alpha-MSH activates immediate defense responses to UV-induced oxidative stress in human melanocytes.
Exposure of cultured human melanocytes to ultraviolet radiation (UV) results in DNA damage. In melanoma, UV-signature mutations resulting from unrepaired photoproducts are rare, suggesting the possible involvement of oxidative DNA damage in melanocyte malignant transformation. Here we present data demonstrating immediate dose-dependent generation of hydrogen peroxide in UV-irradiated melanocytes, which correlated directly with a decrease in catalase activity. Pretreatment of melanocytes with alpha-melanocortin (alpha-MSH) reduced the UV-induced generation of 7,8-dihydro-8-oxyguanine (8-oxodG), a major form of oxidative DNA damage. Pretreatment with alpha-MSH also increased the protein levels of catalase and ferritin. The effect of alpha-MSH on 8-oxodG induction was mediated by activation of the melanocortin 1 receptor (MC1R), as it was absent in melanocytes expressing loss-of-function MC1R, and blocked by concomitant treatment with an analog of agouti signaling protein (ASIP), ASIP-YY. This study provides unequivocal evidence for induction of oxidative DNA damage by UV in human melanocytes and reduction of this damage by alpha-MSH. Our data unravel some mechanisms by which alpha-MSH protects melanocytes from oxidative DNA damage, which partially explain the strong association of loss-of-function MC1R with melanoma.
Song
Xiuzu
X
Department of Dermatology, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
Mosby
Nicole
N
Yang
Jennifer
J
Xu
Aie
A
Abdel-Malek
Zalfa
Z
Kadekaro
Ana Luisa
AL
D000080242:8-Hydroxy-2'-Deoxyguanosine; D054366:Agouti Signaling Protein / Q000378:metabolism; D000975:Antioxidants / Q000378:metabolism; D002374:Catalase / Q000378:metabolism; D002478:Cells, Cultured; D004249:DNA Damage; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D004307:Dose-Response Relationship, Radiation; D005293:Ferritins / Q000378:metabolism; D006728:Hormones / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D008544:Melanocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects*; D016877:Oxidants / Q000378:metabolism; D018384:Oxidative Stress; D014466:Ultraviolet Rays; D000521:alpha-MSH / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology
D054366:Agouti Signaling Protein; D000975:Antioxidants; D006728:Hormones; D016877:Oxidants; D000521:alpha-MSH; D000080242:8-Hydroxy-2'-Deoxyguanosine; D005293:Ferritins; D006861:Hydrogen Peroxide; D002374:Catalase; D003849:Deoxyguanosine