanocytes with α-melanocortin (α-MSH) stimulates eumelanin synthesis and proliferation 1-3). Also, α-MSH enables human melanocytes to overcome the arrest in G1 and induces melanogenesis following UV exposure (4). Recently, we discovered a new role of α-MSH as a survival factor that inhibits the UV-induced apoptosis of human melanocytes. The survival effect of α-MSH is mediated by the activation of the melanocortin 1 receptor (MC1R) and is absent in melanocytes with the loss of function MC1R. Also, the survival effect of α-MSH is independent of stimulation of melanogenesis, because it is evident in tyrosinase-negative albino melanocytes. The anti-apoptotic effect of α-MSH involves the activation of the IP3kinase pathway and is inhibited by LY 294002. Moreover, treatment of UV-irradiated melanocytes with α-MSH activates Akt/PKB, the substrate for IP3kinase. α-MSH suppresses the apoptotic effect of UV by inhibiting the reduction in Bcl2 levels, possibly as a consequence of activating the transcription factor Mitf in melanocytes. α-MSH confers photoprotection not only by stimulating eumelanin synthesis but also by enhancing DNA repair, particularly nucleotide excision repair. We have found that α-MSH enhances the repair of UV-induced cyclobutane pyrimidine dimers and pyrimidine (6-4) pyrimidone photoproducts, thus maintaining the genomic stability and inhibiting mutagenesis of melanocytes. Our findings offer an explanation for the increased susceptibility of individuals with the loss of function mutations in the MC1R gene to sun-induced skin cancer, including melanoma. Supported by NIH grant R01 ES009110 and by Skin Research Grant from Johnson and Johnson Skin Research Center.