The Melanocortin 1 Receptor and the UV Response of Human Melanocytes—A Shift in Paradigm†
Open Access
- 12 February 2008
- journal article
- review article
- Published by Wiley in Photochemistry and Photobiology
- Vol. 84 (2), 501-508
- https://doi.org/10.1111/j.1751-1097.2008.00294.x
Abstract
Cutaneous pigmentation is the major photoprotective mechanism against the carcinogenic and aging effects of UV. Epidermal melanocytes synthesize the pigment melanin, in the form of eumelanin or pheomelanin. Synthesis of the photoprotective eumelanin by human melanocytes is regulated mainly by the melanocortins α‐melanocortin (α‐MSH) and adrenocorticotropic hormone (ACTH), which bind the melanocortin 1 receptor (MC1R) and activate the cAMP pathway that is required for UV‐induced tanning. Melanocortins stimulate proliferation and melanogenesis and inhibit UV‐induced apoptosis of human melanocytes. Importantly, melanocortins reduce the generation of hydrogen peroxide and enhance repair of DNA photoproducts, independently of pigmentation. MC1R is a major contributor to the diversity of human pigmentation and a melanoma susceptibility gene. Certain allelic variants of this gene, namely R151C, R160W and D294H, are strongly associated with red hair phenotype and increased melanoma susceptibility. Natural expression of two of these variants sensitizes melanocytes to the cytotoxic effect of UV, and increases the burden of DNA damage and oxidative stress. We are designing potent melanocortin analogs that mimic the effects of α‐MSH as a strategy to prevent skin cancer, particularly in individuals who express MC1R genotypes that reduce but do not abolish MC1R function, or mutations in other melanoma susceptibility genes, such as p16.Keywords
This publication has 76 references indexed in Scilit:
- Mutations of the BRAF gene in human cancerNature, 2002
- Tyrosinase Gene Expression is Regulated by p53Journal of Investigative Dermatology, 2002
- The Pathogenesis of Melanoma Induced by Ultraviolet RadiationNew England Journal of Medicine, 1999
- Lack ofp53 mutations and loss of heterozygosity in non-cultured human melanocytic lesionsZeitschrift für Krebsforschung und Klinische Onkologie, 1996
- Role of Melanin as a Scavenger of Active Oxygen SpeciesPigment Cell Research, 1993
- Mitogenic, melanogenic, and cAMP responses of cultured neonatal human melanocytes to commonly used mitogensJournal of Cellular Physiology, 1992
- Action of the e Locus of Mice in the Response of Phaeomelanic Hair Follicles to α-Melanocyte-Stimulating Hormone in VitroScience, 1984
- Photocarcinogenesis, skin cancer, and agingJournal of the American Academy of Dermatology, 1983
- Photoprotection by melanin—a comparison of black and Caucasian skinJournal of the American Academy of Dermatology, 1979
- Melanin photoreactions in aerated media: Electron spin resonance evidence for production of superoxide and hydrogen peroxideBiochemical and Biophysical Research Communications, 1978