This paper is part of a special issue dedicated to Professor Hasan Mukhtar on the occasion of his 60th birthday.
The Melanocortin 1 Receptor and the UV Response of Human Melanocytes—A Shift in Paradigm†
Article first published online: 12 FEB 2008
© 2008 The Authors
Photochemistry and Photobiology
Volume 84, Issue 2, pages 501–508, March/April 2008
How to Cite
Abdel-Malek, Z. A., Knittel, J., Kadekaro, A. L., Swope, V. B. and Starner, R. (2008), The Melanocortin 1 Receptor and the UV Response of Human Melanocytes—A Shift in Paradigm. Photochemistry and Photobiology, 84: 501–508. doi: 10.1111/j.1751-1097.2008.00294.x
- Issue published online: 12 FEB 2008
- Article first published online: 12 FEB 2008
- Received 16 November 2007, accepted 29 November 2007
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.