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Nature 443, 340-344 (21 September 2006) | doi:10.1038/nature05098; Received 28 March 2006; Accepted 14 July 2006

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Topical drug rescue strategy and skin protection based on the role of Mc1r in UV-induced tanning

John A. D'Orazio1,2,3, Tetsuji Nobuhisa1,2, Rutao Cui1,2, Michelle Arya1,2, Malinda Spry3, Kazumasa Wakamatsu4, Vivien Igras1,2, Takahiro Kunisada5, Scott R. Granter1,6, Emi K. Nishimura1,2,7, Shosuke Ito4 & David E. Fisher1,2

  1. Melanoma Program and
  2. Department of Pediatric Hematology/Oncology, Dana-Farber Cancer Institute & Children's Hospital, 44 Binney Street, Boston, Massachusetts 02115, USA
  3. Department of Pediatrics, Markey Cancer Center and the Graduate Center for Toxicology, University of Kentucky College of Medicine, Lexington, Kentucky 40536, USA
  4. Department of Chemistry, Fujita Health University, School of Health Sciences, Toyoake, Aichi 470-1192, Japan
  5. Department of Tissue and Organ Development, Gifu University, Graduate School of Medicine, 1-1 Yanagido, Gifu 501, Japan
  6. Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA
  7. Department of Stem Cell Medicine, Kanazawa University, Cancer Research Institute, 13-1 Takaramachi, Kanazawa 920-0934, Japan

Correspondence to: David E. Fisher1,2 Correspondence and requests for materials should be addressed to D.E.F. (Email: david_fisher@dfci.harvard.edu).

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Ultraviolet-light (UV)-induced tanning is defective in numerous 'fair-skinned' individuals, many of whom contain functional disruption of the melanocortin 1 receptor (MC1R)1, 2, 3. Although this suggested a critical role for the MC1R ligand melanocyte stimulating hormone (MSH) in this response, a genetically controlled system has been lacking in which to determine the precise role of MSH–MC1R. Here we show that ultraviolet light potently induces expression of MSH in keratinocytes, but fails to stimulate pigmentation in the absence of functional MC1R in red/blonde-haired Mc1re/e mice. However, pigmentation could be rescued by topical application of the cyclic AMP agonist forskolin, without the need for ultraviolet light, demonstrating that the pigmentation machinery is available despite the absence of functional MC1R. This chemically induced pigmentation was protective against ultraviolet-light-induced cutaneous DNA damage and tumorigenesis when tested in the cancer-prone, xeroderma-pigmentosum-complementation-group-C-deficient genetic background. These data emphasize the essential role of intercellular MSH signalling in the tanning response, and suggest a clinical strategy for topical small-molecule manipulation of pigmentation.